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1. The Multi-Omic Approach to Newborn Screening: Opportunities and Challenges

Author: Alex J. Ashenden, Ayesha Chowdhury, Lucy T. Anastasi, Khoa Lam, Tomas Rozek, Enzo Ranieri, Carol Wai-Kwan Siu, Jovanka King, Emilie Mas, and Karin S. Kassahn
Subjects: newborn screening, multi-omics, mass spectrometry, genomic screening, dried bloodspot, public acceptability, Pediatrics, RJ1-570
Abstract: Newborn screening programs have seen significant evolution since their initial implementation more than 60 years ago, with the primary goal of detecting treatable conditions within the earliest possible timeframe to ensure the optimal treatment and outcomes for the newborn. New technologies have driven the expansion of screening programs to cover additional conditions. In the current era, the breadth of screened conditions could be further expanded by integrating omic technologies such as untargeted metabolomics and genomics. Genomic screening could offer opportunities for lifelong care beyond the newborn period. For genomic newborn screening to be effective and ready for routine adoption, it must overcome barriers such as implementation cost, public acceptability, and scalability. Metabolomics approaches, on the other hand, can offer insight into disease phenotypes and could be used to identify known and novel biomarkers of disease. Given recent advances in metabolomic technologies, alongside advances in genomics including whole-genome sequencing, the combination of complementary multi-omic approaches may provide an exciting opportunity to leverage the best of both approaches and overcome their respective limitations. These techniques are described, along with the current outlook on multi-omic-based NBS research.
Published: 2024
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2. Lost in translation: returning germline genetic results in genome-scale cancer research

Author: Amber L. Johns, Skye H. McKay, Jeremy L. Humphris, Mark Pinese, Lorraine A. Chantrill, R. Scott Mead, Katherine Tucker, Lesley Andrews, Annabel Goodwin, Conrad Leonard, Hilda A. High, Katia Nones, Ann-Marie Patch, Neil D. Merrett, Nick Pavlakis, Karin S. Kassahn, Jaswinder S. Samra, David K. Miller, David K. Chang, Marina Pajic, Australian Pancreatic Cancer Genome Initiative, John V. Pearson, Sean M. Grimmond, Nicola Waddell, Nikolajs Zeps, Anthony J. Gill, and Andrew V. Biankin
Subjects: Genomic data, Return of results, Research ethics, Whole-genome sequencing, Medicine, Genetics, QH426-470
Abstract: Abstract Background The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies. Methods We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium–high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy. Results A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR. Conclusion Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning individual results is currently low.
Published: 2017
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3. Expanding the phenotype of DNMT3A as a cause a congenital myopathy with rhabdomyolysis

Author: Roula Ghaoui, Thuong T. Ha, Jennifer Kerkhof, Haley McConkey, Song Gao, Milena Babic, Rob King, Gianina Ravenscroft, Barbara Koszyca, Sophia Otto, Nigel G. Laing, Hamish Scott, Bekim Sadikovic, Karin S. Kassahn, Ghaoui, Roula, Ha, Thuong T, Kerkhof, Jennifer, McConkey, Haley, Gao, Song, Babic, Milena, King, Rob, Ravenscroft, Gianina, Koszyca, Barbara, Otto, Sophia, Laing, Nigel G, Scott, Hamish, Sadikovic, Bekim, and Kassahn, Karin S
Subjects: Tatton-Brown-Rahman syndrome, Neurology, congenital myopathy, Pediatrics, Perinatology and Child Health, rhabdomyolysis, DNMT3A, DNA methylation studies, Neurology (clinical), hypotonia, Genetics (clinical)
Abstract: Refereed/Peer-reviewed Pathogenic variants in DNMT3A are most commonly associated with Tatton-Brown-Rahman Syndrome (TBRS), but includes other phenotypes such as Heyn-Sproul-Jackson syndrome and acute myeloid leukemia (AML). We describe a patient presenting to the neuromuscular clinic with a de novo missense variant in DNMT3A where the striking clinical feature is that of a congenital myopathy with associated episodes of rhabdomyolysis, severe myalgias and chest pain along with phenotypic features associated with TBRS. Muscle biopsy showed minor myopathic features and cardiac investigations revealed mildly impaired bi-ventricular systolic function. We confirmed the DNA methylation profile matched haplo-insufficient TBRS cases, consistent with a loss of methyltransferase activity. Our report emphasizes the phenotypic overlap of patients with syndromic disorders presenting to neuromuscular clinics and limitations of gene panels in establishing a molecular diagnosis.
Published: 2023

4. Segmental Uniparental Isodisomy Causing an 'Inside-to-Outside' Limb-Girdle Muscular Dystrophy Due to a Homozygous Mutation in POGLUT1

Author: Roula Ghaoui, Samuel Curtis, and Karin S. Kassahn
Subjects: Neurology (clinical)
Abstract: This case report describes segmental uniparental isodisomy causing an “inside-to-outside” limb-girdle muscular dystrophy due to a homozygous mutation in POGLUT1.
Published: 2023

5. Shariant platform: Enabling evidence sharing across Australian clinical genetic-testing laboratories to support variant interpretation

Author: Emma Tudini, James Andrews, David M. Lawrence, Sarah L. King-Smith, Naomi Baker, Leanne Baxter, John Beilby, Bruce Bennetts, Victoria Beshay, Michael Black, Tiffany F. Boughtwood, Kristian Brion, Pak Leng Cheong, Michael Christie, John Christodoulou, Belinda Chong, Kathy Cox, Mark R. Davis, Lucas Dejong, Marcel E. Dinger, Kenneth D. Doig, Evelyn Douglas, Andrew Dubowsky, Melissa Ellul, Andrew Fellowes, Katrina Fisk, Cristina Fortuno, Kathryn Friend, Renee L. Gallagher, Song Gao, Emma Hackett, Johanna Hadler, Michael Hipwell, Gladys Ho, Georgina Hollway, Amanda J. Hooper, Karin S. Kassahn, Rahul Krishnaraj, Chiyan Lau, Huong Le, Huei San Leong, Ben Lundie, Sebastian Lunke, Anthony Marty, Mary McPhillips, Lan T. Nguyen, Katia Nones, Kristen Palmer, John V. Pearson, Michael C.J. Quinn, Lesley H. Rawlings, Simon Sadedin, Louisa Sanchez, Andreas W. Schreiber, Emanouil Sigalas, Aygul Simsek, Julien Soubrier, Zornitza Stark, Bryony A. Thompson, James U, Cassandra G. Vakulin, Amanda V. Wells, Cheryl A. Wise, Rick Woods, Andrew Ziolkowski, Marie-Jo Brion, Hamish S. Scott, Natalie P. Thorne, Amanda B. Spurdle, Lauren Akesson, Richard Allcock, Katie Ashton, Damon A. Bell, Anna Brown, Michael Buckley, John R. Burnett, Linda Burrows, Alicia Byrne, Eva Chan, Corrina Cliffe, Roderick Clifton-Bligh, Susan Dooley, Miriam Fanjul Fernandez, Elizabeth Farnsworth, Thuong Ha, Denae Henry, Duncan Holds, Katherine Holman, Matilda Jackson, Sinlay Kang, Catherine Luxford, Sam McManus, Rachael Mehrtens, Cliff Meldrum, David Mossman, Sarah-Jane Pantaleo, Dean Phelan, Electra Pontikinas, Anja Ravine, Tony Roscioli, Rodney Scott, Keryn Simons, Oliver Vanwageningen, Tudini, Emma, Andrews, James, Lawrence, David M., King-Smith, Sarah L., Schreiber, Andreas W, James, U, and Shariant Consortium
Subjects: genomic variant, variant interpretations, Databases, Genetic, Technology Review, Genetics, Australia, Humans, Genetic Variation, Genetic Testing, Laboratories, Genetics (clinical), Australian laboratories
Abstract: Sharing genomic variant interpretations across laboratories promotes consistency in variant assertions. A landscape analysis of Australian clinical genetic-testing laboratories in 2017 identified that, despite the national-accreditation-body recommendations encouraging laboratories to submit genotypic data to clinical databases, fewer than 300 variants had been shared to the ClinVar public database. Consultations with Australian laboratories identified resource constraints limiting routine application of manual processes, consent issues, and differences in interpretation systems as barriers to sharing. This information was used to define key needs and solutions required to enable national sharing of variant interpretations. The Shariant platform, using both the GRCh37 and GRCh38 genome builds, was developed to enable ongoing sharing of variant interpretations and associated evidence between Australian clinical genetic-testing laboratories. Where possible, two-way automated sharing was implemented so that disruption to laboratory workflows would be minimized. Terms of use were developed through consultation and currently restrict access to Australian clinical genetic-testing laboratories. Shariant was designed to store and compare structured evidence, to promote and record resolution of inter-laboratory classification discrepancies, and to streamline the submission of variant assertions to ClinVar. As of December 2021, more than 14,000 largely prospectively curated variant records from 11 participating laboratories have been shared. Discrepant classifications have been identified for 11% (28/260) of variants submitted by more than one laboratory. We have demonstrated that co-design with clinical laboratories is vital to developing and implementing a national variant-interpretation sharing effort. This approach has improved inter-laboratory concordance and enabled opportunities to standardize interpretation practices.
Published: 2022

6. Whole-Genome Sequencing of SARS-CoV-2 from Quarantine Hotel Outbreak

Author: Ivan Bastian, Lex E. X. Leong, Luke Walters, Mark Turra, Karin S. Kassahn, Geoff Higgins, Katina D'Onise, Nicola Spurrier, Tom Dodd, Emma Denehy, Chuan K Lim, Julien Soubrier, Robert Hall, Leong, Lex EX, Soubrier, Julien, Turra, Mark, Denehy, Emma, Walters, Luke, Kassahn, Karin, Higgins, Geoff, Dodd, Tom, Hall, Robert, D'Onise, Katina, Spurrier, Nicola, Bastian, Ivan, and Lim, Chuan K
Subjects: Microbiology (medical), 2019-20 coronavirus outbreak, Epidemiology, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Infectious and parasitic diseases, RC109-216, Biology, medicine.disease_cause, epidemic, DNA sequencing, law.invention, Disease Outbreaks, respiratory infections, law, Whole-Genome Sequencing of SARS-CoV-2 from Quarantine Hotel Outbreak, Quarantine, medicine, Research Letter, Humans, viruses, Coronavirus, Whole genome sequencing, SARS-CoV-2, Genomic sequencing, quarantine, Australia, Outbreak, COVID-19, vaccines, hotel quarantine, Virology, zoonoses, genome sequencing, Infectious Diseases, coronavirus disease, disease outbreaks, Medicine, human activities, severe acute respiratory syndrome coronavirus 2
Abstract: Refereed/Peer-reviewed Hotel quarantine for international travelers has been used to prevent coronavirus disease spread into Australia. A quarantine hotel–associated community outbreak was detected in South Australia. Real-time genomic sequencing enabled rapid confirmation tracking the outbreak to a recently returned traveler and linked 2 cases of infection in travelers at the same facility.
Published: 2021

7. Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Author: Stephan B. Dreyer, Rosie Upstill-Goddard, Viola Paulus-Hock, Clara Paris, Eirini-Maria Lampraki, Eloise Dray, Bryan Serrels, Giuseppina Caligiuri, Selma Rebus, Dennis Plenker, Zachary Galluzzo, Holly Brunton, Richard Cunningham, Mathias Tesson, Craig Nourse, Ulla-Maja Bailey, Marc Jones, Kim Moran-Jones, Derek W. Wright, Fraser Duthie, Karin Oien, Lisa Evers, Colin J. McKay, Grant A. McGregor, Aditi Gulati, Rachel Brough, Ilirjana Bajrami, Stephan Pettitt, Michele L. Dziubinski, Juliana Candido, Frances Balkwill, Simon T. Barry, Robert Grützmann, Lola Rahib, Amber Johns, Marina Pajic, Fieke E.M. Froeling, Phillip Beer, Elizabeth A. Musgrove, Gloria M. Petersen, Alan Ashworth, Margaret C. Frame, Howard C. Crawford, Diane M. Simeone, Chris Lord, Debabrata Mukhopadhyay, Christian Pilarsky, David A. Tuveson, Susanna L. Cooke, Nigel B. Jamieson, Jennifer P. Morton, Owen J. Sansom, Peter J. Bailey, Andrew V. Biankin, David K. Chang, Sarah Allison, Dario Beraldi, Euan Cameron, Stephan Dreyer, Paul Grimwood, Shane Kelly, John Marshall, Sancha Martin, Brian McDade, Daniel McElroy, Donna Ramsay, Derek Wright, Marc D. Jones, Jane Hair, Paul Westwood, Nicola Williams, Amber L. Johns, Amanda Mawson, Christopher J. Scarlett, Mary-Anne L. Brancato, Sarah J. Rowe, Skye H. Simpson, Mona Martyn-Smith, Michelle T. Thomas, Lorraine A. Chantrill, Venessa T. Chin, Angela Chou, Mark J. Cowley, Jeremy L. Humphris, R. Scott Mead, Adnan M. Nagrial, Jessica Pettit, Mark Pinese, Ilse Rooman, Jianmin Wu, Jiang Tao, Renee DiPietro, Clare Watson, Angela Steinmann, Hong Ching Lee, Rachel Wong, Andreia V. Pinho, Marc Giry-Laterriere, Roger J. Daly, Robert L. Sutherland, Sean M. Grimmond, Nicola Waddell, Karin S. Kassahn, David K. Miller, Peter J. Wilson, Ann-Marie Patch, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Christina Xu, Katia Nones, J. Lynn Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, John V. Pearson, Peter Bailey, Michael Quinn, Shivashankar Nagaraj, Stephen Kazakoff, Nick Waddell, Keerthana Krisnan, Kelly Quek, David Wood, Jaswinder S. Samra, Anthony J. Gill, Nick Pavlakis, Alex Guminski, Christopher Toon, Ray Asghari, Neil D. Merrett, Darren Pavey, Amitabha Das, Peter H. Cosman, Kasim Ismail, Chelsie O’Connnor, Vincent W. Lam, Duncan McLeod, Henry C. Pleass, Arthur Richardson, Virginia James, James G. Kench, Caroline L. Cooper, David Joseph, Charbel Sandroussi, Michael Crawford, James Gallagher, Michael Texler, Cindy Forest, Andrew Laycock, Krishna P. Epari, Mo Ballal, David R. Fletcher, Sanjay Mukhedkar, Nigel A. Spry, Bastiaan DeBoer, Ming Chai, Nikolajs Zeps, Maria Beilin, Kynan Feeney, Nan Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Chuan P. Tan, Tamara Debrencini, John Chen, Mark E. Brooke-Smith, Virginia Papangelis, Henry Tang, Andrew P. Barbour, Andrew D. Clouston, Patrick Martin, Thomas J. O’Rourke, Amy Chiang, Jonathan W. Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson, Christopher Christophi, Mehrdad Nikfarjam, Angela Mountain, Victorian Cancer Biobank, James R. Eshleman, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio-Donahue, Richard D. Schulick, Christopher L. Wolfgang, Richard A. Morgan, Mary Hodgin, Aldo Scarpa, Rita T. Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Claudio Bassi, Margaret A. Tempero, Janet S. Graham, and Basic (bio-) Medical Sciences
Subjects: 0301 basic medicine, HRD, homologous recombination deficiency, DNA Repair, PDAC, pancreatic ductal adenocarcinoma, Cell Culture Techniques, DMSO, dimethyl sulfoxide, Transcriptome, 0302 clinical medicine, Molecular Targeted Therapy, SV, structural variation, Original Research, Cancer, PDCL, patient-derived cell line, Gastroenterology, Organoids, PC, pancreatic cancer, oncology, PARP inhibitor, RNAseq, RNA sequencing, 030211 gastroenterology & hepatology, DNA Damage Response, ICGC, International Cancer Genome Consortium, DNA Replication, DNA repair, DNA damage, RPPA, reverse-phase protein array, EC50, median effective concentration, MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, Adenocarcinoma, Biology, DDR, DNA damage response, TOM, topological overlap measure, 03 medical and health sciences, Pancreatic Cancer, Cell Line, Tumor, Pancreatic cancer, GO, Gene Ontology, medicine, Humans, PDX, patient-derived xenograft, Hepatology, DNA replication, Personalized Medicine, Replication Stress, medicine.disease, Xenograft Model Antitumor Assays, Pancreatic Neoplasms, body regions, 030104 developmental biology, siRNA, small interfering RNA, Cancer research, Full Report: Basic and Translational—Pancreas, HR, homologous recombination, Homologous recombination, Biomarkers, DNA Damage
Abstract: Background & Aims Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC. Methods We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient–derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. Results Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P < .001) and PARP inhibitor therapy (P < .001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P < .018) and WEE1 inhibitor (P < .029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < .001) but was not associated with DDR deficiency. Conclusions Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy., Graphical abstract
Published: 2021

8. Cerebellar output in zebrafish: an analysis of spatial patterns and topography in eurydendroid cell projections

Author: Lucy eHeap, Chi-Ching eGoh, Karin S Kassahn, and Ethan K Scott
Subjects: Cerebellum, Thalamus, Zebrafish, optic tectum, topography, eurydendroid, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: The cerebellum is a brain region responsible for motor coordination and for refining motor programs. While a great deal is known about the structure and connectivity of the mammalian cerebellum, fundamental questions regarding its function in behaviour remain unanswered. Recently, the zebrafish has emerged as a useful model organism for cerebellar studies, owing in part to the similarity in cerebellar circuits between zebrafish and mammals. While the cell types composing cerebellar cortical circuits are generally conserved, zebrafish lack deep cerebellar nuclei, and instead a bulk of cerebellar output comes from a single type of neuron: the eurydendroid cell. To describe spatial patterns of cerebellar output in zebrafish, we have used genetic techniques to label and trace eurydendroid cells individually and en masse. We have found that cerebellar output targets the thalamus and optic tectum, and have confirmed the presence of presynaptic terminals from eurydendroid cells in these structures using a synaptically targeted GFP. By observing individual eurydendroid cells, we have shown that different medial-lateral regions of the cerebellum have eurydendroid cells projecting to different targets. Finally, we found topographic organisation in the connectivity between the cerebellum and the optic tectum, where more medial eurydendroid cells project to the rostral tectum while lateral cells project to the caudal tectum. These findings indicate that there is spatial logic underpinning cerebellar output in zebrafish with likely implications for cerebellar function.
Published: 2013
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9. HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer

Author: Holly Brunton, Giuseppina Caligiuri, Richard Cunningham, Rosie Upstill-Goddard, Ulla-Maja Bailey, Ian M. Garner, Craig Nourse, Stephan Dreyer, Marc Jones, Kim Moran-Jones, Derek W. Wright, Viola Paulus-Hock, Colin Nixon, Gemma Thomson, Nigel B. Jamieson, Grant A. McGregor, Lisa Evers, Colin J. McKay, Aditi Gulati, Rachel Brough, Ilirjana Bajrami, Stephen J. Pettitt, Michele L. Dziubinski, Simon T. Barry, Robert Grützmann, Robert Brown, Edward Curry, Marina Pajic, Elizabeth A. Musgrove, Gloria M. Petersen, Emma Shanks, Alan Ashworth, Howard C. Crawford, Diane M. Simeone, Fieke E.M. Froeling, Christopher J. Lord, Debabrata Mukhopadhyay, Christian Pilarsky, Sean E. Grimmond, Jennifer P. Morton, Owen J. Sansom, David K. Chang, Peter J. Bailey, Andrew V. Biankin, Sarah Allison, Susanna L. Cooke, Paul Grimwood, Shane Kelly, John Marshall, Brian McDade, Daniel McElroy, Donna Ramsay, Selma Rebus, Jane Hair, Paul Westwood, Nicola Williams, Fraser Duthie, Amber L. Johns, Amanda Mawson, Christopher J. Scarlett, Mary-Anne L. Brancato, Sarah J. Rowe, Skye H. Simpson, Mona Martyn-Smith, Michelle T. Thomas, Lorraine A. Chantrill, Venessa T. Chin, Angela Chou, Mark J. Cowley, Jeremy L. Humphris, R. Scott Mead, Adnan M. Nagrial, Jessica Pettit, Mark Pinese, Ilse Rooman, Jianmin Wu, Jiang Tao, Renee DiPietro, Clare Watson, Angela Steinmann, Hong Ching Lee, Rachel Wong, Andreia V. Pinho, Marc Giry-Laterriere, Roger J. Daly, Robert L. Sutherland, Sean M. Grimmond, Nicola Waddell, Karin S. Kassahn, David K. Miller, Peter J. Wilson, Ann-Marie Patch, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Christina Xu, Katia Nones, J. Lynn Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, John V. Pearson, Michael Quinn, Shivashankar Nagaraj, Stephen Kazakoff, Nick Waddell, Keerthana Krisnan, Kelly Quek, David Wood, Jaswinder S. Samra, Anthony J. Gill, Nick Pavlakis, Alex Guminski, Christopher Toon, Ray Asghari, Neil D. Merrett, Darren Pavey, Amitabha Das, Peter H. Cosman, Kasim Ismail, Chelsie O’Connnor, Vincent W. Lam, Duncan McLeod, Henry C. Pleass, Arthur Richardson, Virginia James, James G. Kench, Caroline L. Cooper, David Joseph, Charbel Sandroussi, Michael Crawford, James Gallagher, Michael Texler, Cindy Forest, Andrew Laycock, Krishna P. Epari, Mo Ballal, David R. Fletcher, Sanjay Mukhedkar, Nigel A. Spry, Bastiaan DeBoer, Ming Chai, Nikolajs Zeps, Maria Beilin, Kynan Feeney, Nan Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Chuan P. Tan, Tamara Debrencini, John Chen, Mark E. Brooke-Smith, Virginia Papangelis, Henry Tang, Andrew P. Barbour, Andrew D. Clouston, Patrick Martin, Thomas J. O’Rourke, Amy Chiang, Jonathan W. Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson, Christopher Christophi, Mehrdad Nikfarjam, Angela Mountain, James R. Eshleman, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio-Donahue, Richard D. Schulick, Christopher L. Wolfgang, Richard A. Morgan, Mary Hodgin, Aldo Scarpa, Rita T. Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Claudio Bassi, Margaret A. Tempero, Janet S. Graham, and Basic (bio-) Medical Sciences
Subjects: 0301 basic medicine, Biology, Adenocarcinoma, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, GATA6, GSK-3, Pancreatic cancer, Cell Line, Tumor, GATA6 Transcription Factor, medicine, Biomarkers, Tumor, Humans, GSK3B, chromatin landscapes, metabolic targeting, intronic and distal promoters, medicine.disease, Phenotype, HNF4A, Chromatin, 030104 developmental biology, Hepatocyte nuclear factor 4, Hepatocyte Nuclear Factor 4, PDAC subtypes, oncology, Cancer research, therapeutic tolerance, 030217 neurology & neurosurgery, Carcinoma, Pancreatic Ductal
Abstract: Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.
Published: 2020

10. Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Author: Bailey, Matthew H, Meyerson, William U, Dursi, Lewis Jonathan, Wang, Liang-Bo, Dong, Guanlan, Liang, Wen-Wei, Weerasinghe, Amila, Shantao, Li, Kelso, Sean, Saksena, Gordon, Ellrott, Kyle, Wendl, Michael C, Wheeler, David A, Getz, Gad, Simpson, Jared T, Gerstein, Mark B, Ding, Lirehan, Akbani, Pavana, Anur, Matthew, H Bailey, Alex, Buchanan, Kami, Chiotti, Kyle, Covington, Allison, Creason, Ding, Li, Kyle, Ellrott, Fan, Yu, Steven, Foltz, Gad, Getz, Walker, Hale, David, Haussler, Julian, M Hess, Carolyn, M Hutter, Cyriac, Kandoth, Katayoon, Kasaian, Melpomeni, Kasapi, Dave, Larson, Ignaty, Leshchiner, John, Letaw, Singer, Ma, Michael, D McLellan, Yifei, Men, Gordon, B Mills, Beifang, Niu, Myron, Peto, Amie, Radenbaugh, Sheila, M Reynolds, Gordon, Saksena, Heidi, Sofia, Chip, Stewart, Adam, J Struck, Joshua, M Stuart, Wenyi, Wang, John, N Weinstein, David, A Wheeler, Christopher, K Wong, Liu, Xi, Kai, Ye, Matthias, Bieg, Paul, C Boutros, Ivo, Buchhalter, Adam, P Butler, Ken, Chen, Zechen, Chong, Oliver, Drechsel, Lewis Jonathan Dursi, Roland, Eils, Shadrielle M, G Espiritu, Robert, S Fulton, Shengjie, Gao, Josep L, L Gelpi, Mark, B Gerstein, Santiago, Gonzalez, Ivo, G Gut, Faraz, Hach, Michael, C Heinold, Jonathan, Hinton, Taobo, Hu, Vincent, Huang, Huang, Yi, Barbara, Hutter, David, R Jones, Jongsun, Jung, Natalie, Jäger, Hyung-Lae, Kim, Kortine, Kleinheinz, Sushant, Kumar, Yogesh, Kumar, Christopher, M Lalansingh, Ivica, Letunic, Dimitri, Livitz, Eric, Z Ma, Yosef, E Maruvka, R Jay Mashl, Andrew, Menzies, Ana, Milovanovic, Morten Muhlig Nielsen, Stephan, Ossowski, Nagarajan, Paramasivam, Jakob Skou Pedersen, Marc, D Perry, Montserrat, Puiggròs, Keiran, M Raine, Esther, Rheinbay, Romina, Royo, S Cenk Sahinalp, Iman, Sarrafi, Matthias, Schlesner, Jared, T Simpson, Lucy, Stebbings, Miranda, D Stobbe, Jon, W Teague, Grace, Tiao, David, Torrents, Jeremiah, A Wala, Jiayin, Wang, Sebastian, M Waszak, Joachim, Weischenfeldt, Michael, C Wendl, Johannes, Werner, Zhenggang, Wu, Hong, Xue, Sergei, Yakneen, Takafumi, N Yamaguchi, Venkata, D Yellapantula, Christina, K Yung, Junjun, Zhang, Lauri, A Aaltonen, Federico, Abascal, Adam, Abeshouse, Hiroyuki, Aburatani, David, J Adams, Nishant, Agrawal, Keun Soo Ahn, Sung-Min, Ahn, Hiroshi, Aikata, Rehan, Akbani, Kadir, C Akdemir, Hikmat, Al-Ahmadie, Sultan, T Al-Sedairy, Fatima, Al-Shahrour, Malik, Alawi, Monique, Albert, Kenneth, Aldape, Ludmil, B Alexandrov, Adrian, Ally, Kathryn, Alsop, Eva, G Alvarez, Fernanda, Amary, Samirkumar, B Amin, Brice, Aminou, Ole, Ammerpohl, Matthew, J Anderson, Yeng, Ang, Davide, Antonello, Samuel, Aparicio, Elizabeth, L Appelbaum, Yasuhito, Arai, Axel, Aretz, Koji, Arihiro, Shun-Ichi, Ariizumi, Joshua, Armenia, Laurent, Arnould, Sylvia, Asa, Yassen, Assenov, Gurnit, Atwal, Sietse, Aukema, J Todd Auman, Miriam, R Aure, Philip, Awadalla, Marta, Aymerich, Gary, D Bader, Adrian, Baez-Ortega, Peter, J Bailey, Miruna, Balasundaram, Saianand, Balu, Pratiti, Bandopadhayay, Rosamonde, E Banks, Stefano, Barbi, Andrew, P Barbour, Jonathan, Barenboim, Jill, Barnholtz-Sloan, Hugh, Barr, Elisabet, Barrera, John, Bartlett, Javier, Bartolome, Bassi, Claudio, Oliver, F Bathe, Daniel, Baumhoer, Prashant, Bavi, Stephen, B Baylin, Wojciech, Bazant, Duncan, Beardsmore, Timothy, A Beck, Sam, Behjati, Andreas, Behren, Cindy, Bell, Sergi, Beltran, Christopher, Benz, Andrew, Berchuck, Anke, K Bergmann, Erik, N Bergstrom, Benjamin, P Berman, Daniel, M Berney, Stephan, H Bernhart, Rameen, Beroukhim, Mario, Berrios, Samantha, Bersani, Johanna, Bertl, Miguel, Betancourt, Vinayak, Bhandari, Shriram, G Bhosle, Andrew, V Biankin, Darell, Bigner, Hans, Binder, Ewan, Birney, Michael, Birrer, Nidhan, K Biswas, Bodil, Bjerkehagen, Tom, Bodenheimer, Lori, Boice, Giada, Bonizzato, Johann, S De Bono, Arnoud, Boot, Moiz, S Bootwalla, Ake, Borg, Arndt, Borkhardt, Keith, A Boroevich, Ivan, Borozan, Christoph, Borst, Marcus, Bosenberg, Mattia, Bosio, Jacqueline, Boultwood, Guillaume, Bourque, G Steven Bova, David, T Bowen, Reanne, Bowlby, David D, L Bowtell, Sandrine, Boyault, Rich, Boyce, Jeffrey, Boyd, Alvis, Brazma, Paul, Brennan, Daniel, S Brewer, Arie, B Brinkman, Robert, G Bristow, Russell, R Broaddus, Jane, E Brock, Malcolm, Brock, Annegien, Broeks, Angela, N Brooks, Denise, Brooks, Benedikt, Brors, Søren, Brunak, Timothy J, C Bruxner, Alicia, L Bruzos, Christiane, Buchholz, Susan, Bullman, Hazel, Burke, Birgit, Burkhardt, Kathleen, H Burns, John, Busanovich, Carlos, D Bustamante, Atul, J Butte, Niall, J Byrne, Anne-Lise, Børresen-Dale, Samantha, J Caesar-Johnson, Andy, Cafferkey, Declan, Cahill, Claudia, Calabrese, Carlos, Caldas, Fabien, Calvo, Niedzica, Camacho, Peter, J Campbell, Elias, Campo, Cinzia, Cantù, Shaolong, Cao, Thomas, E Carey, Joana, Carlevaro-Fita, Rebecca, Carlsen, Ivana, Cataldo, Mario, Cazzola, Jonathan, Cebon, Robert, Cerfolio, Dianne, E Chadwick, Dimple, Chakravarty, Don, Chalmers, Calvin Wing Yiu Chan, Kin, Chan, Michelle, Chan-Seng-Yue, Vishal, S Chandan, David, K Chang, Stephen, J Chanock, Lorraine, A Chantrill, Aurélien, Chateigner, Nilanjan, Chatterjee, Kazuaki, Chayama, Hsiao-Wei, Chen, Jieming, Chen, Yiwen, Chen, Zhaohong, Chen, Andrew, D Cherniack, Jeremy, Chien, Yoke-Eng, Chiew, Suet-Feung, Chin, Juok, Cho, Sunghoon, Cho, Jung Kyoon Choi, Wan, Choi, Christine, Chomienne, Su Pin Choo, Angela, Chou, Angelika, N Christ, Elizabeth, L Christie, Eric, Chuah, Carrie, Cibulskis, Kristian, Cibulskis, Sara, Cingarlini, Peter, Clapham, Alexander, Claviez, Sean, Cleary, Nicole, Cloonan, Marek, Cmero, Colin, C Collins, Ashton, A Connor, Susanna, L Cooke, Colin, S Cooper, Leslie, Cope, Corbo, Vincenzo, Matthew, G Cordes, Stephen, M Cordner, Isidro, Cortés-Ciriano, Prue, A Cowin, Brian, Craft, David, Craft, Chad, J Creighton, Yupeng, Cun, Erin, Curley, Ioana, Cutcutache, Karolina, Czajka, Bogdan, Czerniak, Rebecca, A Dagg, Ludmila, Danilova, Maria Vittoria Davi, Natalie, R Davidson, Helen, Davies, Ian, J Davis, Brandi, N Davis-Dusenbery, Kevin, J Dawson, Francisco, M De La Vega, Ricardo De Paoli-Iseppi, Timothy, Defreitas, Angelo, P Dei Tos, Olivier, Delaneau, John, A Demchok, Jonas, Demeulemeester, German, M Demidov, Deniz, Demircioğlu, Nening, M Dennis, Robert, E Denroche, Stefan, C Dentro, Nikita, Desai, Vikram, Deshpande, Amit, G Deshwar, Christine, Desmedt, Jordi, Deu-Pons, Noreen, Dhalla, Neesha, C Dhani, Priyanka, Dhingra, Rajiv, Dhir, Anthony, Dibiase, Klev, Diamanti, Shuai, Ding, Huy, Q Dinh, Luc, Dirix, Harshavardhan, Doddapaneni, Nilgun, Donmez, Michelle, T Dow, Ronny, Drapkin, Ruben, M Drews, Serge, Serge, Tim, Dudderidge, Ana, Dueso-Barroso, Andrew, J Dunford, Michael, Dunn, Fraser, R Duthie, Ken, Dutton-Regester, Jenna, Eagles, Douglas, F Easton, Stuart, Edmonds, Paul, A Edwards, Sandra, E Edwards, Rosalind, A Eeles, Anna, Ehinger, Juergen, Eils, Adel, El-Naggar, Matthew, Eldridge, Serap, Erkek, Georgia, Escaramis, Xavier, Estivill, Dariush, Etemadmoghadam, Jorunn, E Eyfjord, Bishoy, M Faltas, Daiming, Fan, William, C Faquin, Claudiu, Farcas, Matteo, Fassan, Aquila, Fatima, Francesco, Favero, Nodirjon, Fayzullaev, Ina, Felau, Sian, Fereday, Martin, L Ferguson, Vincent, Ferretti, Lars, Feuerbach, Matthew, A Field, J Lynn Fink, Gaetano, Finocchiaro, Cyril, Fisher, Matthew, W Fittall, Anna, Fitzgerald, Rebecca, C Fitzgerald, Adrienne, M Flanagan, Neil, E Fleshner, Paul, Flicek, John, A Foekens, Kwun, M Fong, Nuno, A Fonseca, Christopher, S Foster, Natalie, S Fox, Michael, Fraser, Scott, Frazer, Milana, Frenkel-Morgenstern, William, Friedman, Joan, Frigola, Catrina, C Fronick, Akihiro, Fujimoto, Masashi, Fujita, Masashi, Fukayama, Lucinda, A Fulton, Mayuko, Furuta, P Andrew Futreal, Anja, Füllgrabe, Stacey, B Gabriel, Steven, Gallinger, Carlo, Gambacorti-Passerini, Jianjiong, Gao, Levi, Garraway, Øystein, Garred, Erik, Garrison, Dale, W Garsed, Nils, Gehlenborg, Joshy, George, Daniela, S Gerhard, Clarissa, Gerhauser, Jeffrey, E Gershenwald, Moritz, Gerstung, Mohammed, Ghori, Ronald, Ghossein, Nasra, H Giama, Richard, A Gibbs, Anthony, J Gill, Pelvender, Gill, Dilip, D Giri, Dominik, Glodzik, Vincent, J Gnanapragasam, Maria Elisabeth Goebler, Mary, J Goldman, Carmen, Gomez, Abel, Gonzalez-Perez, Dmitry, A Gordenin, James, Gossage, Kunihito, Gotoh, Ramaswamy, Govindan, Dorthe, Grabau, Janet, S Graham, Robert, C Grant, Anthony, R Green, Eric, Green, Liliana, Greger, Nicola, Grehan, Sonia, Grimaldi, Sean, M Grimmond, Robert, L Grossman, Adam, Grundhoff, Gunes, Gundem, Qianyun, Guo, Manaswi, Gupta, Shailja, Gupta, Marta, Gut, Jonathan, Göke, Gavin, Ha, Andrea, Haake, David, Haan, Siegfried, Haas, Kerstin, Haase, James, E Haber, Nina, Habermann, Syed, Haider, Natsuko, Hama, Freddie, C Hamdy, Anne, Hamilton, Mark, P Hamilton, Leng, Han, George, B Hanna, Martin, Hansmann, Nicholas, J Haradhvala, Olivier, Harismendy, Ivon, Harliwong, Arif, O Harmanci, Eoghan, Harrington, Takanori, Hasegawa, Steve, Hawkins, Shinya, Hayami, Shuto, Hayashi, D Neil Hayes, Stephen, J Hayes, Nicholas, K Hayward, Steven, Hazell, Yao, He, Allison, P Heath, Simon, C Heath, David, Hedley, Apurva, M Hegde, David, I Heiman, Zachary, Heins, Lawrence, E Heisler, Eva, Hellstrom-Lindberg, Mohamed, Helmy, Seong Gu Heo, Austin, J Hepperla, José María Heredia-Genestar, Carl, Herrmann, Peter, Hersey, Holmfridur, Hilmarsdottir, Satoshi, Hirano, Nobuyoshi, Hiraoka, Katherine, A Hoadley, Asger, Hobolth, Ermin, Hodzic, Jessica, I Hoell, Steve, Hoffmann, Oliver, Hofmann, Andrea, Holbrook, Aliaksei, Z Holik, Michael, A Hollingsworth, Oliver, Holmes, Robert, A Holt, Chen, Hong, Eun Pyo Hong, Jongwhi, H Hong, Gerrit, K Hooijer, Henrik, Hornshøj, Fumie, Hosoda, Yong, Hou, Volker, Hovestadt, William, Howat, Alan, P Hoyle, Ralph, H Hruban, Jianhong, Hu, Xing, Hua, Kuan-Lin, Huang, Mei, Huang, Mi Ni Huang, Wolfgang, Huber, Thomas, J Hudson, Michael, Hummel, Jillian, A Hung, David, Huntsman, Ted, R Hupp, Jason, Huse, Matthew, R Huska, Daniel, Hübschmann, Christine, A Iacobuzio-Donahue, Charles David Imbusch, Marcin, Imielinski, Seiya, Imoto, William, B Isaacs, Keren, Isaev, Shumpei, Ishikawa, Murat, Iskar, M Ashiqul Islam, S, Michael, Ittmann, Sinisa, Ivkovic, Jose M, G Izarzugaza, Jocelyne, Jacquemier, Valerie, Jakrot, Nigel, B Jamieson, Gun Ho Jang, Se Jin Jang, Joy, C Jayaseelan, Reyka, Jayasinghe, Stuart, R Jefferys, Karine, Jegalian, Jennifer, L Jennings, Seung-Hyup, Jeon, Lara, Jerman, Yuan, Ji, Wei, Jiao, Peter, A Johansson, Amber, L Johns, Jeremy, Johns, Rory, Johnson, Todd, A Johnson, Clemency, Jolly, Yann, Joly, Jon, G Jonasson, Corbin, D Jones, David T, W Jones, Nic, Jones, Steven J, M Jones, Jos, Jonkers, Young Seok Ju, Hartmut, Juhl, Malene, Juul, Randi Istrup Juul, Sissel, Juul, Rolf, Kabbe, Andre, Kahles, Abdullah, Kahraman, Vera, B Kaiser, Hojabr, Kakavand, Sangeetha, Kalimuthu, Christof von Kalle, Koo Jeong Kang, Katalin, Karaszi, Beth, Karlan, Rosa, Karlić, Dennis, Karsch, Karin, S Kassahn, Hitoshi, Katai, Mamoru, Kato, Hiroto, Katoh, Yoshiiku, Kawakami, Jonathan, D Kay, Stephen, H Kazakoff, Marat, D Kazanov, Maria, Keays, Electron, Kebebew, Richard, F Kefford, Manolis, Kellis, James, G Kench, Catherine, J Kennedy, Jules N, A Kerssemakers, David, Khoo, Vincent, Khoo, Narong, Khuntikeo, Ekta, Khurana, Helena, Kilpinen, Hark Kyun Kim, Hyung-Yong, Kim, Hyunghwan, Kim, Jaegil, Kim, Jihoon, Kim, Jong, K Kim, Youngwook, Kim, Tari, A King, Wolfram, Klapper, Leszek, J Klimczak, Stian, Knappskog, Michael, Kneba, Bartha, M Knoppers, Youngil, Koh, Jan, Komorowski, Daisuke, Komura, Mitsuhiro, Komura, Kong, Gu, Marcel, Kool, Jan, O Korbel, Viktoriya, Korchina, Andrey, Korshunov, Michael, Koscher, Roelof, Koster, Zsofia, Kote-Jarai, Antonios, Koures, Milena, Kovacevic, Barbara, Kremeyer, Helene, Kretzmer, Markus, Kreuz, Savitri, Krishnamurthy, Dieter, Kube, Kiran, Kumar, Pardeep, Kumar, Ritika, Kundra, Kirsten, Kübler, Ralf, Küppers, Jesper, Lagergren, Phillip, H Lai, Peter, W Laird, Sunil, R Lakhani, Emilie, Lalonde, Fabien, C Lamaze, Adam, Lambert, Eric, Lander, Pablo, Landgraf, Landoni, Luca, Anita, Langerød, Andrés, Lanzós, Denis, Larsimont, Erik, Larsson, Mark, Lathrop, Loretta M, S Lau, Chris, Lawerenz, Rita, T Lawlor, Michael, S Lawrence, Alexander, J Lazar, Xuan, Le, Darlene, Lee, Donghoon, Lee, Eunjung Alice Lee, Hee Jin Lee, Jake June-Koo Lee, Jeong-Yeon, Lee, Juhee, Lee, Ming Ta Michael Lee, Henry, Lee-Six, Kjong-Van, Lehmann, Hans, Lehrach, Dido, Lenze, Conrad, R Leonard, Daniel, A Leongamornlert, Louis, Letourneau, Douglas, A Levine, Lora, Lewis, Tim, Ley, Chang, Li, Constance, H Li, Haiyan Irene Li, Jun, Li, Lin, Li, Siliang, Li, Xiaobo, Li, Xiaotong, Li, Xinyue, Li, Yilong, Li, Han, Liang, Sheng-Ben, Liang, Peter, Lichter, Pei, Lin, Ziao, Lin, M Linehan, W, Ole Christian Lingjærde, Dongbing, Liu, Eric Minwei Liu, Fei-Fei, Liu, Fenglin, Liu, Jia, Liu, Xingmin, Liu, Julie, Livingstone, Naomi, Livni, Lucas, Lochovsky, Markus, Loeffler, Georgina, V Long, Armando, Lopez-Guillermo, Shaoke, Lou, David, N Louis, Laurence, B Lovat, Yiling, Lu, Yong-Jie, Lu, Youyong, Lu, Luchini, Claudio, Ilinca, Lungu, Xuemei, Luo, Hayley, J Luxton, Andy, G Lynch, Lisa, Lype, Cristina, López, Carlos, López-Otín, Yussanne, Ma, Gaetan, Macgrogan, Shona, Macrae, Geoff, Macintyre, Tobias, Madsen, Kazuhiro, Maejima, Andrea, Mafficini, Dennis, T Maglinte, Arindam, Maitra, Partha, P Majumder, Luca, Malcovati, Salem, Malikic, Malleo, Giuseppe, Graham, J Mann, Luisa, Mantovani-Löffler, Kathleen, Marchal, Giovanni, Marchegiani, Elaine, R Mardis, Adam, A Margolin, Maximillian, G Marin, Florian, Markowetz, Julia, Markowski, Jeffrey, Marks, Tomas, Marques-Bonet, Marco, A Marra, Luke, Marsden, John W, M Martens, Sancha, Martin, Jose, I Martin-Subero, Iñigo, Martincorena, Alexander, Martinez-Fundichely, Charlie, E Massie, Thomas, J Matthew, Lucy, Matthews, Erik, Mayer, Simon, Mayes, Michael, Mayo, Faridah, Mbabaali, Karen, Mccune, Ultan, Mcdermott, Patrick, D McGillivray, John, D McPherson, John, R McPherson, Treasa, A McPherson, Samuel, R Meier, Alice, Meng, Shaowu, Meng, Neil, D Merrett, Sue, Merson, Matthew, Meyerson, William, U Meyerson, Piotr, A Mieczkowski, George, L Mihaiescu, Sanja, Mijalkovic, Ana Mijalkovic Mijalkovic-Lazic, Tom, Mikkelsen, Milella, Michele, Linda, Mileshkin, Christopher, A Miller, David, K Miller, Jessica, K Miller, Sarah, Minner, Marco, Miotto, Gisela Mir Arnau, Lisa, Mirabello, Chris, Mitchell, Thomas, J Mitchell, Satoru, Miyano, Naoki, Miyoshi, Shinichi, Mizuno, Fruzsina, Molnár-Gábor, Malcolm, J Moore, Richard, A Moore, Sandro, Morganella, Quaid, D Morris, Carl, Morrison, Lisle, E Mose, Catherine, D Moser, Ferran, Muiños, Loris, Mularoni, Andrew, J Mungall, Karen, Mungall, Elizabeth, A Musgrove, Ville, Mustonen, David, Mutch, Francesc, Muyas, Donna, M Muzny, Alfonso, Muñoz, Jerome, Myers, Ola, Myklebost, Peter, Möller, Genta, Nagae, Adnan, M Nagrial, Hardeep, K Nahal-Bose, Hitoshi, Nakagama, Hidewaki, Nakagawa, Hiromi, Nakamura, Toru, Nakamura, Kaoru, Nakano, Tannistha, Nandi, Jyoti, Nangalia, Mia, Nastic, Arcadi, Navarro, Fabio C, P Navarro, David, E Neal, Gerd, Nettekoven, Felicity, Newell, Steven, J Newhouse, Yulia, Newton, Alvin Wei Tian Ng, Anthony, Ng, Jonathan, Nicholson, David, Nicol, Yongzhan, Nie, G Petur Nielsen, Serena, Nik-Zainal, Michael, S Noble, Katia, Nones, Paul, A Northcott, Faiyaz, Notta, Brian, D O'Connor, Peter, O'Donnell, Maria, O'Donovan, Sarah, O'Meara, Brian Patrick O'Neill, J Robert O'Neill, David, Ocana, Angelica, Ochoa, Layla, Oesper, Christopher, Ogden, Hideki, Ohdan, Kazuhiro, Ohi, Lucila, Ohno-Machado, Karin, A Oien, Akinyemi, I Ojesina, Hidenori, Ojima, Takuji, Okusaka, Larsson, Omberg, Choon Kiat Ong, German, Ott, F Francis Ouellette, B, Christine, P'Ng, Marta, Paczkowska, Paiella, Salvatore, Chawalit, Pairojkul, Marina, Pajic, Qiang, Pan-Hammarström, Elli, Papaemmanuil, Irene, Papatheodorou, Ji Wan Park, Joong-Won, Park, Keunchil, Park, Kiejung, Park, Peter, J Park, Joel, S Parker, Simon, L Parsons, Harvey, Pass, Danielle, Pasternack, Alessandro, Pastore, Ann-Marie, Patch, Iris, Pauporté, Antonio, Pea, John, V Pearson, Chandra Sekhar Pedamallu, Paolo, Pederzoli, Martin, Peifer, Nathan, A Pennell, Charles, M Perou, Gloria, M Petersen, Nicholas, Petrelli, Robert, Petryszak, Stefan, M Pfister, Mark, Phillips, Oriol, Pich, Hilda, A Pickett, Todd, D Pihl, Nischalan, Pillay, Sarah, Pinder, Mark, Pinese, Andreia, V Pinho, Esa, Pitkänen, Xavier, Pivot, Elena, Piñeiro-Yáñez, Laura, Planko, Christoph, Plass, Paz, Polak, Tirso, Pons, Irinel, Popescu, Olga, Potapova, Aparna, Prasad, Shaun, R Preston, Manuel, Prinz, Antonia, L Pritchard, Stephenie, D Prokopec, Elena, Provenzano, Xose, S Puente, Sonia, Puig, Sergio, Pulido-Tamayo, Gulietta, M Pupo, Colin, A Purdie, Michael, C Quinn, Raquel, Rabionet, Janet, S Rader, Bernhard, Radlwimmer, Petar, Radovic, Benjamin, Raeder, Manasa, Ramakrishna, Kamna, Ramakrishnan, Suresh, Ramalingam, Benjamin, J Raphael, W Kimryn Rathmell, Tobias, Rausch, Guido, Reifenberger, Jüri, Reimand, Jorge, Reis-Filho, Victor, Reuter, Iker, Reyes-Salazar, Matthew, A Reyna, Yasser, Riazalhosseini, Andrea, L Richardson, Julia, Richter, Matthew, Ringel, Markus, Ringnér, Yasushi, Rino, Karsten, Rippe, Jeffrey, Roach, Lewis, R Roberts, Nicola, D Roberts, Steven, A Roberts, A Gordon Robertson, Alan, J Robertson, Javier Bartolomé Rodriguez, Bernardo, Rodriguez-Martin, F Germán Rodríguez-González, Michael H, A Roehrl, Marius, Rohde, Hirofumi, Rokutan, Gilles, Romieu, Ilse, Rooman, Tom, Roques, Daniel, Rosebrock, Mara, Rosenberg, Philip, C Rosenstiel, Andreas, Rosenwald, Edward, W Rowe, Steven, G Rozen, Yulia, Rubanova, Mark, A Rubin, Carlota, Rubio-Perez, Vasilisa, A Rudneva, Borislav, C Rusev, Ruzzenente, Andrea, Gunnar, Rätsch, Radhakrishnan, Sabarinathan, Veronica, Y Sabelnykova, Sara, Sadeghi, Natalie, Saini, Mihoko, Saito-Adachi, Adriana, Salcedo, Roberto, Salgado, Leonidas, Salichos, Richard, Sallari, Charles, Saller, Salvia, Roberto, Michelle, Sam, Jaswinder, S Samra, Francisco, Sanchez-Vega, Chris, Sander, Grant, Sanders, Rajiv, Sarin, Aya, Sasaki-Oku, Torill, Sauer, Guido, Sauter, Robyn P, M Saw, Maria, Scardoni, Christopher, J Scarlett, Scarpa, Aldo, Ghislaine, Scelo, Dirk, Schadendorf, Jacqueline, E Schein, Markus, B Schilhabel, Thorsten, Schlomm, Heather, K Schmidt, Sarah-Jane, Schramm, Stefan, Schreiber, Nikolaus, Schultz, Steven, E Schumacher, Roland, F Schwarz, Richard, A Scolyer, David, Scott, Ralph, Scully, Raja, Seethala, Ayellet, V Segre, Iris, Selander, Colin, A Semple, Yasin, Senbabaoglu, Subhajit, Sengupta, Elisabetta, Sereni, Stefano, Serra, Dennis, C Sgroi, Mark, Shackleton, Nimish, C Shah, Sagedeh, Shahabi, Catherine, A Shang, Ping, Shang, Ofer, Shapira, Troy, Shelton, Ciyue, Shen, Hui, Shen, Rebecca, Shepherd, Ruian, Shi, Yan, Shi, Yu-Jia, Shiah, Tatsuhiro, Shibata, Juliann, Shih, Eigo, Shimizu, Kiyo, Shimizu, Seung Jun Shin, Yuichi, Shiraishi, Tal, Shmaya, Ilya, Shmulevich, Solomon, I Shorser, Charles, Short, Raunak, Shrestha, Suyash, S Shringarpure, Craig, Shriver, Shimin, Shuai, Nikos, Sidiropoulos, Reiner, Siebert, Anieta, M Sieuwerts, Lina, Sieverling, Sabina, Signoretti, Katarzyna, O Sikora, Michele, Simbolo, Ronald, Simon, Janae, V Simons, Peter, T Simpson, Samuel, Singer, Nasa, Sinnott-Armstrong, Payal, Sipahimalani, Tara, J Skelly, Marcel, Smid, Jaclyn, Smith, Karen, Smith-McCune, Nicholas, D Socci, Heidi, J Sofia, Matthew, G Soloway, Lei, Song, Anil, K Sood, Sharmila, Sothi, Christos, Sotiriou, Cameron, M Soulette, Paul, N Span, Paul, T Spellman, Sperandio, Nicola, Andrew, J Spillane, Oliver, Spiro, Jonathan, Spring, Johan, Staaf, Peter, F Stadler, Peter, Staib, Stefan, G Stark, Ólafur Andri Stefánsson, Oliver, Stegle, Lincoln, D Stein, Alasdair, Stenhouse, Stephan, Stilgenbauer, Michael, R Stratton, Jonathan, R Stretch, Henk, G Stunnenberg, Hong, Su, Xiaoping, Su, Ren, X Sun, Stephanie, Sungalee, Hana, Susak, Akihiro, Suzuki, Fred, Sweep, Monika, Szczepanowski, Holger, Sültmann, Takashi, Yugawa, Angela, Tam, David, Tamborero, Benita Kiat Tee Tan, Donghui, Tan, Patrick, Tan, Hiroko, Tanaka, Hirokazu, Taniguchi, Tomas, J Tanskanen, Maxime, Tarabichi, Roy, Tarnuzzer, Patrick, Tarpey, Morgan, L Taschuk, Kenji, Tatsuno, Simon, Tavaré, Darrin, F Taylor, Amaro, Taylor-Weiner, Bin Tean Teh, Varsha, Tembe, Javier, Temes, Kevin, Thai, Sarah, P Thayer, Nina, Thiessen, Gilles, Thomas, Sarah, Thomas, Alan, Thompson, Alastair, M Thompson, John, F Thompson, R Houston Thompson, Heather, Thorne, Leigh, B Thorne, Adrian, Thorogood, Nebojsa, Tijanic, Lee, E Timms, Roberto, Tirabosco, Marta, Tojo, Stefania, Tommasi, Christopher, W Toon, Umut, H Toprak, Giampaolo, Tortora, Jörg, Tost, Yasushi, Totoki, David, Townend, Nadia, Traficante, Isabelle, Treilleux, Jean-Rémi, Trotta, Lorenz H, P Trümper, Ming, Tsao, Tatsuhiko, Tsunoda, Jose M, C Tubio, Olga, Tucker, Richard, Turkington, Daniel, J Turner, Andrew, Tutt, Masaki, Ueno, Naoto, T Ueno, Christopher, Umbricht, Husen, M Umer, Timothy, J Underwood, Lara, Urban, Tomoko, Urushidate, Tetsuo, Ushiku, Liis, Uusküla-Reimand, Alfonso, Valencia, David, J Van Den Berg, Steven Van Laere, Peter Van Loo, Erwin, G Van Meir, Gert, G Van den Eynden, Theodorus Van der Kwast, Naveen, Vasudev, Miguel, Vazquez, Ravikiran, Vedururu, Umadevi, Veluvolu, Shankar, Vembu, Lieven P, C Verbeke, Peter, Vermeulen, Clare, Verrill, Alain, Viari, David, Vicente, Caterina, Vicentini, K Vijay Raghavan, Juris, Viksna, Ricardo, E Vilain, Izar, Villasante, Anne, Vincent-Salomon, Tapio, Visakorpi, Douglas, Voet, Paresh, Vyas, Ignacio, Vázquez-García, Nick, M Waddell, Nicola, Waddell, Claes, Wadelius, Lina, Wadi, Rabea, Wagener, Jian, Wang, Linghua, Wang, Wang, Qi, Yumeng, Wang, Zhining, Wang, Paul, M Waring, Hans-Jörg, Warnatz, Jonathan, Warrell, Anne, Y Warren, David, C Wedge, Dieter, Weichenhan, Paul, Weinberger, Daniel, J Weisenberger, Ian, Welch, Justin, P Whalley, Hayley, C Whitaker, Dennis, Wigle, Matthew, D Wilkerson, 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[0000-0003-4526-9727], Dursi, Lewis Jonathan [0000-0002-4697-798X], Wang, Liang-Bo [0000-0001-6977-9348], Dong, Guanlan [0000-0002-4747-6036], Weerasinghe, Amila [0000-0003-3568-5823], Li, Shantao [0000-0002-5440-2780], Saksena, Gordon [0000-0001-6630-7935], Ellrott, Kyle [0000-0002-6573-5900], Wheeler, David A. [0000-0002-9056-6299], Getz, Gad [0000-0002-0936-0753], Gerstein, Mark B. [0000-0002-9746-3719], Apollo - University of Cambridge Repository, CCA - Cancer biology and immunology, Graduate School, Laboratory Genetic Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, Bailey, M, Meyerson, W, Dursi, L, Wang, L, Dong, G, Liang, W, Weerasinghe, A, Li, S, Kelso, S, Akbani, R, Anur, P, Buchanan, A, Chiotti, K, Covington, K, Creason, A, Ding, L, Ellrott, K, Fan, Y, Foltz, S, Getz, G, Hale, W, Haussler, D, Hess, J, Hutter, C, Kandoth, C, Kasaian, K, Kasapi, M, Larson, D, Leshchiner, I, Letaw, J, Ma, S, Mclellan, M, Men, Y, Mills, G, Niu, B, Peto, M, Radenbaugh, A, Reynolds, S, Saksena, G, Sofia, H, Stewart, C, Struck, A, Stuart, J, Wang, W, Weinstein, J, Wheeler, D, Wong, C, Xi, L, Ye, K, Bieg, M, Boutros, P, Buchhalter, I, Butler, A, Chen, K, Chong, Z, Drechsel, O, Jonathan Dursi, L, Eils, R, Espiritu, S, Fulton, R, Gao, S, Gelpi, J, Gerstein, M, Gonzalez, S, Gut, I, Hach, F, Heinold, M, Hinton, J, Hu, T, Huang, V, Huang, Y, Hutter, B, Jones, D, Jung, J, Jager, N, Kim, H, Kleinheinz, K, Kumar, S, Kumar, Y, Lalansingh, C, Letunic, I, Livitz, D, Ma, E, Maruvka, Y, Mashl, R, Menzies, A, Milovanovic, A, Nielsen, M, Ossowski, S, Paramasivam, N, Pedersen, J, Perry, M, Puiggros, M, Raine, K, Rheinbay, E, Royo, R, Sahinalp, S, Sarrafi, I, Schlesner, M, Simpson, J, Stebbings, L, Stobbe, M, Teague, J, Tiao, G, Torrents, D, Wala, J, Wang, J, Waszak, S, Weischenfeldt, J, Wendl, M, Werner, J, Wu, Z, Xue, H, Yakneen, S, Yamaguchi, T, Yellapantula, V, Yung, C, Zhang, J, Aaltonen, L, Abascal, F, Abeshouse, A, Aburatani, H, Adams, D, Agrawal, N, Ahn, K, Ahn, S, Aikata, H, Akdemir, K, Al-Ahmadie, H, Al-Sedairy, S, Al-Shahrour, F, Alawi, M, Albert, M, Aldape, K, Alexandrov, L, Ally, A, Alsop, K, Alvarez, E, Amary, F, Amin, S, Aminou, B, Ammerpohl, O, Anderson, M, Ang, Y, Antonello, D, Aparicio, S, Appelbaum, E, Arai, Y, Aretz, A, Arihiro, K, Ariizumi, S, Armenia, J, Arnould, L, Asa, S, Assenov, Y, Atwal, G, Aukema, S, Auman, J, Aure, M, Awadalla, P, Aymerich, M, Bader, G, Baez-Ortega, A, Bailey, P, Balasundaram, M, Balu, S, Bandopadhayay, P, Banks, R, Barbi, S, Barbour, A, Barenboim, J, Barnholtz-Sloan, J, Barr, H, Barrera, E, Bartlett, J, Bartolome, J, Bassi, C, Bathe, O, Baumhoer, D, Bavi, P, Baylin, S, Bazant, W, Beardsmore, D, Beck, T, Behjati, S, Behren, A, Bell, C, Beltran, S, Benz, C, Berchuck, A, Bergmann, A, Bergstrom, E, Berman, B, Berney, D, Bernhart, S, Beroukhim, R, Berrios, M, Bersani, S, Bertl, J, Betancourt, M, Bhandari, V, Bhosle, S, Biankin, A, Bigner, D, Binder, H, Birney, E, Birrer, M, Biswas, N, Bjerkehagen, B, Bodenheimer, T, Boice, L, Bonizzato, G, De Bono, J, Boot, A, Bootwalla, M, Borg, A, Borkhardt, A, Boroevich, K, Borozan, I, Borst, C, Bosenberg, M, Bosio, M, Boultwood, J, Bourque, G, Bova, G, Bowen, D, Bowlby, R, Bowtell, D, Boyault, S, Boyce, R, Boyd, J, Brazma, A, Brennan, P, Brewer, D, Brinkman, A, Bristow, R, Broaddus, R, Brock, J, Brock, M, Broeks, A, Brooks, A, Brooks, D, Brors, B, Brunak, S, Bruxner, T, Bruzos, A, Buchholz, C, Bullman, S, Burke, H, Burkhardt, B, Burns, K, Busanovich, J, Bustamante, C, Butte, A, Byrne, N, Borresen-Dale, A, Caesar-Johnson, S, Cafferkey, A, Cahill, D, Calabrese, C, Caldas, C, Calvo, F, Camacho, N, Campbell, P, Campo, E, Cantu, C, Cao, S, Carey, T, Carlevaro-Fita, J, Carlsen, R, Cataldo, I, Cazzola, M, Cebon, J, Cerfolio, R, Chadwick, D, Chakravarty, D, Chalmers, D, Chan, C, Chan, K, Chan-Seng-Yue, M, Chandan, V, Chang, D, Chanock, S, Chantrill, L, Chateigner, A, Chatterjee, N, Chayama, K, Chen, H, Chen, J, Chen, Y, Chen, Z, Cherniack, A, Chien, J, Chiew, Y, Chin, S, Cho, J, Cho, S, Choi, J, Choi, W, Chomienne, C, Choo, S, Chou, A, Christ, A, Christie, E, Chuah, E, Cibulskis, C, Cibulskis, K, Cingarlini, S, Clapham, P, Claviez, A, Cleary, S, Cloonan, N, Cmero, M, Collins, C, Connor, A, Cooke, S, Cooper, C, Cope, L, Corbo, V, Cordes, M, Cordner, S, Cortes-Ciriano, I, Cowin, P, Craft, B, Craft, D, Creighton, C, Cun, Y, Curley, E, Cutcutache, I, Czajka, K, Czerniak, B, Dagg, R, Danilova, L, Davi, M, Davidson, N, Davies, H, Davis, I, Davis-Dusenbery, B, Dawson, K, De La Vega, F, De Paoli-Iseppi, R, Defreitas, T, Dei Tos, A, Delaneau, O, Demchok, J, Demeulemeester, J, Demidov, G, Demircioglu, D, Dennis, N, Denroche, R, Dentro, S, Desai, N, Deshpande, V, Deshwar, A, Desmedt, C, Deu-Pons, J, Dhalla, N, Dhani, N, Dhingra, P, Dhir, R, Dibiase, A, Diamanti, K, Ding, S, Dinh, H, Dirix, L, Doddapaneni, H, Donmez, N, Dow, M, Drapkin, R, Drews, R, Serge, S, Dudderidge, T, Dueso-Barroso, A, Dunford, A, Dunn, M, Duthie, F, Dutton-Regester, K, Eagles, J, Easton, D, Edmonds, S, Edwards, P, Edwards, S, Eeles, R, Ehinger, A, Eils, J, El-Naggar, A, Eldridge, M, Erkek, S, Escaramis, G, Estivill, X, Etemadmoghadam, D, Eyfjord, J, Faltas, B, Fan, D, Faquin, W, Farcas, C, Fassan, M, Fatima, A, Favero, F, Fayzullaev, N, Felau, I, Fereday, S, Ferguson, M, Ferretti, V, Feuerbach, L, Field, M, Fink, J, Finocchiaro, G, Fisher, C, Fittall, M, Fitzgerald, A, Fitzgerald, R, Flanagan, A, Fleshner, N, Flicek, P, Foekens, J, Fong, K, Fonseca, N, Foster, C, Fox, N, Fraser, M, Frazer, S, Frenkel-Morgenstern, M, Friedman, W, Frigola, J, Fronick, C, Fujimoto, A, Fujita, M, Fukayama, M, Fulton, L, Furuta, M, Futreal, P, Fullgrabe, A, Gabriel, S, Gallinger, S, Gambacorti Passerini, C, Gao, J, Garraway, L, Garred, O, Garrison, E, Garsed, D, Gehlenborg, N, George, J, Gerhard, D, Gerhauser, C, Gershenwald, J, Gerstung, M, Ghori, M, Ghossein, R, Giama, N, Gibbs, R, Gill, A, Gill, P, Giri, D, Glodzik, D, Gnanapragasam, V, Goebler, M, Goldman, M, Gomez, C, Gonzalez-Perez, A, Gordenin, D, Gossage, J, Gotoh, K, Govindan, R, Grabau, D, Graham, J, Grant, R, Green, A, Green, E, Greger, L, Grehan, N, Grimaldi, S, Grimmond, S, Grossman, R, Grundhoff, A, Gundem, G, Guo, Q, Gupta, M, Gupta, S, Gut, M, Goke, J, Ha, G, Haake, A, Haan, D, Haas, S, Haase, K, Haber, J, Habermann, N, Haider, S, Hama, N, Hamdy, F, Hamilton, A, Hamilton, M, Han, L, Hanna, G, Hansmann, M, Haradhvala, N, Harismendy, O, Harliwong, I, Harmanci, A, Harrington, E, Hasegawa, T, Hawkins, S, Hayami, S, Hayashi, S, Hayes, D, Hayes, S, Hayward, N, Hazell, S, He, Y, Heath, A, Heath, S, Hedley, D, Hegde, A, Heiman, D, Heins, Z, Heisler, L, Hellstrom-Lindberg, E, Helmy, M, Heo, S, Hepperla, A, Heredia-Genestar, J, Herrmann, C, Hersey, P, Hilmarsdottir, H, Hirano, S, Hiraoka, N, Hoadley, K, Hobolth, A, Hodzic, E, Hoell, J, Hoffmann, S, Hofmann, O, Holbrook, A, Holik, A, Hollingsworth, M, Holmes, O, Holt, R, Hong, C, Hong, E, Hong, J, Hooijer, G, Hornshoj, H, Hosoda, F, Hou, Y, Hovestadt, V, Howat, W, Hoyle, A, Hruban, R, Hu, J, Hua, X, Huang, K, Huang, M, Huber, W, Hudson, T, Hummel, M, Hung, J, Huntsman, D, Hupp, T, Huse, J, Huska, M, Hubschmann, D, Iacobuzio-Donahue, C, Imbusch, C, Imielinski, M, Imoto, S, Isaacs, W, Isaev, K, Ishikawa, S, Iskar, M, Islam, S, Ittmann, M, Ivkovic, S, Izarzugaza, J, Jacquemier, J, Jakrot, V, Jamieson, N, Jang, G, Jang, S, Jayaseelan, J, Jayasinghe, R, Jefferys, S, Jegalian, K, Jennings, J, Jeon, S, Jerman, L, Ji, Y, Jiao, W, Johansson, P, Johns, A, Johns, J, Johnson, R, Johnson, T, Jolly, C, Joly, Y, Jonasson, J, Jones, C, Jones, N, Jones, S, Jonkers, J, Ju, Y, Juhl, H, Juul, M, Juul, R, Juul, S, Kabbe, R, Kahles, A, Kahraman, A, Kaiser, V, Kakavand, H, Kalimuthu, S, von Kalle, C, Kang, K, Karaszi, K, Karlan, B, Karlic, R, Karsch, D, Kassahn, K, Katai, H, Kato, M, Katoh, H, Kawakami, Y, Kay, J, Kazakoff, S, Kazanov, M, Keays, M, Kebebew, E, Kefford, R, Kellis, M, Kench, J, Kennedy, C, Kerssemakers, J, Khoo, D, Khoo, V, Khuntikeo, N, Khurana, E, Kilpinen, H, Kim, J, Kim, Y, King, T, Klapper, W, Klimczak, L, Knappskog, S, Kneba, M, Knoppers, B, Koh, Y, Jan, K, Komura, D, Komura, M, Kong, G, Kool, M, Korbel, J, Korchina, V, Korshunov, A, Koscher, M, Koster, R, Kote-Jarai, Z, Koures, A, Kovacevic, M, Kremeyer, B, Kretzmer, H, Kreuz, M, Krishnamurthy, S, Kube, D, Kumar, K, Kumar, P, Kundra, R, Kubler, K, Kuppers, R, Lagergren, J, Lai, P, Laird, P, Lakhani, S, Lalonde, E, Lamaze, F, Lambert, A, Lander, E, Landgraf, P, Landoni, L, Langerod, A, Lanzos, A, Larsimont, D, Larsson, E, Lathrop, M, Lau, L, Lawerenz, C, Lawlor, R, Lawrence, M, Lazar, A, Le, X, Lee, D, Lee, E, Lee, H, Lee, J, Lee, M, Lee-Six, H, Lehmann, K, Lehrach, H, Lenze, D, Leonard, C, Leongamornlert, D, Letourneau, L, Levine, D, Lewis, L, Ley, T, Li, C, Li, H, Li, J, Li, L, Li, X, Li, Y, Liang, H, Liang, S, Lichter, P, Lin, P, Lin, Z, Linehan, W, Lingjaerde, O, Liu, D, Liu, E, Liu, F, Liu, J, Liu, X, Livingstone, J, Livni, N, Lochovsky, L, Loeffler, M, Long, G, Lopez-Guillermo, A, Lou, S, Louis, D, Lovat, L, Lu, Y, Luchini, C, Lungu, I, Luo, X, Luxton, H, Lynch, A, Lype, L, Lopez, C, Lopez-Otin, C, Ma, Y, Macgrogan, G, Macrae, S, Macintyre, G, Madsen, T, Maejima, K, Mafficini, A, Maglinte, D, Maitra, A, Majumder, P, Malcovati, L, Malikic, S, Malleo, G, Mann, G, Mantovani-Loffler, L, Marchal, K, Marchegiani, G, Mardis, E, Margolin, A, Marin, M, Markowetz, F, Markowski, J, Marks, J, Marques-Bonet, T, Marra, M, Marsden, L, Martens, J, Martin, S, Martin-Subero, J, Martincorena, I, Martinez-Fundichely, A, Massie, C, Matthew, T, Matthews, L, Mayer, E, Mayes, S, Mayo, M, Mbabaali, F, Mccune, K, Mcdermott, U, Mcgillivray, P, Mcpherson, J, Mcpherson, T, Meier, S, Meng, A, Meng, S, Merrett, N, Merson, S, Meyerson, M, Mieczkowski, P, Mihaiescu, G, Mijalkovic, S, Mijalkovic-Lazic, A, Mikkelsen, T, Milella, M, Mileshkin, L, Miller, C, Miller, D, Miller, J, Minner, S, Miotto, M, Arnau, G, Mirabello, L, Mitchell, C, Mitchell, T, Miyano, S, Miyoshi, N, Mizuno, S, Molnar-Gabor, F, Moore, M, Moore, R, Morganella, S, Morris, Q, Morrison, C, Mose, L, Moser, C, Muinos, F, Mularoni, L, Mungall, A, Mungall, K, Musgrove, E, Mustonen, V, Mutch, D, Muyas, F, Muzny, D, Munoz, A, Myers, J, Myklebost, O, Moller, P, Nagae, G, Nagrial, A, Nahal-Bose, H, Nakagama, H, Nakagawa, H, Nakamura, H, Nakamura, T, Nakano, K, Nandi, T, Nangalia, J, Nastic, M, Navarro, A, Navarro, F, Neal, D, Nettekoven, G, Newell, F, Newhouse, S, Newton, Y, Ng, A, Nicholson, J, Nicol, D, Nie, Y, Nielsen, G, Nik-Zainal, S, Noble, M, Nones, K, Northcott, P, Notta, F, O'Connor, B, O'Donnell, P, O'Donovan, M, O'Meara, S, O'Neill, B, O'Neill, J, Ocana, D, Ochoa, A, Oesper, L, Ogden, C, Ohdan, H, Ohi, K, Ohno-Machado, L, Oien, K, Ojesina, A, Ojima, H, Okusaka, T, Omberg, L, Ong, C, Ott, G, Ouellette, B, P'Ng, C, Paczkowska, M, Paiella, S, Pairojkul, C, Pajic, M, Pan-Hammarstrom, Q, Papaemmanuil, E, Papatheodorou, I, Park, J, Park, K, Park, P, Parker, J, Parsons, S, Pass, H, Pasternack, D, Pastore, A, Patch, A, Pauporte, I, Pea, A, Pearson, J, Pedamallu, C, Pederzoli, P, Peifer, M, Pennell, N, Perou, C, Petersen, G, Petrelli, N, Petryszak, R, Pfister, S, Phillips, M, Pich, O, Pickett, H, Pihl, T, Pillay, N, Pinder, S, Pinese, M, Pinho, A, Pitkanen, E, Pivot, X, Pineiro-Yanez, E, Planko, L, Plass, C, Polak, P, Pons, T, Popescu, I, Potapova, O, Prasad, A, Preston, S, Prinz, M, Pritchard, A, Prokopec, S, Provenzano, E, Puente, X, Puig, S, Pulido-Tamayo, S, Pupo, G, Purdie, C, Quinn, M, Rabionet, R, Rader, J, Radlwimmer, B, Radovic, P, Raeder, B, Ramakrishna, M, Ramakrishnan, K, Ramalingam, S, Raphael, B, Rathmell, W, Rausch, T, Reifenberger, G, Reimand, J, Reis-Filho, J, Reuter, V, Reyes-Salazar, I, Reyna, M, Riazalhosseini, Y, Richardson, A, Richter, J, Ringel, M, Ringner, M, Rino, Y, Rippe, K, Roach, J, Roberts, L, Roberts, N, Roberts, S, Robertson, A, Rodriguez, J, Rodriguez-Martin, B, Rodriguez-Gonzalez, F, Roehrl, M, Rohde, M, Rokutan, H, Romieu, G, Rooman, I, Roques, T, Rosebrock, D, Rosenberg, M, Rosenstiel, P, Rosenwald, A, Rowe, E, Rozen, S, Rubanova, Y, Rubin, M, Rubio-Perez, C, Rudneva, V, Rusev, B, Ruzzenente, A, Ratsch, G, Sabarinathan, R, Sabelnykova, V, Sadeghi, S, Saini, N, Saito-Adachi, M, Salcedo, A, Salgado, R, Salichos, L, Sallari, R, Saller, C, Salvia, R, Sam, M, Samra, J, Sanchez-Vega, F, Sander, C, Sanders, G, Sarin, R, Sasaki-Oku, A, Sauer, T, Sauter, G, Saw, R, Scardoni, M, Scarlett, C, Scarpa, A, Scelo, G, Schadendorf, D, Schein, J, Schilhabel, M, Schlomm, T, Schmidt, H, Schramm, S, Schreiber, S, Schultz, N, Schumacher, S, Schwarz, R, Scolyer, R, Scott, D, Scully, R, Seethala, R, Segre, A, Selander, I, Semple, C, Senbabaoglu, Y, Sengupta, S, Sereni, E, Serra, S, Sgroi, D, Shackleton, M, Shah, N, Shahabi, S, Shang, C, Shang, P, Shapira, O, Shelton, T, Shen, C, Shen, H, Shepherd, R, Shi, R, Shi, Y, Shiah, Y, Shibata, T, Shih, J, Shimizu, E, Shimizu, K, Shin, S, Shiraishi, Y, Shmaya, T, Shmulevich, I, Shorser, S, Short, C, Shrestha, R, Shringarpure, S, Shriver, C, Shuai, S, Sidiropoulos, N, Siebert, R, Sieuwerts, A, Sieverling, L, Signoretti, S, Sikora, K, Simbolo, M, Simon, R, Simons, J, Simpson, P, Singer, S, Sinnott-Armstrong, N, Sipahimalani, P, Skelly, T, Smid, M, Smith, J, Smith-McCune, K, Socci, N, Soloway, M, Song, L, Sood, A, Sothi, S, Sotiriou, C, Soulette, C, Span, P, Spellman, P, Sperandio, N, Spillane, A, Spiro, O, Spring, J, Staaf, J, Stadler, P, Staib, P, Stark, S, Stefansson, O, Stegle, O, Stein, L, Stenhouse, A, Stilgenbauer, S, Stratton, M, Stretch, J, Stunnenberg, H, Su, H, Su, X, Sun, R, Sungalee, S, Susak, H, Suzuki, A, Sweep, F, Szczepanowski, M, Sultmann, H, Yugawa, T, Tam, A, Tamborero, D, Tan, B, Tan, D, Tan, P, Tanaka, H, Taniguchi, H, Tanskanen, T, Tarabichi, M, Tarnuzzer, R, Tarpey, P, Taschuk, M, Tatsuno, K, Tavare, S, Taylor, D, Taylor-Weiner, A, Teh, B, Tembe, V, Temes, J, Thai, K, Thayer, S, Thiessen, N, Thomas, G, Thomas, S, Thompson, A, Thompson, J, Thompson, R, Thorne, H, Thorne, L, Thorogood, A, Tijanic, N, Timms, L, Tirabosco, R, Tojo, M, Tommasi, S, Toon, C, Toprak, U, Tortora, G, Tost, J, Totoki, Y, Townend, D, Traficante, N, Treilleux, I, Trotta, J, Trumper, L, Tsao, M, Tsunoda, T, Tubio, J, Tucker, O, Turkington, R, Turner, D, Tutt, A, Ueno, M, Ueno, N, Umbricht, C, Umer, H, Underwood, T, Urban, L, Urushidate, T, Ushiku, T, Uuskula-Reimand, L, Valencia, A, Van Den Berg, D, Van Laere, S, Van Loo, P, Van Meir, E, Van den Eynden, G, Van der Kwast, T, Vasudev, N, Vazquez, M, Vedururu, R, Veluvolu, U, Vembu, S, Verbeke, L, Vermeulen, P, Verrill, C, Viari, A, Vicente, D, Vicentini, C, Raghavan, K, Viksna, J, Vilain, R, Villasante, I, Vincent-Salomon, A, Visakorpi, T, Voet, D, Vyas, P, Vazquez-Garcia, I, Waddell, N, Wadelius, C, Wadi, L, Wagener, R, Wang, Q, Wang, Y, Wang, Z, Waring, P, Warnatz, H, Warrell, J, Warren, A, Wedge, D, Weichenhan, D, Weinberger, P, Weisenberger, D, Welch, I, Whalley, J, Whitaker, H, Wigle, D, Wilkerson, M, Williams, A, Wilmott, J, Wilson, G, Wilson, J, Wilson, R, Winterhoff, B, Wintersinger, J, Wiznerowicz, M, Wolf, S, Wong, B, Wong, T, Wong, W, Woo, Y, Wood, S, Wouters, B, Wright, A, Wright, D, Wright, M, Wu, C, Wu, D, Wu, G, Wu, J, Wu, K, Wu, Y, Xia, T, Xiang, Q, Xiao, X, Xing, R, Xiong, H, Xu, Q, Xu, Y, Yachida, S, Yamaguchi, R, Yamamoto, M, Yamamoto, S, Yamaue, H, Yang, F, Yang, H, Yang, J, Yang, L, Yang, S, Yang, T, Yang, Y, Yao, X, Yaspo, M, Yates, L, Yau, C, Ye, C, Yoon, C, Yoon, S, Yousif, F, Yu, J, Yu, K, Yu, W, Yu, Y, Yuan, K, Yuan, Y, Yuen, D, Zaikova, O, Zamora, J, Zapatka, M, Zenklusen, J, Zenz, T, Zeps, N, Zhang, C, Zhang, F, Zhang, H, Zhang, X, Zhang, Y, Zhang, Z, Zhao, Z, Zheng, L, Zheng, X, Zhou, W, Zhou, Y, Bin, Z, Zhu, H, Zhu, J, Zhu, S, Zou, L, Zou, X, Defazio, A, van As, N, van Deurzen, C, van de Vijver, M, van't Veer, L, von Mering, C, Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Tampere University, BioMediTech, TAYS Cancer Centre, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, University of St Andrews. Cellular Medicine Division, University of St Andrews. Statistics, University of St Andrews. School of Medicine, University of Zurich, Gerstein, Mark B, Ding, Li, Bailey, Matthew H [0000-0003-4526-9727], Wheeler, David A [0000-0002-9056-6299], Gerstein, Mark B [0000-0002-9746-3719], Faculty of Economic and Social Sciences and Solvay Business School, Lauri Antti Aaltonen / Principal Investigator, Genome-Scale Biology (GSB) Research Program, Department of Medical and Clinical Genetics, Organismal and Evolutionary Biology Research Programme, Helsinki Institute for Information Technology, Institute of Biotechnology, Bioinformatics, Department of Computer Science, Faculty of Medicine, and HUS Helsinki and Uusimaa Hospital District
Subjects: VARIANTS, 0302 clinical medicine, 706/648/697/129/2043, Databases, Genetic, Cancer genomics, SOMATIC POINT MUTATIONS, Càncer, lcsh:Science, Exome, Exome sequencing, Cancer, Base Composition, Neoplasms -- genetics, 1184 Genetics, developmental biology, physiology, 3100 General Physics and Astronomy, 3. Good health, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, Transformació genètica, Genetic databases, Erfðarannsóknir, Human, GENES, Science, 1600 General Chemistry, General Biochemistry, Genetics and Molecular Biology, RC0254, 03 medical and health sciences, Genetic, SDG 3 - Good Health and Well-being, 1300 General Biochemistry, Genetics and Molecular Biology, Exome Sequencing, Genetics, Humans, Author Correction, Retrospective Studies, Whole genome sequencing, Comparative genomics, Science & Technology, RC0254 Neoplasms. Tumors. Oncology (including Cancer), INSERTIONS, DNA, PERFORMANCE, Human genetics, Communication and replication, Cancérologie, 692/4028/67/69, Genòmica, 030104 developmental biology, Mutation, Genome mutation, Human genome, lcsh:Q, COMPREHENSIVE CHARACTERIZATION, Genètica, 0301 basic medicine, Medizin, General Physics and Astronomy, Genome, Whole Exome Sequencing, Genetic transformation, International Cancer Genome Consortium, Neoplasms, 631/114/2399, Genamengi, Medicine and Health Sciences, Medicine(all), Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, 318 Medical biotechnology, Exome -- genetics, article, Exons, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Multidisciplinary Sciences, CAPTURE, 1181 Ecology, evolutionary biology, oncology, DNA, Intergenic, 139, Medical Genetics, Biotechnology, ICGC/TCGA Pan-Cancer Analysis, 3122 Cancers, 610 Medicine & health, 45/23, QH426 Genetics, Biology, MC3 Working Group, Databases, Germline mutation, PCAWG novel somatic mutation calling methods working group, Krabbameinsrannsóknir, Cancer Genome Atlas, Genome, Human -- genetics, ddc:610, QH426, Medicinsk genetik, Krabbamein, Intergenic, Whole Genome Sequencing, Genome, Human, Human Genome, PCAWG Consortium, DAS, General Chemistry, DELETIONS, Good Health and Well Being, 10032 Clinic for Oncology and Hematology, 3111 Biomedicine, 631/1647/2217/748
Abstract: MC3 Working Group: Rehan Akbani21, Pavana Anur22, Matthew H. Bailey1,2,3, Alex Buchanan9, Kami Chiotti9, Kyle Covington12,23, Allison Creason9, Li Ding1,2,3,20, Kyle Ellrott9, Yu Fan21, Steven Foltz1,2, Gad Getz8,14,15,16, Walker Hale12, David Haussler24,25, Julian M. Hess8,26, Carolyn M. Hutter27, Cyriac Kandoth28, Katayoon Kasaian29,30, Melpomeni Kasapi27, Dave Larson1 , Ignaty Leshchiner8, John Letaw31, Singer Ma32, Michael D. McLellan1,3,20, Yifei Men32, Gordon B. Mills33,34, Beifang Niu35, Myron Peto22, Amie Radenbaugh24, Sheila M. Reynolds36, Gordon Saksena8, Heidi Sofia27, Chip Stewart8, Adam J. Struck31, Joshua M. Stuart24,37, Wenyi Wang21, John N. Weinstein38, David A. Wheeler12,13, Christopher K. Wong24,39, Liu Xi12 & Kai Ye40,41 21Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. 22Molecular and Medical Genetics, OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA. 23Castle Biosciences Inc, Friendswood, TX 77546, USA. 24UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 25Howard Hughes Medical Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 26Massachusetts General Hospital Center for Cancer Research, Charlestown, MA 02114, USA. 27National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20894, USA. 28Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. 29Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada. 30Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V5Z 4S6, Canada. 31Computational Biology Program, School of Medicine, Oregon Health and Science University, Portland, OR 97239, USA. 32DNAnexus Inc, Mountain View, CA 94040, USA. 33Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX 77030, USA. 34Precision Oncology, OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA. 35Computer Network Information Center, Chinese Academy of Sciences, Beijing, China. 36Institute for Systems Biology, Seattle, WA 98109, USA. 37Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 38Department of Bioinformatics and Computational Biology and Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. 39Biomolecular Engineering Department, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 40School of Elect, PCAWG novel somatic mutation calling methods working group: Matthew H. Bailey1,2,3, Beifang Niu35, Matthias Bieg42,43, Paul C. Boutros6,44,45,46, Ivo Buchhalter43,47,48, Adam P. Butler49, Ken Chen50, Zechen Chong51, Li Ding1,2,3,20, Oliver Drechsel52,53, Lewis Jonathan Dursi6,7, Roland Eils47,48,54,55, Kyle Ellrott9, Shadrielle M. G. Espiritu6, Yu Fan21, Robert S. Fulton1,3,20, Shengjie Gao56, Josep L. l. Gelpi57,58, Mark B. Gerstein5,18,19, Gad Getz8,14,15,16, Santiago Gonzalez59,60, Ivo G. Gut52,61, Faraz Hach62,63, Michael C. Heinold47,48, Julian M. Hess8,26, Jonathan Hinton49, Taobo Hu64, Vincent Huang6, Yi Huang65,66, Barbara Hutter43,67,68, David R. Jones49, Jongsun Jung69, Natalie Jäger47, Hyung-Lae Kim70, Kortine Kleinheinz47,48, Sushant Kumar5,19, Yogesh Kumar64, Christopher M. Lalansingh6, Ignaty Leshchiner8, Ivica Letunic71, Dimitri Livitz8, Eric Z. Ma64, Yosef E. Maruvka8,26,72, R. Jay Mashl1,2, Michael D. McLellan1,3,20, Andrew Menzies49, Ana Milovanovic57, Morten Muhlig Nielsen73, Stephan Ossowski52,53,74, Nagarajan Paramasivam43,47, Jakob Skou Pedersen73,75, Marc D. Perry76,77, Montserrat Puiggròs57, Keiran M. Raine49, Esther Rheinbay8,14,72, Romina Royo57, S. Cenk Sahinalp62,78,79, Gordon Saksena8, Iman Sarrafi62,78, Matthias Schlesner47,80, Jared T. Simpson6,17, Lucy Stebbings49, Chip Stewart8, Miranda D. Stobbe52,61, Jon W. Teague49, Grace Tiao8, David Torrents57,81, Jeremiah A. Wala8,14,82, Jiayin Wang1,40,66, Wenyi Wang21, Sebastian M. Waszak60, Joachim Weischenfeldt60,83,84, Michael C. Wendl1,10,11, Johannes Werner47,85, Zhenggang Wu64, Hong Xue64, Sergei Yakneen60, Takafumi N. Yamaguchi6, Kai Ye40,41, Venkata D. Yellapantula20,86, Christina K. Yung76 & Junjun Zhang76, PCAWG Consortium: Lauri A. Aaltonen87, Federico Abascal49, Adam Abeshouse88, Hiroyuki Aburatani89, David J. Adams49, Nishant Agrawal90, Keun Soo Ahn91, Sung-Min Ahn92, Hiroshi Aikata93, Rehan Akbani21, Kadir C. Akdemir50, Hikmat Al-Ahmadie88, Sultan T. Al-Sedairy94, Fatima Al-Shahrour95, Malik Alawi96,97, Monique Albert98, Kenneth Aldape99,100, Ludmil B. Alexandrov49,101,102, Adrian Ally30, Kathryn Alsop103, Eva G. Alvarez104,105,106, Fernanda Amary107, Samirkumar B. Amin108,109,110, Brice Aminou76, Ole Ammerpohl111,112, Matthew J. Anderson113, Yeng Ang114, Davide Antonello115, Pavana Anur22, Samuel Aparicio116, Elizabeth L. Appelbaum1,117, Yasuhito Arai118, Axel Aretz119, Koji Arihiro93, Shun-ichi Ariizumi120, Joshua Armenia121, Laurent Arnould122, Sylvia Asa123,124, Yassen Assenov125, Gurnit Atwal6,126,127, Sietse Aukema112,128, J. Todd Auman129, Miriam R. Aure130, Philip Awadalla6,126, Marta Aymerich131, Gary D. Bader126, Adrian Baez-Ortega132, Matthew H. Bailey1,2,3, Peter J. Bailey133, Miruna Balasundaram30, Saianand Balu134, Pratiti Bandopadhayay8,135,136, Rosamonde E. Banks137, Stefano Barbi138, Andrew P. Barbour139,140, Jonathan Barenboim6, Jill Barnholtz-Sloan141,142, Hugh Barr143, Elisabet Barrera59, John Bartlett98,144, Javier Bartolome57, Claudio Bassi115, Oliver F. Bathe145,146, Daniel Baumhoer147, Prashant Bavi148, Stephen B. Baylin149,150, Wojciech Bazant59, Duncan Beardsmore151, Timothy A. Beck152,153, Sam Behjati49, Andreas Behren154, Beifang Niu35, Cindy Bell155, Sergi Beltran52,61, Christopher Benz156, Andrew Berchuck157, Anke K. Bergmann158, Erik N. Bergstrom101,102, Benjamin P. Berman159,160,161, Daniel M. Berney162, Stephan H. Bernhart163,164,165, Rameen Beroukhim8,14,82, Mario Berrios166, Samantha Bersani167, Johanna Bertl73,168, Miguel Betancourt169, Vinayak Bhandari6,44, Shriram G. Bhosle49, Andrew V. Biankin133,170,171,172, Matthias Bieg42,43, Darell Bigner173, Hans Binder163,164, Ewan Birney59, Michael Birrer72, Nidhan K. Biswas174, Bodil Bjerkehagen147,175, Tom Bodenheimer134, Lori Boice176, Giada Bonizzato177, Johann S. De Bono178, Arnoud Boot179,180, Moiz S. Bootwalla166, Ake Borg181, Arndt Borkhardt182, Keith A. Boroevich183,184, Ivan Borozan6, Christoph Borst185, Marcus Bosenberg186, Mattia Bosio52,53,57, Jacqueline Boultwood187, Guillaume Bourque188,189, Paul C. Boutros6,44,45,46, G. Steven Bova190, David T. Bowen49,191, Reanne Bowlby30, David D. L. Bowtell103, Sandrine Boyault192, Rich Boyce59, Jeffrey Boyd193, Alvis Brazma59, Paul Brennan194, Daniel S. Brewer195,196, Arie B. Brinkman197, Robert G. Bristow44,198,199,200,201, Russell R. Broaddus99, Jane E. Brock202, Malcolm Brock203, Annegien Broeks204, Angela N. Brooks8,24,37,82, Denise Brooks30, Benedikt Brors67,205,206, Søren Brunak207,208, Timothy J. C. Bruxner113,209, Alicia L. Bruzos104,105,106, Alex Buchanan9, Ivo Buchhalter43,47,48, Christiane Buchholz210, Susan Bullman8,82, Hazel Burke211, Birgit Burkhardt212, Kathleen H. Burns213,214, John Busanovich8,215, Carlos D. Bustamante216,217, Adam P. Butler49, Atul J. Butte218, Niall J. Byrne76, Anne-Lise Børresen-Dale130,219, Samantha J. Caesar-Johnson220, Andy Cafferkey59, Declan Cahill221, Claudia Calabrese59,60, Carlos Caldas222,223, Fabien Calvo224, Niedzica Camacho178, Peter J. Campbell49,225, Elias Campo226,227, Cinzia Cantù177, Shaolong Cao21, Thomas E. Carey228, Joana Carlevaro-Fita229,230,231, Rebecca Carlsen30, Ivana Cataldo167,177, Mario Cazzola232, Jonathan Cebon154, Robert Cerfolio233, Dianne E. Chadwick234, Dimple Chakravarty235, Don Chalmers236, Calvin Wing Yiu Chan47,237, Kin Chan238, Michelle Chan-Seng-Yue148, Vishal S. Chandan239, David K. Chang133,170, Stephen J. Chanock240, Lorraine A. Chantrill170,241, Aurélien Chateigner76,242, Nilanjan Chatterjee149,243, Kazuaki Chayama93, Hsiao-Wei Chen114,121, Jieming Chen218, Ken Chen50, Yiwen Chen21, Zhaohong Chen244, Andrew D. Cherniack8,82, Jeremy Chien245, Yoke-Eng Chiew246,247, Suet-Feung Chin222,223, Juok Cho8, Sunghoon Cho248, Jung Kyoon Choi249, Wan Choi250, Christine Chomienne251, Zechen Chong51, Su Pin Choo252, Angela Chou170,246, Angelika N. Christ113, Elizabeth L. Christie103, Eric Chuah30, Carrie Cibulskis8, Kristian Cibulskis8, Sara Cingarlini253, Peter Clapham49, Alexander Claviez254, Sean Cleary148,255, Nicole Cloonan256, Marek Cmero257,258,259, Colin C. Collins62, Ashton A. Connor255,260, Susanna L. Cooke133, Colin S. Cooper178,196,261, Leslie Cope149, Vincenzo Corbo138,177, Matthew G. Cordes1,262, Stephen M. Cordner263, Isidro Cortés-Ciriano264,265,266, Kyle Covington12,23, Prue A. Cowin267, Brian Craft24, David Craft8,268, Chad J. Creighton269, Yupeng Cun270, Erin Curley271, Ioana Cutcutache179,180, Karolina Czajka272, Bogdan Czerniak99,273, Rebecca A. Dagg274, Ludmila Danilova149, Maria Vittoria Davi275, Natalie R. Davidson276,277,278,279,280, Helen Davies49,281,282, Ian J. Davis283, Brandi N. Davis-Dusenbery284, Kevin J. Dawson49, Francisco M. De La Vega216,217,285, Ricardo De Paoli-Iseppi211, Timothy Defreitas8, Angelo P. Dei Tos286, Olivier Delaneau287,288,289, John A. Demchok220, Jonas Demeulemeester290,291, German M. Demidov52,53,74, Deniz Demircioğlu292,293, Nening M. Dennis221, Robert E. Denroche148, Stefan C. Dentro49,290,294, Nikita Desai76, Vikram Deshpande72, Amit G. Deshwar295, Christine Desmedt296,297, Jordi Deu-Pons298,299, Noreen Dhalla30, Neesha C. Dhani300, Priyanka Dhingra301,302, Rajiv Dhir303, Anthony DiBiase304, Klev Diamanti305, Li Ding1,2,3,20, Shuai Ding306, Huy Q. Dinh159, Luc Dirix307, HarshaVardhan Doddapaneni12, Nilgun Donmez62,78, Michelle T. Dow244, Ronny Drapkin308, Oliver Drechsel52,53, Ruben M. Drews223, Serge Serge49, Tim Dudderidge150,221, Ana Dueso-Barroso57, Andrew J. Dunford8, Michael Dunn309, Lewis Jonathan Dursi6,7, Fraser R. Duthie133,310, Ken Dutton-Regester311, Jenna Eagles272, Douglas F. Easton312,313, Stuart Edmonds314, Paul A. Edwards223,315, Sandra E. Edwards178, Rosalind A. Eeles178,221, Anna Ehinger316, Juergen Eils54,55, Roland Eils47,48,54,55, Adel El-Naggar99,273, Matthew Eldridge223, Kyle Ellrott9, Serap Erkek60, Georgia Escaramis53,317,318, Shadrielle M. G. Espiritu6, Xavier Estivill53,319, Dariush Etemadmoghadam103, Jorunn E. Eyfjord320, Bishoy M. Faltas280, Daiming Fan321, Yu Fan21, William C. Faquin72, Claudiu Farcas244, Matteo Fassan322, Aquila Fatima323, Francesco Favero324, Nodirjon Fayzullaev76, Ina Felau220, Sian Fereday103, Martin L. Ferguson325, Vincent Ferretti76,326, Lars Feuerbach205, Matthew A. Field327, J. Lynn Fink57,113, Gaetano Finocchiaro328, Cyril Fisher221, Matthew W. Fittall290, Anna Fitzgerald329, Rebecca C. Fitzgerald282, Adrienne M. Flanagan330, Neil E. Fleshner331, Paul Flicek59, John A. Foekens332, Kwun M. Fong333, Nuno A. Fonseca59,334, Christopher S. Foster335,336, Natalie S. Fox6, Michael Fraser6, Scott Frazer8, Milana Frenkel-Morgenstern337, William Friedman338, Joan Frigola298, Catrina C. Fronick1,262, Akihiro Fujimoto184, Masashi Fujita184, Masashi Fukayama339, Lucinda A. Fulton1 , Robert S. Fulton1,3,20, Mayuko Furuta184, P. Andrew Futreal340, Anja Füllgrabe59, Stacey B. Gabriel8, Steven Gallinger148,255,260, Carlo Gambacorti-Passerini341, Jianjiong Gao121, Shengjie Gao56, Levi Garraway82, Øystein Garred342, Erik Garrison49, Dale W. Garsed103, Nils Gehlenborg8,343, Josep L. l. Gelpi57,58, Joshy George110, Daniela S. Gerhard344, Clarissa Gerhauser345, Jeffrey E. Gershenwald346,347, Mark B. Gerstein5,18,19, Moritz Gerstung59,60, Gad Getz8,14,15,16, Mohammed Ghori49, Ronald Ghossein348, Nasra H. Giama349, Richard A. Gibbs12, Anthony J. Gill170,350, Pelvender Gill351, Dilip D. Giri348, Dominik Glodzik49, Vincent J. Gnanapragasam352,353, Maria Elisabeth Goebler354, Mary J. Goldman24, Carmen Gomez355, Santiago Gonzalez59,60, Abel Gonzalez-Perez298,299,356, Dmitry A. Gordenin357, James Gossage358, Kunihito Gotoh359, Ramaswamy Govindan3, Dorthe Grabau360, Janet S. Graham133,361, Robert C. Grant148,260, Anthony R. Green315, Eric Green27, Liliana Greger59, Nicola Grehan282, Sonia Grimaldi177, Sean M. Grimmond362, Robert L. Grossman363, Adam Grundhoff97,364, Gunes Gundem88, Qianyun Guo75, Manaswi Gupta8, Shailja Gupta365, Ivo G. Gut52,61, Marta Gut52,61, Jonathan Göke292,366, Gavin Ha8, Andrea Haake111, David Haan37, Siegfried Haas185, Kerstin Haase290, James E. Haber367, Nina Habermann60, Faraz Hach62,63, Syed Haider6, Natsuko Hama118, Freddie C. Hamdy351, Anne Hamilton267, Mark P. Hamilton368, Leng Han369, George B. Hanna370, Martin Hansmann371, Nicholas J. Haradhvala8,72, Olivier Harismendy102,372, Ivon Harliwong113, Arif O. Harmanci5,373, Eoghan Harrington374, Takanori Hasegawa375, David Haussler24,25, Steve Hawkins223, Shinya Hayami376, Shuto Hayashi375, D. Neil Hayes134,377,378, Stephen J. Hayes379,380, Nicholas K. Hayward211,311, Steven Hazell221, Yao He381, Allison P. Heath382, Simon C. Heath52,61, David Hedley300, Apurva M. Hegde38, David I. Heiman8, Michael C. Heinold47,48, Zachary Heins88, Lawrence E. Heisler152, Eva Hellstrom-Lindberg383, Mohamed Helmy384, Seong Gu Heo385, Austin J. Hepperla134, José María Heredia-Genestar386, Carl Herrmann47,48,387, Peter Hersey211, Julian M. Hess8,26, Holmfridur Hilmarsdottir320, Jonathan Hinton49, Satoshi Hirano388, Nobuyoshi Hiraoka389, Katherine A. Hoadley134,390, Asger Hobolth75,168, Ermin Hodzic78, Jessica I. Hoell182, Steve Hoffmann163,164,165,391, Oliver Hofmann392, Andrea Holbrook166, Aliaksei Z. Holik53, Michael A. Hollingsworth393, Oliver Holmes209,311, Robert A. Holt30, Chen Hong205,237, Eun Pyo Hong385, Jongwhi H. Hong394, Gerrit K. Hooijer395, Henrik Hornshøj73, Fumie Hosoda118, Yong Hou56,396, Volker Hovestadt397, William Howat352, Alan P. Hoyle134, Ralph H. Hruban149, Jianhong Hu12, Taobo Hu64, Xing Hua240, Kuan-lin Huang1,398, Mei Huang176, Mi Ni Huang179,180, Vincent Huang6, Yi Huang65,66, Wolfgang Huber60, Thomas J. Hudson272,399, Michael Hummel400, Jillian A. Hung246,247, David Huntsman401, Ted R. Hupp402, Jason Huse88, Matthew R. Huska403, Barbara Hutter43,67,68, Carolyn M. Hutter27, Daniel Hübschmann48,54,404,405,406, Christine A. Iacobuzio-Donahue348, Charles David Imbusch205, Marcin Imielinski407,408, Seiya Imoto375, William B. Isaacs409, Keren Isaev6,44, Shumpei Ishikawa410, Murat Iskar397, S. M. Ashiqul Islam244, Michael Ittmann411,412,413, Sinisa Ivkovic284, Jose M. G. Izarzugaza414, Jocelyne Jacquemier415, Valerie Jakrot211, Nigel B. Jamieson133,172,416, Gun Ho Jang148, Se Jin Jang417, Joy C. Jayaseelan12, Reyka Jayasinghe1 , Stuart R. Jefferys134, Karine Jegalian418, Jennifer L. Jennings419, Seung-Hyup Jeon250, Lara Jerman60,420, Yuan Ji421,422, Wei Jiao6, Peter A. Johansson311, Amber L. Johns170, Jeremy Johns272, Rory Johnson230,423, Todd A. Johnson183, Clemency Jolly290, Yann Joly424, Jon G. Jonasson320, Corbin D. Jones425, David R. Jones49, David T. W. Jones426,427, Nic Jones428, Steven J. M. Jones30, Jos Jonkers204, Young Seok Ju49,249, Hartmut Juhl429, Jongsun Jung69, Malene Juul73, Randi Istrup Juul73, Sissel Juul374, Natalie Jäger47, Rolf Kabbe47, Andre Kahles276,277,278,279,430, Abdullah Kahraman431,432,433, Vera B. Kaiser434, Hojabr Kakavand211, Sangeetha Kalimuthu148, Christof von Kalle405, Koo Jeong Kang91, Katalin Karaszi351, Beth Karlan435, Rosa Karlić436, Dennis Karsch437, Katayoon Kasaian29,30, Karin S. Kassahn113,438, Hitoshi Katai439, Mamoru Kato440, Hiroto Katoh410, Yoshiiku Kawakami93, Jonathan D. Kay117, Stephen H. Kazakoff209,311, Marat D. Kazanov441,442,443, Maria Keays59, Electron Kebebew444,445, Richard F. Kefford446, Manolis Kellis8,447, James G. Kench170,350,448, Catherine J. Kennedy246,247, Jules N. A. Kerssemakers47, David Khoo273, Vincent Khoo221, Narong Khuntikeo115,449, Ekta Khurana301,302,450,451, Helena Kilpinen117, Hark Kyun Kim452, Hyung-Lae Kim70, Hyung-Yong Kim415, Hyunghwan Kim250, Jaegil Kim8, Jihoon Kim453, Jong K. Kim454, Youngwook Kim455,456, Tari A. King457,458,459, Wolfram Klapper128, Kortine Kleinheinz47,48, Leszek J. Klimczak460, Stian Knappskog49,461, Michael Kneba437, Bartha M. Knoppers424, Youngil Koh462,463, Jan Komorowski305,464, Daisuke Komura410, Mitsuhiro Komura375, Gu Kong415, Marcel Kool426,465, Jan O. Korbel59,60, Viktoriya Korchina12, Andrey Korshunov465, Michael Koscher465, Roelof Koster466, Zsofia Kote-Jarai178, Antonios Koures244, Milena Kovacevic284, Barbara Kremeyer49, Helene Kretzmer164,165, Markus Kreuz467, Savitri Krishnamurthy99,468, Dieter Kube469, Kiran Kumar8, Pardeep Kumar221, Sushant Kumar5,19, Yogesh Kumar64, Ritika Kundra114,121, Kirsten Kübler8,14,72, Ralf Küppers470, Jesper Lagergren383,471, Phillip H. Lai166, Peter W. Laird472, Sunil R. Lakhani473, Christopher M. Lalansingh6, Emilie Lalonde6, Fabien C. Lamaze6, Adam Lambert351, Eric Lander8, Pablo Landgraf474,475, Luca Landoni115, Anita Langerød130, Andrés Lanzós230,231,423, Denis Larsimont476, Erik Larsson477, Mark Lathrop189, Loretta M. S. Lau478, Chris Lawerenz55, Rita T. Lawlor177, Michael S. Lawrence8,72,183, Alexander J. Lazar99,108, Xuan Le479, Darlene Lee30, Donghoon Lee5, Eunjung Alice Lee480, Hee Jin Lee417, Jake June-Koo Lee264,266, Jeong-Yeon Lee481, Juhee Lee482, Ming Ta Michael Lee340, Henry Lee-Six49, Kjong-Van Lehmann276,277,278,279,430, Hans Lehrach483, Dido Lenze400, Conrad R. Leonard209,311, Daniel A. Leongamornlert49,178, Ignaty Leshchiner8, Louis Letourneau484, Ivica Letunic71, Douglas A. Levine88,485, Lora Lewis12, Tim Ley486, Chang Li56,396, Constance H. Li6,44, Haiyan Irene Li30, Jun Li21, Lin Li56, Shantao Li5, Siliang Li56,396, Xiaobo Li56,396, Xiaotong Li5, Xinyue Li56, Yilong Li49, Han Liang21, Sheng-Ben Liang234, Peter Lichter68,397, Pei Lin8, Ziao Lin8,487, W. M. Linehan488, Ole Christian Lingjærde489, Dongbing Liu56,396, Eric Minwei Liu88,301,302, Fei-Fei Liu201,490, Fenglin Liu381,491, Jia Liu492, Xingmin Liu56,396, Julie Livingstone6, Dimitri Livitz8, Naomi Livni221, Lucas Lochovsky5,19,110, Markus Loeffler467, Georgina V. Long211, Armando Lopez-Guillermo493, Shaoke Lou5,19, David N. Louis72, Laurence B. Lovat117, Yiling Lu38, Yong-Jie Lu162,494, Youyong Lu495,496,497, Claudio Luchini167, Ilinca Lungu144,148, Xuemei Luo152, Hayley J. Luxton117, Andy G. Lynch223,315,498, Lisa Lype36, Cristina López111,112, Carlos López-Otín499, Eric Z. Ma64, Yussanne Ma30, Gaetan MacGrogan500, Shona MacRae501, Geoff Macintyre223, Tobias Madsen73, Kazuhiro Maejima184, Andrea Mafficini177, Dennis T. Maglinte166,502, Arindam Maitra174, Partha P. Majumder174, Luca Malcovati232, Salem Malikic62,78, Giuseppe Malleo115, Graham J. Mann211,246,503, Luisa Mantovani-Löffler504, Kathleen Marchal505,506, Giovanni Marchegiani115, Elaine R. Mardis1,193,507, Adam A. Margolin31, Maximillian G. Marin37, Florian Markowetz223,315, Julia Markowski403, Jeffrey Marks508, Tomas Marques-Bonet61,81,386,509, Marco A. Marra30, Luke Marsden351, John W. M. Martens332, Sancha Martin49,510, Jose I. Martin-Subero81,511, Iñigo Martincorena49, Alexander Martinez-Fundichely301,302,451 Yosef E. Maruvka8,26,72, R. Jay Mashl1,2, Charlie E. Massie223, Thomas J. Matthew37, Lucy Matthews178, Erik Mayer221,512, Simon Mayes513, Michael Mayo30, Faridah Mbabaali272, Karen McCune514, Ultan McDermott49, Patrick D. McGillivray19, Michael D. McLellan1,3,20, John D. McPherson148,272,515, John R. McPherson179,180, Treasa A. McPherson260, Samuel R. Meier8, Alice Meng516, Shaowu Meng134, Andrew Menzies49, Neil D. Merrett115,517, Sue Merson178, Matthew Meyerson8,14,82, William U. Meyerson4,5, Piotr A. Mieczkowski518, George L. Mihaiescu76, Sanja Mijalkovic284, Ana Mijalkovic Mijalkovic-Lazic284, Tom Mikkelsen519, Michele Milella253, Linda Mileshkin103, Christopher A. Miller1 , David K. Miller113,170, Jessica K. Miller272, Gordon B. Mills33,34, Ana Milovanovic57, Sarah Minner520, Marco Miotto115, Gisela Mir Arnau267, Lisa Mirabello240, Chris Mitchell103, Thomas J. Mitchell49,315,352, Satoru Miyano375, Naoki Miyoshi375, Shinichi Mizuno521, Fruzsina Molnár-Gábor522, Malcolm J. Moore300, Richard A. Moore30, Sandro Morganella49, Quaid D. Morris127,490, Carl Morrison523,524, Lisle E. Mose134, Catherine D. Moser349, Ferran Muiños298,299, Loris Mularoni298,299, Andrew J. Mungall30, Karen Mungall30, Elizabeth A. Musgrove133, Ville Mustonen525,526,527, David Mutch528, Francesc Muyas52,53,74, Donna M. Muzny12, Alfonso Muñoz59, Jerome Myers529, Ola Myklebost461, Peter Möller530, Genta Nagae89, Adnan M. Nagrial170, Hardeep K. Nahal-Bose76, Hitoshi Nakagama531, Hidewaki Nakagawa184, Hiromi Nakamura118, Toru Nakamura388, Kaoru Nakano184, Tannistha Nandi532, Jyoti Nangalia49, Mia Nastic284, Arcadi Navarro61,81,386, Fabio C. P. Navarro19, David E. Neal223,352, Gerd Nettekoven533, Felicity Newell209,311, Steven J. Newhouse59, Yulia Newton37, Alvin Wei Tian Ng534, Anthony Ng535, Jonathan Nicholson49, David Nicol221, Yongzhan Nie321,536, G. Petur Nielsen72, Morten Muhlig Nielsen73, Serena Nik-Zainal49,281,282,537, Michael S. Noble8, Katia Nones209,311, Paul A. Northcott538, Faiyaz Notta148,539, Brian D. O’Connor76,540, Peter O’Donnell541, Maria O’Donovan282, Sarah O’Meara49, Brian Patrick O’Neill542, J. Robert O’Neill543, David Ocana59, Angelica Ochoa88, Layla Oesper544, Christopher Ogden221, Hideki Ohdan93, Kazuhiro Ohi375, Lucila Ohno-Machado244, Karin A. Oien523,545, Akinyemi I. Ojesina546,547,548, Hidenori Ojima549, Takuji Okusaka550, Larsson Omberg551, Choon Kiat Ong552, Stephan Ossowski52,53,74, German Ott553, B. F. Francis Ouellette76,554, Christine P’ng6, Marta Paczkowska6, Salvatore Paiella115, Chawalit Pairojkul523, Marina Pajic170, Qiang Pan-Hammarström56,555, Elli Papaemmanuil49, Irene Papatheodorou59, Nagarajan Paramasivam43,47, Ji Wan Park385, Joong-Won Park556, Keunchil Park557,558, Kiejung Park559, Peter J. Park264,266, Joel S. Parker518, Simon L. Parsons124, Harvey Pass560, Danielle Pasternack272, Alessandro Pastore276, Ann-Marie Patch209,311, Iris Pauporté251, Antonio Pea115, John V. Pearson209,311, Chandra Sekhar Pedamallu8,14,82, Jakob Skou Pedersen73,75, Paolo Pederzoli115, Martin Peifer270, Nathan A. Pennell561, Charles M. Perou129,518, Marc D. Perry76,77, Gloria M. Petersen562, Myron Peto22, Nicholas Petrelli563, Robert Petryszak59, Stefan M. Pfister426,465,564, Mark Phillips424, Oriol Pich298,299, Hilda A. Pickett478, Todd D. Pihl565, Nischalan Pillay566, Sarah Pinder567, Mark Pinese170, Andreia V. Pinho568, Esa Pitkänen60, Xavier Pivot569, Elena Piñeiro-Yáñez95, Laura Planko533, Christoph Plass345, Paz Polak8,14,15, Tirso Pons570, Irinel Popescu571, Olga Potapova572, Aparna Prasad52, Shaun R. Preston573, Manuel Prinz47, Antonia L. Pritchard311, Stephenie D. Prokopec6, Elena Provenzano574, Xose S. Puente499, Sonia Puig176, Montserrat Puiggròs57, Sergio Pulido-Tamayo505,506, Gulietta M. Pupo246, Colin A. Purdie575, Michael C. Quinn209,311, Raquel Rabionet52,53,576, Janet S. Rader577, Bernhard Radlwimmer397, Petar Radovic284, Benjamin Raeder60, Keiran M. Raine49, Manasa Ramakrishna49, Kamna Ramakrishnan49, Suresh Ramalingam578, Benjamin J. Raphael579, W. Kimryn Rathmell580, Tobias Rausch60, Guido Reifenberger475, Jüri Reimand6,44, Jorge Reis-Filho348, Victor Reuter348, Iker Reyes-Salazar298, Matthew A. Reyna579, Sheila M. Reynolds36, Esther Rheinbay8,14,72, Yasser Riazalhosseini189, Andrea L. Richardson323, Julia Richter111,128, Matthew Ringel581, Markus Ringnér181, Yasushi Rino582, Karsten Rippe405, Jeffrey Roach583, Lewis R. Roberts349, Nicola D. Roberts49, Steven A. Roberts584, A. Gordon Robertson30, Alan J. Robertson113, Javier Bartolomé Rodriguez57, Bernardo Rodriguez-Martin104,105,106, F. Germán Rodríguez-González83,332, Michael H. A. Roehrl44,123,148,234,585,586, Marius Rohde587, Hirofumi Rokutan440, Gilles Romieu588, Ilse Rooman170, Tom Roques262, Daniel Rosebrock8, Mara Rosenberg8,72, Philip C. Rosenstiel589, Andreas Rosenwald590, Edward W. Rowe221,591, Romina Royo57, Steven G. Rozen179,180,592, Yulia Rubanova17,127, Mark A. Rubin423,593,594,595,596, Carlota Rubio-Perez298,299,597, Vasilisa A. Rudneva60, Borislav C. Rusev177, Andrea Ruzzenente598, Gunnar Rätsch276,277,278,279,280,430, Radhakrishnan Sabarinathan298,299,599, Veronica Y. Sabelnykova6, Sara Sadeghi30, S. Cenk Sahinalp62,78,79, Natalie Saini357, Mihoko Saito-Adachi440, Gordon Saksena8, Adriana Salcedo6, Roberto Salgado600, Leonidas Salichos5,19, Richard Sallari8, Charles Saller601, Roberto Salvia115, Michelle Sam272, Jaswinder S. Samra115,602, Francisco Sanchez-Vega114,121, Chris Sander276,603,604, Grant Sanders134, Rajiv Sarin605, Iman Sarrafi62,78, Aya Sasaki-Oku184, Torill Sauer489, Guido Sauter520, Robyn P. M. Saw211, Maria Scardoni167, Christopher J. Scarlett170,606, Aldo Scarpa177, Ghislaine Scelo194, Dirk Schadendorf68,607, Jacqueline E. Schein30, Markus B. Schilhabel589, Matthias Schlesner47,80, Thorsten Schlomm84,608, Heather K. Schmidt1 , Sarah-Jane Schramm246, Stefan Schreiber609, Nikolaus Schultz121, Steven E. Schumacher8,323, Roland F. Schwarz59,403,405,610, Richard A. Scolyer211,448,602, David Scott428, Ralph Scully611, Raja Seethala612, Ayellet V. Segre8,613, Iris Selander260, Colin A. Semple434, Yasin Senbabaoglu276, Subhajit Sengupta614, Elisabetta Sereni115, Stefano Serra585, Dennis C. Sgroi72, Mark Shackleton103, Nimish C. Shah352, Sagedeh Shahabi234, Catherine A. Shang329, Ping Shang211, Ofer Shapira8,323, Troy Shelton271, Ciyue Shen603,604, Hui Shen615, Rebecca Shepherd49, Ruian Shi490, Yan Shi134, Yu-Jia Shiah6, Tatsuhiro Shibata118,616, Juliann Shih8,82, Eigo Shimizu375, Kiyo Shimizu617, Seung Jun Shin618, Yuichi Shiraishi375, Tal Shmaya285, Ilya Shmulevich36, Solomon I. Shorser6, Charles Short59, Raunak Shrestha62, Suyash S. Shringarpure217, Craig Shriver619, Shimin Shuai6,126, Nikos Sidiropoulos83, Reiner Siebert112,620, Anieta M. Sieuwerts332, Lina Sieverling205,237, Sabina Signoretti202,621, Katarzyna O. Sikora177, Michele Simbolo138, Ronald Simon520, Janae V. Simons134, Jared T. Simpson6,17, Peter T. Simpson473, Samuel Singer115,458, Nasa Sinnott-Armstrong8,217, Payal Sipahimalani30, Tara J. Skelly390, Marcel Smid332, Jaclyn Smith622, Karen Smith-McCune514, Nicholas D. Socci276, Heidi J. Sofia27, Matthew G. Soloway134, Lei Song240, Anil K. Sood623,624,625, Sharmila Sothi626, Christos Sotiriou244, Cameron M. Soulette37, Paul N. Span627, Paul T. Spellman22, Nicola Sperandio177, Andrew J. Spillane211, Oliver Spiro8, Jonathan Spring628, Johan Staaf181, Peter F. Stadler163,164,165, Peter Staib629, Stefan G. Stark277,279,618,630, Lucy Stebbings49, Ólafur Andri Stefánsson631, Oliver Stegle59,60,632, Lincoln D. Stein6,126, Alasdair Stenhouse633, Chip Stewart8, Stephan Stilgenbauer634, Miranda D. Stobbe52,61, Michael R. Stratton49, Jonathan R. Stretch211, Adam J. Struck31, Joshua M. Stuart24,37, Henk G. Stunnenberg396,635, Hong Su56,396, Xiaoping Su99, Ren X. Sun6, Stephanie Sungalee60, Hana Susak52,53, Akihiro Suzuki89,636, Fred Sweep637, Monika Szczepanowski128, Holger Sültmann67,638, Takashi Yugawa617, Angela Tam30, David Tamborero298,299, Benita Kiat Tee Tan639, Donghui Tan518, Patrick Tan180,532,592,640, Hiroko Tanaka375, Hirokazu Taniguchi616, Tomas J. Tanskanen641, Maxime Tarabichi49,290, Roy Tarnuzzer220, Patrick Tarpey642, Morgan L. Taschuk152, Kenji Tatsuno89, Simon Tavaré223,643, Darrin F. Taylor113, Amaro Taylor-Weiner8, Jon W. Teague49, Bin Tean Teh180,592,640,644,645, Varsha Tembe246, Javier Temes104,105, Kevin Thai76, Sarah P. Thayer393, Nina Thiessen30, Gilles Thomas646, Sarah Thomas221, Alan Thompson221, Alastair M. Thompson633, John F. Thompson211, R. Houston Thompson647, Heather Thorne103, Leigh B. Thorne176, Adrian Thorogood424, Grace Tiao8, Nebojsa Tijanic284, Lee E. Timms272, Roberto Tirabosco648, Marta Tojo106, Stefania Tommasi649, Christopher W. Toon170, Umut H. Toprak48,650, David Torrents57,81, Giampaolo Tortora651,652, Jörg Tost653, Yasushi Totoki118, David Townend654, Nadia Traficante103, Isabelle Treilleux655,656, Jean-Rémi Trotta61, Lorenz H. P. Trümper469, Ming Tsao124,539, Tatsuhiko Tsunoda183,657,658,659, Jose M. C. Tubio104,105,106, Olga Tucker660, Richard Turkington661, Daniel J. Turner513, Andrew Tutt323, Masaki Ueno376, Naoto T. Ueno662, Christopher Umbricht151,213,663, Husen M. Umer305,664, Timothy J. Underwood665, Lara Urban59,60, Tomoko Urushidate616, Tetsuo Ushiku339, Liis Uusküla-Reimand666,667, Alfonso Valencia57,81, David J. Van Den Berg166, Steven Van Laere307, Peter Van Loo290,291, Erwin G. Van Meir668, Gert G. Van den Eynden307, Theodorus Van der Kwast123, Naveen Vasudev137, Miguel Vazquez57,669, Ravikiran Vedururu267, Umadevi Veluvolu518, Shankar Vembu490,670, Lieven P. C. Verbeke506,671, Peter Vermeulen307, Clare Verrill351,672, Alain Viari177, David Vicente57, Caterina Vicentini177, K. Vijay Raghavan365, Juris Viksna673, Ricardo E. Vilain674, Izar Villasante57, Anne Vincent-Salomon635, Tapio Visakorpi190, Douglas Voet8, Paresh Vyas311,351, Ignacio Vázquez-García49,86,675,676, Nick M. Waddell209, Nicola Waddell209,311, Claes Wadelius677, Lina Wadi6, Rabea Wagener111,112, Jeremiah A. Wala8,14,82, Jian Wang56, Jiayin Wang1,40,66, Linghua Wang12, Qi Wang465, Wenyi Wang21, Yumeng Wang21, Zhining Wang220, Paul M. Waring523, Hans-Jörg Warnatz483, Jonathan Warrell5,19, Anne Y. Warren352,678, Sebastian M. Waszak60, David C. Wedge49,294,679, Dieter Weichenhan345, Paul Weinberger680, John N. Weinstein38, Joachim Weischenfeldt60,83,84, Daniel J. Weisenberger166, Ian Welch681, Michael C. Wendl1,10,11, Johannes Werner47,85, Justin P. Whalley61,682, David A. Wheeler12,13, Hayley C. Whitaker117, Dennis Wigle683, Matthew D. Wilkerson518, Ashley Williams244, James S. Wilmott211, Gavin W. Wilson6,148, Julie M. Wilson148, Richard K. Wilson1,684, Boris Winterhoff685, Jeffrey A. Wintersinger17,127,384, Maciej Wiznerowicz686,687, Stephan Wolf688, Bernice H. Wong689, Tina Wong1,30, Winghing Wong690, Youngchoon Woo250, Scott Wood209,311, Bradly G. Wouters44, Adam J. Wright6, Derek W. Wright133,691, Mark H. Wright217, Chin-Lee Wu72, Dai-Ying Wu285, Guanming Wu692, Jianmin Wu170, Kui Wu56,396, Yang Wu179,180, Zhenggang Wu64, Liu Xi12, Tian Xia693, Qian Xiang76, Xiao Xiao66, Rui Xing497, Heng Xiong56,396, Qinying Xu209,311, Yanxun Xu694, Hong Xue64, Shinichi Yachida118,695, Sergei Yakneen60, Rui Yamaguchi375, Takafumi N. Yamaguchi6, Masakazu Yamamoto120, Shogo Yamamoto89, Hiroki Yamaue376, Fan Yang490, Huanming Yang56, Jean Y. Yang696, Liming Yang220, Lixing Yang697, Shanlin Yang306, Tsun-Po Yang270, Yang Yang369, Xiaotong Yao408,698, Marie-Laure Yaspo483, Lucy Yates49, Christina Yau156, Chen Ye56,396, Kai Ye40,41, Venkata D. Yellapantula20,86, Christopher J. Yoon249, Sung-Soo Yoon463, Fouad Yousif6, Jun Yu699, Kaixian Yu700, Willie Yu701, Yingyan Yu702, Ke Yuan223,510,703, Yuan Yuan21, Denis Yuen6, Takashi Yugawa617, Christina K. Yung76, Olga Zaikova704, Jorge Zamora49,104,105,106, Marc Zapatka397, Jean C. Zenklusen220, Thorsten Zenz67, Nikolajs Zeps705,706, Cheng-Zhong Zhang8,707, Fan Zhang381, Hailei Zhang8, Hongwei Zhang494, Hongxin Zhang121, Jiashan Zhang220, Jing Zhang5, Junjun Zhang76, Xiuqing Zhang56, Xuanping Zhang66,369, Yan Zhang5,708,709, Zemin Zhang381,710, Zhongming Zhao711, Liangtao Zheng381, Xiuqing Zheng381, Wanding Zhou615, Yong Zhou56, Bin Zhu240, Hongtu Zhu700,712, Jingchun Zhu24, Shida Zhu56,396, Lihua Zou713, Xueqing Zou49, Anna deFazio246,247,714, Nicholas van As221, Carolien H. M. van Deurzen715, Marc J. van de Vijver523, L. van’t Veer716 & Christian von Mering433,717, The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.
Published: 2020

11. qpure: A tool to estimate tumor cellularity from genome-wide single-nucleotide polymorphism profiles.

Author: Sarah Song, Katia Nones, David Miller, Ivon Harliwong, Karin S Kassahn, Mark Pinese, Marina Pajic, Anthony J Gill, Amber L Johns, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Qinying Xu, Felicity Newell, Mark J Cowley, Jianmin Wu, Peter Wilson, Lynn Fink, Andrew V Biankin, Nic Waddell, Sean M Grimmond, and John V Pearson
Subjects: Medicine, Science
Abstract: Tumour cellularity, the relative proportion of tumour and normal cells in a sample, affects the sensitivity of mutation detection, copy number analysis, cancer gene expression and methylation profiling. Tumour cellularity is traditionally estimated by pathological review of sectioned specimens; however this method is both subjective and prone to error due to heterogeneity within lesions and cellularity differences between the sample viewed during pathological review and tissue used for research purposes. In this paper we describe a statistical model to estimate tumour cellularity from SNP array profiles of paired tumour and normal samples using shifts in SNP allele frequency at regions of loss of heterozygosity (LOH) in the tumour. We also provide qpure, a software implementation of the method. Our experiments showed that there is a medium correlation 0.42 ([Formula: see text]-value=0.0001) between tumor cellularity estimated by qpure and pathology review. Interestingly there is a high correlation 0.87 ([Formula: see text]-value [Formula: see text] 2.2e-16) between cellularity estimates by qpure and deep Ion Torrent sequencing of known somatic KRAS mutations; and a weaker correlation 0.32 ([Formula: see text]-value=0.004) between IonTorrent sequencing and pathology review. This suggests that qpure may be a more accurate predictor of tumour cellularity than pathology review. qpure can be downloaded from https://sourceforge.net/projects/qpure/.
Published: 2012
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12. Lost in translation: returning germline genetic results in genome-scale cancer research

Author: Hilda High, Jeremy L. Humphris, Lorraine A. Chantrill, Conrad Leonard, Marina Pajic, Annabel Goodwin, Nick Pavlakis, Sean M. Grimmond, Amber L. Johns, Andrew V. Biankin, Jaswinder S. Samra, David Miller, Karin S. Kassahn, Nikolajs Zeps, John V. Pearson, Skye McKay, Anthony J. Gill, Ann-Marie Patch, Mark Pinese, Katia Nones, Lesley Andrews, David K. Chang, Katherine M. Tucker, Nicola Waddell, Neil D. Merrett, and R. Scott Mead
Subjects: Adult, 0301 basic medicine, Candidate gene, lcsh:QH426-470, DNA Mutational Analysis, lcsh:Medicine, Context (language use), Genomics, Return of results, Bioinformatics, Research ethics, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Genetics, Genomic data, Humans, Medicine, Computer Simulation, Genetic Predisposition to Disease, Molecular Biology, Exome, Germ-Line Mutation, Genetics (clinical), Aged, Aged, 80 and over, Whole-genome sequencing, Genome, Human, business.industry, Research, lcsh:R, Australia, Middle Aged, Penetrance, Human genetics, 3. Good health, Pancreatic Neoplasms, lcsh:Genetics, 030104 developmental biology, 030220 oncology & carcinogenesis, Molecular Medicine, business
Abstract: Background The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies. Methods We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium–high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy. Results A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR. Conclusion Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning individual results is currently low. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0430-4) contains supplementary material, which is available to authorized users.
Published: 2017

13. Identification and targeted management of a neurodegenerative disorder caused by biallelic mutations in SLC5A6

Author: Alicia B. Byrne, Peer Arts, Christopher N. Hahn, Steven W. Polyak, Dylan A. Mordaunt, Nicholas J.C. Smith, Hamish S. Scott, Andreas W. Schreiber, Janice M. Fletcher, Drago Bratkovic, Grant W. Booker, Jillian Lipsett, Karin S. Kassahn, Jinghua Feng, Byrne, Alicia B, Arts, Peer, Polyak, Steven W, Feng, Jinghua, Schreiber, Andreas, Kassahn, Karin S, Hahn, Christopher N, Mordaunt, Dylan A, Fletcher, Janice M, Lipsett, Jillian, Bratkovic, Drago, Booker, Grant W, Smith, Nicholas J, and Scott, Hamish S
Subjects: 0301 basic medicine, Vitamin, lcsh:QH426-470, Mutant, Metabolic disorders, lcsh:Medicine, Case Report, Compound heterozygosity, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Biotin, Genetics, medicine, Molecular Biology, Genetics (clinical), Exome sequencing, SLC5A6 mutations, business.industry, lcsh:R, Neurodevelopmental disorders, Genetic disorder, Transporter, Translational research, medicine.disease, Personalized medicine, Phenotype, 3. Good health, lcsh:Genetics, 030104 developmental biology, chemistry, business, neurodegenerative disorder, Medical genomics, 030217 neurology & neurosurgery, biallelic mutations
Abstract: We describe a sibling pair displaying an early infantile-onset, progressive neurodegenerative phenotype, with symptoms of developmental delay and epileptic encephalopathy developing from 12 to 14 months of age. Using whole exome sequencing, compound heterozygous variants were identified in SLC5A6, which encodes the sodium-dependent multivitamin transporter (SMVT) protein. SMVT is an important transporter of the B-group vitamins biotin, pantothenate, and lipoate. The protein is ubiquitously expressed and has major roles in vitamin uptake in the digestive system, as well as transport of these vitamins across the blood–brain barrier. Pathogenicity of the identified variants was demonstrated by impaired biotin uptake of mutant SMVT. Identification of this vitamin transporter as the genetic basis of this disorder guided targeted therapeutic intervention, resulting clinically in improvement of the patient’s neurocognitive and neuromotor function. This is the second report of biallelic mutations in SLC5A6 leading to a neurodegenerative disorder due to impaired biotin, pantothenate and lipoate uptake. The genetic and phenotypic overlap of these cases confirms mutations in SLC5A6 as the genetic cause of this disease phenotype. Recognition of the genetic disorder caused by SLC5A6 mutations is essential for early diagnosis and to facilitate timely intervention by triple vitamin (biotin, pantothenate, and lipoate) replacement therapy.
Published: 2019

14. Review of 12 months of copy number variant calling on a clinical next generation sequencing pipeline

Author: Song Gao, Julien Soubrier, Dylan A. Mordaunt, Janice M. Fletcher, Karin S. Kassahn, Lesley Rawlings, S. Yu, and Jillian Nicholl
Subjects: Computer science, Pipeline (computing), Computational biology, Copy-number variation, DNA sequencing, Pathology and Forensic Medicine
Published: 2020

15. Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

Author: Sylvia Varland, Margaret Yoon, Jill A. Rosenfeld, Alison Gardner, Jennifer S. Beighley, Derek Lim, Ning Ma, Sonal Mahida, Magdalena Walkiewicz, Linyan Meng, Christopher Barnett, Claudia A. L. Ruivenkamp, Tjitske Kleefstra, Corrado Romano, Marie Shaw, Andrea M. Lewis, R. Frank Kooy, Avinash V. Dharmadhikari, Nicolette S. den Hollander, Elizabeth E. Palmer, Anke Van Dijck, Geert Vandeweyer, Emanuela Stracuzzi, Sébastien Küry, Kym M. Boycott, Stefania Giusto, Deepti Domingo, Asbjørg Stray-Pedersen, Fan Xia, Mauro Longoni, Grazia M.S. Mancini, Mohammad K. Eldomery, Yaping Yang, Zeynep Coban Akdemir, Evan E. Eichler, Raphael Bernier, Hanyin Cheng, Rebecca Willaert, Arie van Haeringen, Katherine Agre, Parul Jayakar, Sakkubai Naidu, Jozef Gecz, Lucinda Murray, Samantha K Rojas, Mathilde Nizon, Frances A. High, Joseph C. Wu, Richard E. Person, Gregory M. Cooper, Mark A. Corbett, Karin S. Kassahn, Thomas Arnesen, Rolph Pfundt, Erin Conboy, Vernon R. Sutton, Bronwyn Kerr, Holly A.F. Stessman, Ruth Armstrong, Sarah R. Crews, Marjon van Slegtenhorst, Jennifer E. Posey, James R. Lupski, Wendy K. Chung, Alan F. Rope, Jolanda H. Schieving, Robert Kleyner, Michael Parker, Gholson J. Lyon, Candice R. Finnila, Marjolijn J. Jongmans, Bert B.A. de Vries, and Clinical Genetics
Subjects: Male, 0301 basic medicine, Autism Spectrum Disorder, Messenger, N-terminal acetyltransferases (NATs), Neurodevelopmental disorder, Intellectual disability, N-terminal acetylation (NTA), Missense mutation, N-Terminal Acetyltransferase E, Child, N-Terminal Acetyltransferase A, Genetics (clinical), Genetics, Exons, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], congenital heart defects, Pedigree, Phenotype, Autism spectrum disorder, Female, Abnormalities, Haploinsufficiency, Multiple, Ogden syndrome, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, Adolescent, autism, Saccharomyces cerevisiae, Biology, Cell Line, 03 medical and health sciences, Report, Intellectual Disability, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, RNA, Messenger, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genetic Variation, medicine.disease, neurodevelopmental disorder, Ogden Syndrome, 030104 developmental biology, NAA10, Gene Expression Regulation, NatA complex, Mutation, RNA, Autism, Human medicine, NAA15
Abstract: Item does not contain fulltext N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.
Published: 2018

16. Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance

Author: Mythily Mariasegaram, Ann-Marie Patch, Conrad Leonard, Admire Matsika, Sean M. Grimmond, Fares Al-Ejeh, Margaret C. Cummings, Rosalind L. Jeffree, Georgia Chenevix-Trench, Oliver Holmes, Leonard Da Silva, Nur Aishah Taib, Adrienne M. Flanagan, Teresa K. Withers, Matthew J. Anderson, Vairavan Narayanan, Ehsan Nourbakhsh, Queenie Lau, Sunil R. Lakhani, J. Lynn Fink, kConFab, Felicity Newell, Katia Nones, Stephen H. Kazakoff, Colleen Niland, Parmjit S. Jat, Ivon Harliwong, Peter T. Simpson, Lynne Reid, Nicola Waddell, Soo Hwang Teo, Karin S. Kassahn, Sebastian Brandner, John V. Pearson, Nick Waddell, Qinying Xu, Scott Wood, Darrin Taylor, Senel Idrisoglu, Peter Wilson, Timothy J. C. Bruxner, Kum Kum Khanna, Craig Nourse, Shivangi Wani, Angelika N. Christ, David Miller, Amy E. McCart Reed, Michael C.J. Quinn, Yock Ping Chow, Jodi M. Saunus, Suzanne Manning, and Peter Bailey
Subjects: medicine.medical_treatment, Cancer, Genomic signature, Biology, medicine.disease, Bioinformatics, Pathology and Forensic Medicine, Targeted therapy, Gene expression profiling, Breast cancer, ErbB, medicine, Cancer research, skin and connective tissue diseases, Exome, Brain metastasis
Abstract: Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2) = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.
Published: 2015

17. Hypermutation In Pancreatic Cancer

Author: Borislav Rusev, Krishna Epari, Peter Bailey, Christopher J. Scarlett, Suzanne Manning, Marina Pajic, Conrad Leonard, Skye McKay, Michael C.J. Quinn, Oliver Hofmann, Margaret A. Tempero, Anthony J. Gill, Nikolajs Zeps, Marc Giry-Laterriere, James G. Kench, Christian Pilarsky, Karin A. Oien, Christine A. Iacobuzio-Donahue, Jennifer P. Morton, Janet Graham, Ilse Rooman, Ehsan Nourbakhsh, Euan J. Dickson, Felicity Newell, Ann-Marie Patch, Sean M. Grimmond, Amber L. Johns, Mark J. Cowley, Timothy J. C. Bruxner, C. Ross Carter, Ivana Cataldo, Rita T. Lawlor, Andrew V. Biankin, David K. Chang, Peter J. Wilson, Christopher L. Wolfgang, Mark Pinese, Roberto Salvia, Karin S. Kassahn, Ralph H. Hruban, Richard D. Schulick, Adnan Nagrial, David Miller, Elizabeth A. Musgrove, Venessa T. Chin, Owen J. Sansom, Ronald S Mead, Angela Chou, Nam Q. Nguyen, J. Lynn Fink, Katia Nones, Craig Nourse, Robert Grützmann, Andreia V. Pinho, Lorraine A. Chantrill, Matthew J. Anderson, Nigel B. Jamieson, Fraser Duthie, Qinying Xu, Stephen H. Kazakoff, Jianmin Wu, Nicola Waddell, Amanda Mawson, Neil D. Merrett, Ivon Harliwong, Andrew Stone, Jaswinder S. Samra, Scott Wood, James R. Eshleman, Jeremy L. Humphris, Vincenzo Corbo, Anirban Maitra, Colin J. McKay, Andrew Barbour, Christopher W. Toon, Aldo Scarpa, Oliver Holmes, Angelika N. Christ, John V. Pearson, Giampaolo Tortora, Nick Waddell, Marc D. Jones, Jane Hair, Senel Idrisoglu, Richard A. Morgan, Cell Differentiation, Basic (bio-) Medical Sciences, and Laboratory for Medical and Molecular Oncology
Subjects: 0301 basic medicine, Male, DNA Mutational Analysis, Carcinoma, Pancreatic Ductal/genetics, DNA Mismatch Repair/genetics, medicine.disease_cause, DNA Mismatch Repair, 0302 clinical medicine, Sequencing, Pancreatic Adenocarcinoma, Aged, 80 and over, Mutation, Genome, Gastroenterology, Middle Aged, 3. Good health, MutS Homolog 2 Protein, 030220 oncology & carcinogenesis, Somatic Rearrangement, Cancer Genetics, DNA mismatch repair, Female, MutL Protein Homolog 1, MutS Homolog 2 Protein/genetics, Carcinoma, Pancreatic Ductal, Adult, DNA repair, Somatic hypermutation, Biology, MLH1, Proto-Oncogene Proteins p21(ras)/genetics, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Pancreatic cancer, medicine, Humans, Aged, Settore MED/06 - ONCOLOGIA MEDICA, Hepatology, MutL Protein Homolog 1/genetics, Cancer, medicine.disease, Pancreatic Neoplasms/genetics, Pancreatic Neoplasms, 030104 developmental biology, MSH2, Cancer research, Transcriptome
Abstract: Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.
Published: 2017

18. A workflow to increase verification rate of chromosomal structural rearrangements using high-throughput next-generation sequencing

Author: Craig Nourse, Andrew V. Biankin, Shivangi Wani, Matthew J. Anderson, David Miller, Anita L Steptoe, Nic Waddell, J. Lynn Fink, Ivon Harliwong, Nicole Cloonan, John V. Pearson, Katia Nones, Timothy J. C. Bruxner, Darrin Taylor, Ehsan Nourbakhsh, Scott Wood, Senel Idrisoglu, Kelly Quek, Suzanne Manning, Angelika N. Christ, Ann-Marie Patch, Muhammad Zaki Hidayatullah Fadlullah, Peter Wilson, Conrad Leonard, Felicity Newell, Oliver Holmes, Qinying Xu, Sean M. Grimmond, and Karin S. Kassahn
Subjects: Molecular Sequence Data, Chromosome Breakpoints, Biology, Polymerase Chain Reaction, General Biochemistry, Genetics and Molecular Biology, DNA sequencing, Deep sequencing, Workflow, symbols.namesake, Neoplasms, Chromosomes, Human, Humans, DNA Primers, Chromosome Aberrations, Genetics, Sanger sequencing, Massive parallel sequencing, Base Sequence, Contig, High-Throughput Nucleotide Sequencing, Ion semiconductor sequencing, Pancreatic Neoplasms, symbols, Carcinoma, Pancreatic Ductal, Biotechnology
Abstract: Somatic rearrangements, which are commonly found in human cancer genomes, contribute to the progression and maintenance of cancers. Conventionally, the verification of somatic rearrangements comprises many manual steps and Sanger sequencing. This is labor intensive when verifying a large number of rearrangements in a large cohort. To increase the verification throughput, we devised a high-throughput workflow that utilizes benchtop next-generation sequencing and in-house bioinformatics tools to link the laboratory processes. In the proposed workflow, primers are automatically designed. PCR and an optional gel electrophoresis step to confirm the somatic nature of the rearrangements are performed. PCR products of somatic events are pooled for Ion Torrent PGM and/or Illumina MiSeq sequencing, the resulting sequence reads are assembled into consensus contigs by a consensus assembler, and an automated BLAT is used to resolve the breakpoints to base level. We compared sequences and breakpoints of verified somatic rearrangements between the conventional and high-throughput workflow. The results showed that next-generation sequencing methods are comparable to conventional Sanger sequencing. The identified breakpoints obtained from next-generation sequencing methods were highly accurate and reproducible. Furthermore, the proposed workflow allows hundreds of events to be processed in a shorter time frame compared with the conventional workflow.
Published: 2014

19. Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling

Author: Lynn Fink, Sean M. Grimmond, Ann-Marie Patch, Sarah Song, Jianmin Wu, Amber L. Johns, Giovanni Butturini, Karin S. Kassahn, Conrad Leonard, Michelle Thomas, Marina Pajic, Rita T. Lawlor, Clare Watson, Suzanne Manning, Vincenzo Corbo, Giuseppe Zamboni, Anna Malpaga, Mark J. Cowley, Stephen H. Kazakoff, David Miller, Craig Nourse, Ilse Rooman, David L. A. Wood, Stefano Crippa, Nic Waddell, Anthony J. Gill, Peter Bailey, Paola Castelli, Katia Nones, Andrew V. Biankin, Massimo Falconi, Angelika N. Christ, Aldo Scarpa, Mark Pinese, John V. Pearson, Marc D. Jones, Darrin Taylor, and David K. Chang
Subjects: Regulation of gene expression, Cancer Research, Wnt signaling pathway, Methylation, Biology, medicine.disease_cause, Oncology, CpG site, ROBO1, DNA methylation, Cancer research, medicine, Epigenetics, Carcinogenesis
Abstract: The importance of epigenetic modifications such as DNA methylation in tumorigenesis is increasingly being appreciated. To define the genome-wide pattern of DNA methylation in pancreatic ductal adenocarcinomas (PDAC), we captured the methylation profiles of 167 untreated resected PDACs and compared them to a panel of 29 adjacent nontransformed pancreata using high-density arrays. A total of 11,634 CpG sites associated with 3,522 genes were significantly differentially methylated (DM) in PDAC and were capable of segregating PDAC from non-malignant pancreas, regardless of tumor cellularity. As expected, PDAC hypermethylation was most prevalent in the 5' region of genes (including the proximal promoter, 5'UTR and CpG islands). Approximately 33% DM genes showed significant inverse correlation with mRNA expression levels. Pathway analysis revealed an enrichment of aberrantly methylated genes involved in key molecular mechanisms important to PDAC: TGF-β, WNT, integrin signaling, cell adhesion, stellate cell activation and axon guidance. Given the recent discovery that SLIT-ROBO mutations play a clinically important role in PDAC, the role of epigenetic perturbation of axon guidance was pursued in more detail. Bisulfite amplicon deep sequencing and qRT-PCR expression analyses confirmed recurrent perturbation of axon guidance pathway genes SLIT2, SLIT3, ROBO1, ROBO3, ITGA2 and MET and suggests epigenetic suppression of SLIT-ROBO signaling and up-regulation of MET and ITGA2 expression. Hypomethylation of MET and ITGA2 correlated with high gene expression, which was associated with poor survival. These data suggest that aberrant methylation plays an important role in pancreatic carcinogenesis affecting core signaling pathways with potential implications for the disease pathophysiology and therapy.
Published: 2014

20. Integrating Massively Parallel Sequencing into Diagnostic Workflows and Managing the Annotation and Clinical Interpretation Challenge

Author: Karin S. Kassahn, Melody Caramins, Hamish S. Scott, Kassahn, Karin S, Scott, Hamish S, and Caramins, Melody C
Subjects: pathogenicity prediction, databases, Best practice, Genomics, Biology, Bioinformatics, DNA sequencing, Workflow, Annotation, diagnostics, Genetics, Humans, Genetic Predisposition to Disease, clinical annotation, clinical reporting, Genetics (clinical), Massive parallel sequencing, Scope (project management), Genetic Variation, High-Throughput Nucleotide Sequencing, Molecular Sequence Annotation, Data science, Pipeline (software), Molecular Diagnostic Techniques, Practice Guidelines as Topic, next-generation sequencing, Software
Abstract: usc Massively parallel sequencing has become a powerful tool for the clinical management of patients with applications in diagnosis, guidance of treatment, prediction of drug response, and carrier screening. A considerable challenge for the clinical implementation of these technologies is the management of the vast amount of sequence data generated, in particular the annotation and clinical interpretation of genomic variants. Here, we describe annotation steps that can be automated and common strategies employed for variant prioritization. The definition of best practice standards for variant annotation and prioritization is still ongoing; at present, there is limited consensus regarding an optimal clinical sequencing pipeline. We provide considerations to help define these. For the first time, clinical genetics and genomics is not limited by our ability to sequence, but our ability to clinically interpret and use genomic information in health management. We argue that the development of standardized variant annotation and interpretation approaches and software tools implementing these warrants further support. As we gain a better understanding of the significance of genomic variation through research, patients will be able to benefit from the full scope that these technologies offer. Refereed/Peer-reviewed
Published: 2014

21. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Author: Conrad Leonard, Stefano Serra, Jeremy L. Humphris, J. Lynn Fink, Vincenzo Corbo, Deepa Pai, Ami Panchal, Jennifer Drummond, Anirban Maitra, Katia Nones, Mark J. Cowley, Nam Q. Nguyen, Marc D. Jones, David A. Largaespada, Karen M. Mann, Ralph H. Hruban, Nicole Cloonan, Timothy Beck, Marie-Claude Gingras, Sally E. Hodges, Darrin Taylor, Andrew V. Biankin, Angela Chou, Craig Nourse, Marina Pajic, Gloria M. Petersen, Kimberly Begley, Richard A. Morgan, Rita T. Lawlor, Senel Idrisoglu, Jessica A. Lovell, Lincoln Stein, Christina K. Yung, Lee Timms, Adnan Nagrial, Giampaolo Tortora, Shivangi Wani, Mark Pinese, Angelika N. Christ, Amanda Mawson, Neil D. Merrett, Maria Scardoni, Min Wang, Ann-Marie Patch, Steven Gallinger, Huyen Dinh, Richard A. Gibbs, John Douglas Mcpherson, Amber L. Johns, Nipun Kakkar, David A. Wheeler, Andrew Barbour, Patricia Shaw, Milena Gongora, Emily S. Humphrey, Christopher J. Scarlett, Matthew J. Anderson, Lodewyk F. A. Wessels, Andrew M.K. Brown, Christopher W. Toon, Felicity Newell, Margaret A. Tempero, Fengmei Zhao, Richard D. Schulick, Paola Capelli, Timothy J. C. Bruxner, Christine A. Iacobuzio-Donahue, Ivon Harliwong, Richard de Borja, Pedro A. Perez-Mancera, Jianmin Wu, Emily K. Colvin, Michelle Sam, Warren Kaplan, Debabrata Mukhopadhyay, John V. Pearson, Gabriel Kolle, Oliver Holmes, Lorraine A. Chantrill, Lora Lewis, Jaswinder S. Samra, Scott Wood, Lakshmi Muthuswamy, James R. Eshleman, Neal G. Copeland, Peter Wilson, David Miller, Anthony J. Gill, Qinying Xu, Nicola Waddell, Ming-Sound Tsao, Karin S. Kassahn, Venessa T. Chin, James G. Kench, David K. Chang, William E. Fisher, Kyle Chang, Aldo Scarpa, Christopher L. Wolfgang, Roger J. Daly, Alistair G. Rust, Ehsan Nourbakhsh, Jeffrey G. Reid, Nikolajs Zeps, Nicole Onetto, Donna M. Muzny, Brooke Gardiner, Robert E. Denroche, Yuan Qing Wu, Nancy A. Jenkins, Sean M. Grimmond, R. Scott Mead, David A. Tuveson, David J. Adams, Yi Han, F. Charles Brunicardi, Andreia V. Pinho, Elizabeth A. Musgrove, Sarah Song, Ilse Rooman, Thomas J. Hudson, Christian J. Buhay, Robert L. Sutherland, Suzanne Manning, Nicholas Buchner, Krishna Epari, Basic (bio-) Medical Sciences, and Laboratory for Medical and Molecular Oncology
Subjects: Exome sequencing, Gene Dosage, Copy number analysis, PDAC, KRAS, Kaplan-Meier Estimate, Biology, medicine.disease_cause, Mice, CDKN2A, Pancreatic cancer, medicine, Animals, Humans, Genetics, Mutation, Genome, Multidisciplinary, Proteins, Cancer, medicine.disease, Axons, Gene Expression Regulation, Neoplastic, Pancreatic Neoplasms, Cancer research, Carcinogenesis, Carcinoma, Pancreatic Ductal, Signal Transduction
Abstract: Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
Published: 2012

22. Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma

Author: David J. Adams, David W. Dawson, Todd E. Sheetz, Benjamin T. Brett, Christopher Chin Kuan Yew, Nicola Waddell, Anne N. Kovochich, Karin S. Kassahn, David K. Chang, Jerrold M. Ward, Adam J. Dupuy, Neal G. Copeland, Karen M. Mann, Nancy A. Jenkins, Sean M. Grimmond, Alistair G. Rust, Michael A. Black, and Andrew V. Biankin
Subjects: Delta Catenin, Mice, 129 Strain, Mice, Transgenic, Adenocarcinoma, Biology, medicine.disease_cause, Mice, Pancreatic cancer, medicine, Animals, Humans, Genetic Predisposition to Disease, Pancreas, Survival rate, Mutation, Multidisciplinary, Point mutation, Cancer, Catenins, Biological Sciences, medicine.disease, Immunohistochemistry, Survival Analysis, GTP-Binding Protein alpha Subunits, Pancreatic Neoplasms, Disease Models, Animal, Mutagenesis, Insertional, Genes, ras, medicine.anatomical_structure, DNA Transposable Elements, Cancer research, GTP-Binding Protein alpha Subunits, Gq-G11, KRAS, Genome-Wide Association Study, Signal Transduction
Abstract: Pancreatic cancer is one of the most deadly cancers affecting the Western world. Because the disease is highly metastatic and difficult to diagnosis until late stages, the 5-y survival rate is around 5%. The identification of molecular cancer drivers is critical for furthering our understanding of the disease and development of improved diagnostic tools and therapeutics. We have conducted a mutagenic screen using Sleeping Beauty ( SB ) in mice to identify new candidate cancer genes in pancreatic cancer. By combining SB with an oncogenic Kras allele, we observed highly metastatic pancreatic adenocarcinomas. Using two independent statistical methods to identify loci commonly mutated by SB in these tumors, we identified 681 loci that comprise 543 candidate cancer genes (CCGs); 75 of these CCGs, including Mll3 and Ptk2 , have known mutations in human pancreatic cancer. We identified point mutations in human pancreatic patient samples for another 11 CCGs, including Acvr2a and Map2k4 . Importantly, 10% of the CCGs are involved in chromatin remodeling, including Arid4b , Kdm6a , and Nsd3 , and all SB tumors have at least one mutated gene involved in this process; 20 CCGs, including Ctnnd1 , Fbxo11 , and Vgll4 , are also significantly associated with poor patient survival. SB mutagenesis provides a rich resource of mutations in potential cancer drivers for cross-comparative analyses with ongoing sequencing efforts in human pancreatic adenocarcinoma.
Published: 2012

23. Genetic Predisposition to Therapy-Related Myeloid Neoplasm By Rare, Deleterious Germline Variants in DNA Repair Pathway and Myeloid Driver Genes

Author: Andreas W. Schreiber, Joel Goeghegan, Jinghua Feng, Nimit Singhal, Ian D. Lewis, Karin S. Kassahn, Devendra K Hiwase, Richard J D'Andrea, Deepak Singhal, Anna L. Brown, Amilia Wee, Susan Branford, Rakchha Chhetri, Monika M Kutyna, Peer Arts, Wendy T Parker, Hamish S. Scott, Cassandra M. Hirsch, Smita Hiwase, Christopher N. Hahn, Milena Babic, and Jaroslaw P. Maciejewski
Subjects: Oncology, medicine.medical_specialty, education.field_of_study, medicine.diagnostic_test, business.industry, Immunology, Population, Cell Biology, Hematology, Gene mutation, medicine.disease, Biochemistry, Breast cancer, Germline mutation, Internal medicine, medicine, Genetic predisposition, Family history, business, education, Leiden Open Variation Database, Genetic testing
Abstract: Therapy-related myeloid neoplasm (t-MN) is considered to be a direct stochastic complication of chemotherapy and/or radiotherapy for primary cancer or autoimmune diseases. However, genetic predisposition is reported in 8-12% of sporadic adult cancer patients [Lu et al Nature Communication 2015 and Huang et al Cell 2018]. Similarly, genetic predispositions to t-MN have also been reported in limited single institute studies of small numbers of patients [Churpek et al Cancer 2016]. In this study, we performed comprehensive germline and somatic mutation profiling in t-MN using next generation sequencing. Matched germline material was available for 62/194 (32%) patients. Mutation profiling was correlated with clinical features including family history in 194 patients enrolled in the South Australian MDS (SA-MDS) registry and Cleveland Clinic (CC). An in-house well established filtering pipeline was used for identification of somatic mutations. Only variants with Genome Aggregation Database (gnomAD) minor allele frequency (MAF) of ≤0.01% and variant allele frequency (VAF) of ≥35% were selected for further analysis of germline variants. Variants reported in in the Catalogue of Somatic Mutations in Cancer database and MDS/AML were excluded from further analysis. Variants reported pathogenic in Breast Cancer Information Core (BIC) database and Leiden Open Variation Database (LOVD) were retained. Other variants were included if truncating (nonsense, indels, splice alterations), CADD>20, or predicted deleterious by >4/6 scoring algorithms (GERP>4, PhyloP>2, SIFT, PolyPhen2, MutationTaster and FATHMM). Forty-one (21%) t-MN patients harbored 45 rare (MAF The frequency of these germline mutations in our t-MN cohort is higher than in the general population (gnomAD; Table 1) and in patients with primary malignancies such as breast cancer and lymphoma [Lu et al Nature Communication 2015 and Churpek et al Cancer 2016]. Intriguingly, the frequency of germline FA gene mutations (FAMT) in our therapy-related myelodysplastic syndrome (t-MDS) patients is also higher than those reported in primary MDS patients (18% vs 9%, p=0.02) [Przychodzen et al 2018]. Additionally, of those with available family history, 62% of t-MN patients have first and/or second degree relatives with non-skin cancers. Significantly more patients with FA mutation (FAMT) had first and second degree relatives with cancers compared to patients without FA (FAWT) mutations (82% vs 58%; p=0.03). Additionally, chromosomes 3 and 7 abnormalities, as well as monosomal karyotype, were more frequent in FAMT cases compared to FAWT. Similarly, somatic mutations in GATA2 (10% vs 2%; p=0.02), BCOR (13% vs 4%; p=0.03) and IDH2 (10% vs 2%; p=0.02) were more frequent in FAMT compared to FAWT cases (Figure 1C). In summary, we show that at least one in five t-MN patients harbor deleterious germline mutations, and 82% of FAMT patients have a first or second degree relative with cancers. These findings have implication in management of not only t-MN patients but genetic testing for their family members. Disclosures Branford: Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cepheid: Honoraria. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy. Hiwase:Celgene: Research Funding; Novartis: Research Funding.
Published: 2018

24. Evolution of gene function and regulatory control after whole-genome duplication: Comparative analyses in vertebrates

Author: Mark A. Ragan, Vinh T. Dang, Andrew C. Perkins, Simon J. Wilkins, and Karin S. Kassahn
Subjects: Fish Proteins, Embryo, Nonmammalian, Letter, Protein domain, Gene regulatory network, Genomics, Biology, Synteny, Genome, Evolution, Molecular, Mice, Genes, Duplicate, Gene Duplication, Gene duplication, Genetics, Animals, Humans, Gene Regulatory Networks, Phylogeny, Genetics (clinical), Genome, Human, Gene Expression Profiling, PAX2 Transcription Factor, Fishes, Chromosome Mapping, Computational Biology, Gene Expression Regulation, Developmental, Evolutionary biology, Vertebrates, Neofunctionalization, Human genome, Algorithms
Abstract: The significance of whole-genome duplications (WGD) for vertebrate evolution remains controversial, in part because the mechanisms by which WGD contributed to functional evolution or speciation are still incompletely characterized. Fish genomes provide an ideal context in which to examine the consequences of WGD, because the teleost lineage experienced an additional WGD soon after divergence from tetrapods and because five teleost genomes are available for comparative analysis. Here we present an integrated approach to characterize these post-duplication genomes based on genome-scale synteny, phylogenetic, temporal, and spatial gene expression and on protein sequence data. A minimum of 3%–4% of protein-coding loci have been retained in two copies in each of the five fish genomes, and many of these duplicates are key developmental genes that function as transcription factors or signaling molecules. Almost all duplicate gene pairs we examined have diverged in spatial and/or temporal expression during embryogenesis. A quarter of duplicate pairs have diverged in function via the acquisition of novel protein domains or via changes in the subcellular localization of their encoded proteins. We compared the spatial expression and protein domain architecture of zebrafish WGD-duplicates to those of their single mouse ortholog and found many examples supporting a model of neofunctionalization. WGD-duplicates have acquired novel protein domains more often than have single-copy genes. Post-WGD changes at the gene regulatory level were more common than changes at the protein level. We conclude that the most significant consequence of WGD for vertebrate evolution has been to enable more-specialized regulatory control of development via the acquisition of novel spatiotemporal expression domains. We find limited evidence that reciprocal gene loss led to reproductive isolation and speciation in this lineage.
Published: 2009

25. Animal performance and stress: responses and tolerance limits at different levels of biological organisation

Author: M. Julian Caley, Ross H. Crozier, Hans O. Pörtner, and Karin S. Kassahn
Subjects: Regulation of gene expression, Ecology, Stressor, Oxygen transport, Environment, Biology, medicine.disease_cause, Adaptation, Physiological, Biological Evolution, General Biochemistry, Genetics and Molecular Biology, Cell biology, Transcriptome, Gene expression profiling, Gene Expression Regulation, Stress, Physiological, medicine, Animals, Heat shock, General Agricultural and Biological Sciences, Transcription factor, Oxidative stress
Abstract: Recent advances in molecular biology and the use of DNA microarrays for gene expression profiling are providing new insights into the animal stress response, particularly the effects of stress on gene regulation. However, interpretation of the complex transcriptional changes that occur during stress still poses many challenges because the relationship between changes at the transcriptional level and other levels of biological organisation is not well understood. To confront these challenges, a conceptual model linking physiological and transcriptional responses to stress would be helpful. Here, we provide the basis for one such model by synthesising data from organismal, endocrine, cellular, molecular, and genomic studies. We show using available examples from ectothermic vertebrates that reduced oxygen levels and oxidative stress are common to many stress conditions and that the responses to different types of stress, such as environmental, handling and confinement stress, often converge at the challenge of dealing with oxygen imbalance and oxidative stress. As a result, a common set of stress responses exists that is largely independent of the type of stressor applied. These common responses include the repair of DNA and protein damage, cell cycle arrest or apoptosis, changes in cellular metabolism that reflect the transition from a state of cellular growth to one of cellular repair, the release of stress hormones, changes in mitochondrial densities and properties, changes in oxygen transport capacities and changes in cardio-respiratory function. Changes at the transcriptional level recapitulate these common responses, with many stress-responsive genes functioning in cell cycle control, regulation of transcription, protein turnover, metabolism, and cellular repair. These common transcriptional responses to stress appear coordinated by only a limited number of stress-inducible and redox-sensitive transcription factors and signal transduction pathways, such as the immediate early genes c-fos and c-jun, the transcription factors NFkappaB and HIF-1alpha, and the JNK and p38 kinase signalling pathways. As an example of environmental stress responses, we present temperature response curves at organismal, cellular and molecular levels. Acclimation and physiological adjustments that can shift the threshold temperatures for the onset of these responses are discussed and include, for example, adjustments of the oxygen delivery system, the heat shock response, cellular repair system, and transcriptome. Ultimately, however, an organism's ability to cope with environmental change is largely determined by its ability to maintain aerobic scope and to prevent loss in performance. These systemic constraints can determine an organism's long-term survival well before cellular and molecular functions are disturbed. The conceptual model we propose here discusses some of the crosslinks between responses at different levels of biological organisation and the central role of oxygen balance and oxidative stress in eliciting these responses with the aim to help the interpretation of environmental genomic data in the context of organismal function and performance.
Published: 2009

26. Microarrays for comparative and ecological genomics: beyond single-species applications of array technologies

Author: Karin S. Kassahn
Subjects: Regulation of gene expression, Genetics, Microarray, Microarray analysis techniques, Gene chip analysis, Genomics, Computational biology, Aquatic Science, DNA microarray, Biology, Ecology, Evolution, Behavior and Systematics, DNA sequencing, Conserved sequence
Abstract: Microarray technology has become an important tool to understand the biological significance of gene regulation. Microarray gene expression profiling has provided insight into development, maturation, infection and the response to pollutants and environmental stressors. However, the development of species-specific microarrays can be time consuming and costly. Therefore, where a microarray for a closely related species is available, use of a heterologous microarray platform can provide an attractive alternative. Heterologous microarray experiments are also of great interest in comparative studies where the aim is to compare gene regulation across a number of species. This review describes the principles underlying heterologous microarray experiments and discusses some examples of their use that have already helped advance the understanding of fish biology. However, sequence mismatches between the probes on the microarray and the target sequences can confound measures of gene regulation when using microarrays across species. The impact of sequence mismatches on the accurate detection of gene regulation is discussed. Interspecies genomic hybridization experiments comparing genomic DNA from different species can help identify which probes on the microarray can be used reliably to assay gene regulation across species. Finally, a number of recent advances in platform development for transcriptomics are described. These include multispecies microarrays that represent probes derived from multiple species and universal microarrays where the probes are designed to match evolutionarily conserved sequence regions. Next generation sequencing technologies are also likely to find broader application in transcriptomics in the near future.
Published: 2008

27. Heterologous microarray experiments used to identify the early gene response to heat stress in a coral reef fish

Author: Alister C. Ward, Ross H. Crozier, M. Julian Caley, Glenn Stone, Ashley R. Connolly, and Karin S. Kassahn
Subjects: Candidate gene, Microarray, biology, Coral reef fish, Ecology, fungi, Computational biology, biology.organism_classification, Pomacentrus moluccensis, Genetics, Gene chip analysis, DNA microarray, Functional genomics, Ecology, Evolution, Behavior and Systematics, Comparative genomic hybridization
Abstract: Coral reef fishes are expected to experience rising sea surface temperatures due to climate change. How well tropical reef fishes will respond to these increased temperatures and which genes are important in the response to elevated temperatures is not known. Microarray technology provides a powerful tool for gene discovery studies, but the development of microarrays for individual species can be expensive and time-consuming. In this study, we tested the suitability of a Danio rerio oligonucleotide microarray for application in a species with few genomic resources, the coral reef fish Pomacentrus moluccensis. Results from a comparative genomic hybridization experiment and direct sequence comparisons indicate that for most genes there is considerable sequence similarity between the two species, suggesting that the D. rerio array is useful for genomic studies of P. moluccensis. We employed this heterologous microarray approach to characterize the early transcriptional response to heat stress in P. moluccensis. A total of 111 gene loci, many of which are involved in protein processing, transcription, and cell growth, showed significant changes in transcript abundance following exposure to elevated temperatures. Changes in transcript abundance were validated for a selection of candidate genes using quantitative real-time polymerase chain reaction. This study demonstrates that heterologous microarrays can be successfully employed to study species for which specific microarrays have not yet been developed, and so have the potential to greatly enhance the utility of microarray technology to the field of environmental and functional genomics.
Published: 2007

28. Genomic and microarray approaches to coral reef conservation biology

Author: Karin S. Kassahn, Sylvain Forêt, Akira Iguchi, David J. Miller, Eldon E. Ball, Lauretta C. Grasso, and David C. Hayward
Subjects: Comparative genomics, Candidate gene, geography, geography.geographical_feature_category, biology, Ecology, Microarray analysis techniques, fungi, Genomics, Coral reef, Aquatic Science, biology.organism_classification, Evolutionary biology, Acropora, Identification (biology), DNA microarray
Abstract: New technologies based on DNA microarrays and comparative genomics hold great promise for providing the background biological information necessary for effective coral reef conservation and management. Microarray analysis has been used in a wide range of applications across the biological sciences, most frequently to examine simultaneous changes in the expression of large numbers of genes in response to experimental manipulation or environmental variation. Other applications of microarray methods include the assessment of divergence in gene sequences between species and the identification of fast-evolving genes. Arrays are presently available for only a limited range of species, but with appropriate controls they can be used for related species, thus avoiding the considerable costs associated with development of a system de novo. Arrays are in use or preparation to study stress responses, early development, and symbiosis in Acropora and Montastraea. Ongoing projects on several corals are making available large numbers of expressed gene sequences, enabling the identification of candidate genes for studies on gamete specificity, allorecognition and symbiont interactions. Over the next few years, microarray and comparative genomic approaches are likely to assume increasingly important and widespread use to study many aspects of the biology of coral reef organisms. Application of these genomic approaches to enhance our understanding of genetic and physiological correlates during stress, environmental disturbance and disease bears direct relevance to the conservation of coral reef ecosystems.
Published: 2007

29. Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance

Author: Jodi M, Saunus, Michael C J, Quinn, Ann-Marie, Patch, John V, Pearson, Peter J, Bailey, Katia, Nones, Amy E, McCart Reed, David, Miller, Peter J, Wilson, Fares, Al-Ejeh, Mythily, Mariasegaram, Queenie, Lau, Teresa, Withers, Rosalind L, Jeffree, Lynne E, Reid, Leonard, Da Silva, Admire, Matsika, Colleen M, Niland, Margaret C, Cummings, Timothy J C, Bruxner, Angelika N, Christ, Ivon, Harliwong, Senel, Idrisoglu, Suzanne, Manning, Craig, Nourse, Ehsan, Nourbakhsh, Shivangi, Wani, Matthew J, Anderson, J Lynn, Fink, Oliver, Holmes, Stephen, Kazakoff, Conrad, Leonard, Felicity, Newell, Darrin, Taylor, Nick, Waddell, Scott, Wood, Qinying, Xu, Karin S, Kassahn, Vairavan, Narayanan, Nur Aishah, Taib, Soo-Hwang, Teo, Yock Ping, Chow, kConFab, Parmjit S, Jat, Sebastian, Brandner, Adrienne M, Flanagan, Kum Kum, Khanna, Georgia, Chenevix-Trench, Sean M, Grimmond, Peter T, Simpson, Nicola, Waddell, and Sunil R, Lakhani
Subjects: Receptor, ErbB-4, Receptor, ErbB-3, Brain Neoplasms, Receptor, ErbB-2, Gene Expression Profiling, DNA Mutational Analysis, Gene Amplification, Gene Dosage, Genomics, Ligands, Immunohistochemistry, Enzyme Activation, Gene Expression Regulation, Neoplastic, Phenotype, Predictive Value of Tests, Mutation, Biomarkers, Tumor, Tumor Microenvironment, Humans, Genetic Predisposition to Disease, Molecular Targeted Therapy, Phosphorylation, Precision Medicine, Protein Kinase Inhibitors, Genetic Association Studies
Abstract: Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2) = 0.496; p0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.
Published: 2015

30. Genomic analyses identify molecular subtypes of pancreatic cancer

Author: J. Lynn Fink, Jeremy L. Humphris, Katia Nones, Robert Grützmann, Anirban Maitra, Paola Capelli, Peter J. Wilson, William E. Fisher, Aldo Scarpa, Christopher J. Scarlett, Richard A. Morgan, Ann-Marie Patch, Debabrata Mukhopadhyay, Murtaugh Lc, Oliver Hofmann, Marc Giry-Laterriere, Borislav Rusev, Jennifer P. Morton, Nicole Cloonan, David A. Wheeler, Anthony J. Gill, Krishna Epari, Nam Q. Nguyen, Amber L. Johns, James G. Kench, Saadia A. Karim, Lorena Pantano, Craig Nourse, Nigel B. Jamieson, Ivon Harliwong, Stephen H. Kazakoff, Darrin Taylor, Felicity Newell, Christian Pilarsky, Giampaolo Tortora, Shivangi Wani, Nicola Waddell, Mark J. Cowley, Jaswinder S. Samra, Scott Wood, Munzy Dm, Conrad Leonard, Laura Mincarelli, Suzanne Manning, Timothy J. C. Bruxner, Mark Pinese, Michael C.J. Quinn, Hair J, Andreia V. Pinho, R. L. Sutherland, Amanda Mawson, Neil D. Merrett, Andrew Barbour, Rita T. Lawlor, Jones, Corbo, Ilse Rooman, Lorraine A. Chantrill, Marie-Claude Gingras, Christopher W. Toon, Senel Idrisoglu, Emily S. Humphrey, Kelly Quek, Sean M. Grimmond, Christopher L. Wolfgang, Oliver Holmes, Andrew V. Biankin, Fraser Duthie, Qinying Xu, Kim Moran-Jones, Gloria M. Petersen, Lisa Evers, Peter Bailey, Elizabeth A. Musgrove, Alan J. Robertson, Marina Pajic, Emily K. Colvin, John V. Pearson, Nikolajs Zeps, David K. Chang, Karin S. Kassahn, David Miller, Janet Graham, Ehsan Nourbakhsh, Ralph H. Hruban, Luis Navarro Sanchez, Ulla-Maja Bailey, Chin, Jessica A. Lovell, Angelika N. Christ, Richard A. Gibbs, Eshleman, Karin A. Oien, Christine A. Iacobuzio-Donahue, Claudio Bassi, Adnan Nagrial, Matthew J. Anderson, Owen J. Sansom, Angela Chou, Roberto Salvia, Jianmin Wu, Cell Differentiation, Basic (bio-) Medical Sciences, and Laboratory for Medical and Molecular Oncology
Subjects: 0301 basic medicine, Transcription, Genetic, Receptors, Cytoplasmic and Nuclear, medicine.disease_cause, Transcriptome, Mice, 0302 clinical medicine, RNA-SEQ DATA, DUCTAL ADENOCARCINOMA, NETWORK ANALYSIS, EXPRESSION DATA, CELL FORMATION, BREAST-CANCER, MUTATIONS, PACKAGE, TUMOR, DIFFERENTIATION, Basic Helix-Loop-Helix Transcription Factors, Gene Regulatory Networks, Regulation of gene expression, Histone Demethylases, Multidisciplinary, Wnt signaling pathway, Nuclear Proteins, Genomics, Prognosis, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Homeobox Protein Nkx-2.2, 030220 oncology & carcinogenesis, DNA methylation, Hepatocyte Nuclear Factor 3-beta, PDX1, KRAS, Carcinoma, Pancreatic Ductal, Biology, 03 medical and health sciences, Downregulation and upregulation, Pancreatic cancer, Cell Line, Tumor, medicine, Animals, Humans, Homeodomain Proteins, Settore MED/06 - ONCOLOGIA MEDICA, Genome, Human, Tumor Suppressor Proteins, DNA Methylation, Zebrafish Proteins, medicine.disease, Molecular biology, Survival Analysis, Pancreatic Neoplasms, 030104 developmental biology, Mutation, Trans-Activators, Tumor Suppressor Protein p53, Hepatocyte Nuclear Factor 3-gamma, Genes, Neoplasm, Transcription Factors
Abstract: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
Published: 2015

31. The ReFuGe 2020 Consortium—using 'omics' approaches to explore the adaptability and resilience of coral holobionts to environmental change

Author: Theresa Fyffe, Eldon E. Ball, Madeleine J. H. van Oppen, Timothy Ravasi, Shunichi Takahashi, Christian R. Voolstra, Hua Ying, Petra Lundgren, Susanne Sprungala, Mark A. Ragan, Nedeljka Rosic, Karin S. Kassahn, Ary A. Hoffmann, David J. Miller, Roger Beeden, Ove Hoegh-Guldberg, Michael L. Berumen, Kathleen M. Morrow, Karen D. Weynberg, Sylvain Forêt, Eva Abal, William Leggat, David G. Bourne, Michael Imelfort, Gene W. Tyson, and Cheong Xin Chan
Subjects: lcsh:QH1-199.5, Environmental change, Coral, Ocean Engineering, adaptation, lcsh:General. Including nature conservation, geographical distribution, Aquatic Science, Biology, Oceanography, Symbiodinium, Great Barrier Reef, Marine Science, lcsh:Science, resilience, Reef, holobiont, Water Science and Technology, Global and Planetary Change, geography, geography.geographical_feature_category, Resilience of coral reefs, Ecology, global environmental change, Ocean acidification, Coral reef, Red Sea, biology.organism_classification, Holobiont, coral reef ecosystem, lcsh:Q, metaorganism
Abstract: Human-induced environmental changes have been linked directly with loss of biodiversity. Coral reefs, which have been severely impacted by anthropogenic activities over the last few decades, exemplify this global problem and provide an opportunity to develop research addressing key knowledge gaps through “omics”-based approaches. While many stressors, e.g., global warming, ocean acidification, overfishing, and coastal development have been identified, there is an urgent need to understand how corals function at a basic level in order to conceive strategies for mitigating future reef loss. In this regard, availability of fully sequenced genomes has been immensely valuable in providing answers to questions of organismal biology. Given that corals are metaorganisms comprised of the coral animal host, its intracellular photosynthetic algae, and associated microbiota (i.e., bacteria, archaea, fungi, viruses), these efforts must focus on entire coral holobionts. The Reef Future Genomics 2020 (ReFuGe 2020) Consortium has formed to sequence hologenomes of 10 coral species representing different physiological or functional groups to provide foundation data for coral reef adaptation research that is freely available to the research community.
Published: 2015

32. Whole-genome characterization of chemoresistant ovarian cancer

Author: Catherine Kennedy, Peter Bailey, Michael Friedlander, Conrad Leonard, Euan A. Stronach, Jodie Leditschke, Prue A. Cowin, Darrin Taylor, David D.L. Bowtell, Chris Mitchell, Felicity Newell, Senel Idrisoglu, Ravikiran Vedururu, Kathryn Alsop, Ehsan Nourbakhsh, Patricia C. M. O’Brien, Nathan E. Hall, Collin Stewart, Ann-Marie Patch, Linda Mileshkin, Gisela Mir Arnau, Charlotte Wilhelm-Benartzi, Shivashankar H. Nagaraj, Nadia Traficante, Angelika N. Christ, Edward Curry, Qinying Xu, Stephen H. Kazakoff, Emma Markham, Kate Strachan, Timothy J. C. Bruxner, David Miller, Nick Waddell, Yoke Eng Chiew, Karin S. Kassahn, A. Jewell, Barsha Poudel, Ronny Drapkin, Ernst Lengyel, Oliver Holmes, George Au-Yeung, Joshy George, Kelly Quek, Richard W. Tothill, Orla McNally, John V. Pearson, J. Lynn Fink, Greg Young, Nicola Waddell, Elizabeth L. Christie, Jillian Hung, Michael C. J. Quinn, Ivon Harliwong, Jan Pyman, Jason Ellul, Walid J Azar, Katia Nones, Andrew Lonie, Sian Fereday, Craig Nourse, Stephen Cordner, Dariush Etemadmoghadam, Anna deFazio, Paul R. Harnett, Scott Wood, Maria A. Doyle, Michael C.J. Quinn, Robert S. Brown, Hani Gabra, Peter Wilson, Joy Hendley, Timothy P. Holloway, Sean M. Grimmond, Heather Thorne, Matthew J. Anderson, Mark Shackleton, Suzanne Manning, Anne Hamilton, Dale W. Garsed, Huei San Leong, Timothy Semple, and Paul Waring
Subjects: DNA Mutational Analysis, Genes, BRCA2, Genes, BRCA1, Drug resistance, Biology, Retinoblastoma Protein, Germline, Cohort Studies, Germline mutation, Cyclin E, Genes, Neurofibromatosis 1, medicine, PTEN, Humans, ATP Binding Cassette Transporter, Subfamily B, Member 1, Promoter Regions, Genetic, Germ-Line Mutation, Genetics, Oncogene Proteins, Ovarian Neoplasms, Multidisciplinary, Genome, Human, PTEN Phosphohydrolase, Combination chemotherapy, DNA Methylation, medicine.disease, Cystadenocarcinoma, Serous, DNA-Binding Proteins, Serous fluid, Drug Resistance, Neoplasm, Mutagenesis, DNA methylation, Cancer research, biology.protein, Female, Ovarian cancer
Abstract: Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.
Published: 2014

33. Molecular and morphological analyses of the cuttlefish Sepia apama indicate a complex population structure

Author: Karina C. Hall, Karin S. Kassahn, Mark Adams, Paul W. Shaw, Anthony J. Fowler, and Stephen C. Donnellan
Subjects: 0106 biological sciences, Cuttlefish, Morphometrics, 0303 health sciences, Panmixia, Ecology, biology, Sepia apama, Population genetics, Zoology, Reproductive isolation, Aquatic Science, biology.organism_classification, 010603 evolutionary biology, 01 natural sciences, 03 medical and health sciences, Vicariance, Microsatellite, 14. Life underwater, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology
Abstract: The giant Australian cuttlefish Sepia apama Gray, 1849 annually forms a massive and unique spawning aggregation in northern Spencer Gulf, South Australia, which has attracted commercial fishing interests in recent years. However, many basic life-history characteristics of S. apama are unknown, and anecdotal evidence suggests that there is more than one species. The present study assessed the population structure and species status of S. apama using data from allozyme electrophoresis, microsatellite loci, nucleotide sequences of the mitochondrial COXIII gene, multivariate morphometrics and colour patterns. Analyses of allozyme and microsatellite allele frequencies revealed two very divergent but geographically separated populations consisting of specimens from the east coast and southern Australia. However, the presence of a heterozygote in a putative contact zone between the east coast and southern Australia suggested that these populations were not reproductively isolated. Mitochondrial haplo-types seem to have introgressed further north into the contact zone than have nuclear alleles. Differences in colour patterns that previously had been attributed anecdotally to different geographic populations were, in fact, correlated with sexual dimorphism. These data are most consistent with S. apama being one species the populations of which were geographically isolated in the past (historical vicariance) and have come into secondary contact. Comparison of microsatellite allele frequencies among four South Australian samples indicated significant deviations from panmixia. South Australian samples were also reliably diagnosed by means of multivariate morphometrics. Significant differences in mantle length were observed among populations.
Published: 2003

34. Presentation of m.3243AG (MT-TL1; tRNALeu) variant with focal neurology in infancy

Author: David Ketteridge, Dylan A. Mordaunt, Hamish S. Scott, Drago Bratkovic, Karin S. Kassahn, Afdal Ibrahim, Nicholas Smith, Liam C. McIntyre, Hayley Salvemini, Mordaunt, David A, McIntyre, Liam C, Salvemini, Hayley, Ibrahim, Afdal, Bratkovic, Drago, Ketteridge, David, Scott, Hamish S, Kassahn, Karin S, and Smith, Nicholas
Subjects: Male, Hemiparesis, G%22">M.3243A>G, medicine.medical_specialty, Mitochondrial DNA, Neurology, RNA, Transfer, Leu, Encephalopathy, Mitochondrion, Biology, medicine.disease_cause, DNA, Mitochondrial, 7q36.3 duplication, Genetics, medicine, Humans, Exome, Genetics (clinical), Mutation, Infant, Newborn, Infant, Sequence Analysis, DNA, medicine.disease, Magnetic Resonance Imaging, Mitochondria, Maternally inherited diabetes and deafness (MIDD), MT-TL1, Lactic acidosis, Child, Preschool, Female, Nervous System Diseases
Abstract: The Mitochondrial tRNALeu (MT-TL1) mutation, m.3243A>G constitutes the commonest identified mitochondrial genome mutation. Characteristically, giving rise to MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), a phenotypic spectrum associated with this genetic variant is now apparent. We report on the first patient with infantile hemiparesis, without comorbid encephalopathy, attributed to this variant. This further expands the recognized disease spectrum and highlights the need to consider mitochondrial genomic mutations in cases of cryptogenic focal neurological deficit in infancy. The potential for genetic disease modifiers is additionally discussed. usc Refereed/Peer-reviewed
Published: 2014

35. Clinical and molecular characterization of HER2 amplified-pancreatic cancer

Author: Christopher W. Toon, Jaswinder S. Samra, Lorraine A. Chantrill, Mark Pinese, Ilse Rooman, Nicola Waddell, David Goldstein, Katia Nones, Jeremy L. Humphris, Mark J. Cowley, Anthony J. Gill, John V. Pearson, David Miller, Harpreet Wasan, Andrew V. Biankin, Venessa T. Chin, Adrienne Morey, Marina Pajic, Adnan Nagrial, Jianmin Wu, Karin S. Kassahn, Angela Chou, Elizabeth A. Musgrove, Amber L. Johns, Sean M. Grimmond, R. Scott Mead, Ann-Marie Patch, David K. Chang, Basic (bio-) Medical Sciences, and Laboratory for Medical and Molecular Oncology
Subjects: Oncology, medicine.medical_specialty, endocrine system diseases, Disease, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Trastuzumab, Pancreatic cancer, Internal medicine, Genetics, medicine, HER2 Amplification, Genetics(clinical), Lung cancer, skin and connective tissue diseases, Molecular Biology, neoplasms, Genetics (clinical), 030304 developmental biology, 0303 health sciences, business.industry, Research, medicine.disease, Human genetics, Gemcitabine, digestive system diseases, 3. Good health, 030220 oncology & carcinogenesis, Molecular Medicine, business, medicine.drug
Abstract: Background:\ud Pancreatic cancer is one of the most lethal and molecularly diverse malignancies. Repurposing of therapeutics that target specific molecular mechanisms in different disease types offers potential for rapid improvements in outcome. Although HER2 amplification occurs in pancreatic cancer, it is inadequately characterized to exploit the potential of anti-HER2 therapies.\ud \ud Methods:\ud HER2 amplification was detected and further analyzed using multiple genomic sequencing approaches. Standardized reference laboratory assays defined HER2 amplification in a large cohort of patients (n = 469) with pancreatic ductal adenocarcinoma (PDAC).\ud \ud Results:\ud An amplified inversion event (1 MB) was identified at the HER2 locus in a patient with PDAC. Using standardized laboratory assays, we established diagnostic criteria for HER2 amplification in PDAC, and observed a prevalence of 2%. Clinically, HER2- amplified PDAC was characterized by a lack of liver metastases, and a preponderance of lung and brain metastases. Excluding breast and gastric cancer, the incidence of HER2-amplified cancers in the USA is >22,000 per annum.\ud \ud Conclusions:\ud HER2 amplification occurs in 2% of PDAC, and has distinct features with implications for clinical practice. The molecular heterogeneity of PDAC implies that even an incidence of 2% represents an attractive target for anti-HER2 therapies, as options for PDAC are limited. Recruiting patients based on HER2 amplification, rather than organ of origin, could make trials of anti-HER2 therapies feasible in less common cancer types.
Published: 2013

36. Complex genetic test requests in SA: An MDT approach

Author: Karin S. Kassahn, Peter A. Kaub, and Janice M. Fletcher
Subjects: Computer science, Data mining, computer.software_genre, computer, Pathology and Forensic Medicine, Test (assessment)
Published: 2016

37. Complex evolutionary relationships among four classes of modular RNA-binding splicing regulators in eukaryotes: the hnRNP, SR, ELAV-like and CELF proteins

Author: Karin S. Kassahn, Adam Skarshewski, Siew Ping Han, Joseph A. Rothnagel, Yue Hang Tang, and Ross Smith
Subjects: CCAAT-Enhancer-Binding Protein-delta, Heterogeneous nuclear ribonucleoprotein, Protein family, RNA Splicing, Amino Acid Motifs, Molecular Sequence Data, RNA-binding protein, Computational biology, Biology, Heterogeneous-Nuclear Ribonucleoproteins, Evolution, Molecular, Consensus Sequence, Genetics, Animals, Cluster Analysis, Humans, Amino Acid Sequence, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, Phylogeny, Phylogenetic tree, Serine-Arginine Splicing Factors, Alternative splicing, Computational Biology, Eukaryota, Nuclear Proteins, RNA-Binding Proteins, Structural Classification of Proteins database, ELAV Proteins, RNA splicing, Sequence Alignment
Abstract: Alternative RNA splicing in multicellular organisms is regulated by a large group of proteins of mainly unknown origin. To predict the functions of these proteins, classification of their domains at the sequence and structural level is necessary. We have focused on four groups of splicing regulators, the heterogeneous nuclear ribonucleoprotein (hnRNP), serine–arginine (SR), embryonic lethal, abnormal vision (ELAV)-like, and CUG-BP and ETR-like factor (CELF) proteins, that show increasing diversity among metazoa. Sequence and phylogenetic analyses were used to obtain a broader understanding of their evolutionary relationships. Surprisingly, when we characterised sequence similarities across full-length sequences and conserved domains of ten metazoan species, we found some hnRNPs were more closely related to SR, ELAV-like and CELF proteins than to other hnRNPs. Phylogenetic analyses and the distribution of the RRM domains suggest that these proteins diversified before the last common ancestor of the metazoans studied here through domain acquisition and duplication to create genes of mixed evolutionary origin. We propose that these proteins were derived independently rather than through the expansion of a single protein family. Our results highlight inconsistencies in the current classification system for these regulators, which does not adequately reflect their evolutionary relationships, and suggests that a domain-based classification scheme may have more utility.
Published: 2012

38. PINA v2.0: mining interactome modules

Author: Sampsa Hautaniemi, Mark Pinese, Mark J. Cowley, Andrew V. Biankin, John V. Pearson, Nic Waddell, Jianmin Wu, Karin S. Kassahn, Sean M. Grimmond, Genome-Scale Biology (GSB) Research Program, Department of Biochemistry and Developmental Biology, and Bioinformatics
Subjects: education, Computational biology, Biology, Bioinformatics, computer.software_genre, protein interactions, Interactome, Set (abstract data type), 03 medical and health sciences, Mice, 0302 clinical medicine, Interaction network, Protein Interaction Mapping, Genetics, Computer Graphics, Animals, Cluster Analysis, Data Mining, Humans, KEGG, Cluster analysis, Databases, Protein, 030304 developmental biology, 0303 health sciences, Proteins, Molecular Sequence Annotation, bioinformatics, Articles, Visualization, Rats, 030220 oncology & carcinogenesis, 3111 Biomedicine, computer, Algorithms, Software, Data integration
Abstract: The Protein Interaction Network Analysis (PINA) platform is a comprehensive web resource, which includes a database of unified protein-protein interaction data integrated from six manually curated public databases, and a set of built-in tools for network construction, filtering, analysis and visualization. The second version of PINA enhances its utility for studies of protein interactions at a network level, by including multiple collections of interaction modules identified by different clustering approaches from the whole network of protein interactions ('interactome') for six model organisms. All identified modules are fully annotated by enriched Gene Ontology terms, KEGG pathways, Pfam domains and the chemical and genetic perturbations collection from MSigDB. Moreover, a new tool is provided for module enrichment analysis in addition to simple query function. The interactome data are also available on the web site for further bioinformatics analysis. PINA is freely accessible at http://cbg.garvan.unsw.edu.au/pina/.
Published: 2011

39. Deep-transcriptome and ribonome sequencing redefines the molecular networks of pluripotency\ud and the extracellular space in human embryonic stem cells

Author: Shivangi Wani, Darrin Taylor, Nicole Cloonan, Qi Zhou, Hun S. Chy, Scott Kuersten, Jill L. Shepherd, Ehsan Nourbakhsh, Kevin McKernan, David L. A. Wood, Brooke Gardiner, Andrew L. Laslett, Gabriel Kolle, Sean M. Grimmond, and Karin S. Kassahn
Subjects: Genetics, Pluripotent Stem Cells, Models, Genetic, Three prime untranslated region, Sequence Analysis, RNA, Research, RNA, Computational biology, Biology, Stem cell marker, Q1, Embryonic stem cell, Cell Line, Transcriptome, Transcription (biology), Humans, Induced pluripotent stem cell, Gene, 3' Untranslated Regions, Genetics (clinical), Embryonic Stem Cells
Abstract: Recent RNA-sequencing studies have shown remarkable complexity in the mammalian transcriptome. The ultimate impact of this complexity on the predicted proteomic output is less well defined. We have undertaken strand-specific RNA sequencing of multiple cellular RNA fractions (>20 Gb) to uncover the transcriptional complexity of human embryonic stem cells (hESCs). We have shown that human embryonic stem (ES) cells display a high degree of transcriptional diversity, with more than half of active genes generating RNAs that differ from conventional gene models. We found evidence that more than 1000 genes express long 5′ and/or extended 3′UTRs, which was confirmed by “virtual Northern” analysis. Exhaustive sequencing of the membrane-polysome and cytosolic/untranslated fractions of hESCs was used to identify RNAs encoding peptides destined for secretion and the extracellular space and to demonstrate preferential selection of transcription complexity for translation in vitro. The impact of this newly defined complexity on known gene-centric network models such as the Plurinet and the cell surface signaling machinery in human ES cells revealed a significant expansion of known transcript isoforms at play, many predicting possible alternative functions based on sequence alterations within key functional domains.
Published: 2011

40. Mineralocorticoid receptors: evolutionary and pathophysiological considerations

Author: John W. Funder, Karin S. Kassahn, and Mark A. Ragan
Subjects: Models, Molecular, medicine.medical_specialty, medicine.drug_class, Protein Conformation, Estrogen receptor, Whole genome duplication, Trees (plant), Biology, Evolution, Molecular, Endocrinology, Mineralocorticoid receptor, Receptors, Glucocorticoid, Internal medicine, medicine, Animals, Humans, Receptor, Phylogeny, Phylogenetic tree, Bayes Theorem, Receptors, Mineralocorticoid, Nuclear receptor, Mineralocorticoid, Receptors, Androgen, Receptors, Progesterone
Abstract: Mineralocorticoid receptors (MR), glucocorticoid receptors (GR), progesterone receptors (PR), and androgen receptors (AR) comprise a closely related subfamily within the human 49-member nuclear receptor family. These receptors and their cognate ligands play major roles in homeostasis, reproduction, growth, and development, despite which their evolution and diversification remains incompletely understood. Several conflicting models have been advanced for the evolution of this subfamily. We have thus undertaken Bayesian and maximum likelihood phylogenetic analyses of this subfamily. The Bayesian consensus and maximum likelihood trees support a basal position for MR, with the PR and AR forming a sister clade. We next performed analyses using topological constraints to directly contrast the likelihood of seven phylogenetic models. In these analyses, three models have similar support: one proposes two sister clades (MR and GR, PR and AR); the other two propose a different subfamily member (MR or GR) to be the first to have diverged. Ancestral state reconstructions at sites critical for physiological function show that the S810L mutation in the MR, which results in the MR being similar to estrogen receptors and the more distantly related retinoic acid receptor-α is likely to reflect the ancestral receptor sequence before the divergence of this subfamily and provides further support for MR having been the first of the subfamily to diverge. Finally, we drew on pathophysiological comparisons to help to distinguish the different models. On the basis of our phylogenetic analyses and pathophysiological considerations, we propose that the MR was the first to diverge from the ancestral gene lineage from which this subfamily derived.
Published: 2011

41. Sequencing transcriptomes in toto

Author: Sean M. Grimmond, Nic Waddell, and Karin S. Kassahn
Subjects: Genetics, Base Sequence, Gene Expression Profiling, Molecular Sequence Data, Biophysics, RNA-Seq, Locus (genetics), Computational biology, Biology, Biochemistry, Transcriptome, Gene expression profiling, microRNA, RNA, Base sequence, Human genome, Illumina dye sequencing, Algorithms, Oligonucleotide Array Sequence Analysis
Abstract: The development of next-generation sequencing technologies has enabled the transcriptome to be measured and characterized at a level which was previously unattainable. Shot gun sequencing of RNAs, or RNA-Seq as it is known, is providing the means to simultaneously survey locus activity, transcript-specific expression, sequence content of transcripts and transcriptome discovery. This article discusses the current state of RNA-Seq, its potential for redefining transcriptomics and some of the challenges associated with this revolutionary technology.
Published: 2011

42. Ensuring clinical validity - modernising genetic testing services

Author: Hamish S. Scott, Janice M. Fletcher, and Karin S. Kassahn
Subjects: medicine.diagnostic_test, Referral, business.industry, Mechanism (biology), media_common.quotation_subject, Bioinformatics, Payment, Pathology and Forensic Medicine, Test (assessment), Risk analysis (engineering), Clinical diagnosis, medicine, Clinical validity, Personalized medicine, business, Genetic testing, media_common
Abstract: Genomic testing using gene panels and whole-exome sequence data are becoming increasingly attractive options to support the clinical management of patients. Whole-exome sequencing to diagnose rare genetic disorders in paediatrics offers a cost-effective and efficient first screen for cases where there is no obvious clinical diagnosis, thus fundamentally shifting medical service provision paradigms. In other areas of medicine, the implementation of targeted gene panels using next generation sequencing is associated with improved diagnosis rate and faster time to diagnosis. Successful integration of genomic testing into the patient management pathway requires updating of the traditional models of test provision. Important factors to be considered include: who should qualify for what genomic test, payment for testing, the appropriate referral mechanism, and how to effectively communicate the results and limitations of genomic tests to patients and clinicians. We discuss strategies and give examples from implementing gene panels and whole-exome sequencing in clinical diagnostics to support the management of patients in South Australia. The next few years are likely to be an exciting and challenging time in genomic test provision in Australia, as these new platforms establish themselves as part of routine medical care and different stakeholders (local, international, direct-to-consumer) define their share of the clinical sequencing market.
Published: 2014

43. Functional implications of the emergence of alternative splicing in hnRNP A/B transcripts

Author: Mark A. Ragan, Adam Skarshewski, Siew Ping Han, Karin S. Kassahn, Joseph A. Rothnagel, and Ross Smith
Subjects: Genetics, Splice site mutation, Alternative splicing, Exonic splicing enhancer, Intron, Biology, Regulatory Sequences, Ribonucleic Acid, Heterogeneous ribonucleoprotein particle, Article, Rats, Evolution, Molecular, Exon, Splicing factor, Alternative Splicing, Mice, RNA splicing, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Animals, Humans, RNA Splice Sites, RNA, Messenger, Molecular Biology, HeLa Cells
Abstract: The heterogeneous nuclear ribonucleoproteins (hnRNPs) A/B are a family of RNA-binding proteins that participate in various aspects of nucleic acid metabolism, including mRNA trafficking, telomere maintenance, and splicing. They are both regulators and targets of alternative splicing, and the patterns of alternative splicing of their transcripts have diverged between paralogs and between orthologs in different species. Surprisingly, the extent of this splicing variation and its implications for post-transcriptional regulation have remained largely unexplored. Here, we conducted a detailed analysis of hnRNP A/B sequences and expression patterns across six vertebrates. Alternative exons emerged via the introduction of new splice sites, changes in the strengths of existing splice sites, and the accumulation of auxiliary splicing regulatory motifs. Observed isoform expression patterns could be attributed to the frequency and strength of cis-elements. We found a trend toward increased splicing variation in mammals and identified novel alternatively spliced isoforms in human and chicken. Pulldown and translational assays demonstrated that the inclusion of alternative exons altered the affinity of hnRNP A/B proteins for their cognate nucleic acids and modified protein expression levels. As the hnRNPs A/B regulate several key steps in mRNA processing, the involvement of diverse hnRNP isoforms in multiple cellular contexts and species implies concomitant differences in the transcriptional output of these systems. We conclude that the emergence of alternative splicing in the hnRNPs A/B has contributed to the diversification of their roles in the regulation of alternative splicing and has thus added an unexpected layer of regulatory complexity to transcription in vertebrates.
Published: 2010

44. A visual framework for sequence analysis using n-grams and spectral rearrangement

Author: Jasmyn A. Dunn, Siew Ping Han, Eva Z. Curley, Stefan Maetschke, Karin S. Kassahn, Katryn J. Stacey, and Mark A. Ragan
Subjects: Statistics and Probability, Genetics, Multiple sequence alignment, Shuffling, Sequence analysis, Proteins, Sequence alignment, Computational biology, Biology, Biochemistry, Computer Science Applications, Computational Mathematics, Sequence logo, Computational Theory and Mathematics, Protein methods, Sequence Analysis, Protein, Consensus sequence, Computer Graphics, Databases, Protein, Molecular Biology, Sequence Alignment, Alignment-free sequence analysis
Abstract: Motivation: Protein sequences are often composed of regions that have distinct evolutionary histories as a consequence of domain shuffling, recombination or gene conversion. New approaches are required to discover, visualize and analyze these sequence regions and thus enable a better understanding of protein evolution. Results: Here, we have developed an alignment-free and visual approach to analyze sequence relationships. We use the number of shared n-grams between sequences as a measure of sequence similarity and rearrange the resulting affinity matrix applying a spectral technique. Heat maps of the affinity matrix are employed to identify and visualize clusters of related sequences or outliers, while n-gram-based dot plots and conservation profiles allow detailed analysis of similarities among selected sequences. Using this approach, we have identified signatures of domain shuffling in an otherwise poorly characterized family, and homology clusters in another. We conclude that this approach may be generally useful as a framework to analyze related, but highly divergent protein sequences. It is particularly useful as a fast method to study sequence relationships prior to much more time-consuming multiple sequence alignment and phylogenetic analysis. Availability: A software implementation (MOSAIC) of the framework described here can be downloaded from http://bioinformatics.org.au/mosaic/ Contact: m.ragan@uq.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.
Published: 2010

45. Identification of human haploinsufficient genes and their genomic proximity to segmental duplications

Author: Mark A. Ragan, Vinh T. Dang, Karin S. Kassahn, and Andrés Esteban Marcos
Subjects: Genetics, PubMed, Genome, Human, Non-allelic homologous recombination, Genetic Diseases, Inborn, Low copy repeats, Biology, Genome, Gene Duplication, Gene duplication, Chromosomes, Human, Humans, Human genome, Copy-number variation, Haploinsufficiency, Genetics (clinical), Software, Segmental duplication
Abstract: Despite the significance of haploinsufficiency in human disease, no systematic study has been reported into the types of genes that are haploinsufficient in human, or into the mechanisms that commonly lead to their deletion and to the expression of the haploinsufficient phenotype. We have applied a rigorous text-searching and database-mining strategy to extract, as comprehensively as possible, from PubMed and OMIM an annotated list of currently known human haploinsufficient genes, including their functions and associated diseases. Gene-set enrichment analysis shows that genes-encoding transcription factors, and genes that function in development, the cell cycle, and nucleic acid metabolism are overrepresented among haploinsufficient genes in human. Many of the phenotypes associated with loss-of-function or deletion of one copy of a haploinsufficient gene describe mental retardation, developmental or metabolic disorders, or tumourigenesis. We also found that haploinsufficient genes are less likely than the complete set of human genes to be situated between pairs of segmental duplications (SDs) that are in close proximity to each other on the same chromosome. Given that SDs can initiate non-allelic homologous recombination (NAHR) and the deletion of adjacent genomic regions, this suggests that the location of haploinsufficient genes between SD pairs, from whence they may suffer intra-genomic rearrangement and loss, is selectively disadvantageous. We describe a custom-made Java visualization tool, HaploGeneMapper, to aid in visualizing the proximity of human haploinsufficient genes to SDs and to enable identification of haploinsufficient genes that are vulnerable to NAHR-mediated deletion.
Published: 2008

46. Heterologous microarray experiments used to identify the early gene response to heat stress in a coral reef fish

Author: Karin S, Kassahn, M Julian, Caley, Alister C, Ward, Ashley R, Connolly, Glenn, Stone, and Ross H, Crozier
Subjects: Base Sequence, Gene Expression Regulation, Gene Expression Profiling, Animals, RNA, Messenger, Polymerase Chain Reaction, Conserved Sequence, Heat-Shock Response, Zebrafish, Oligonucleotide Array Sequence Analysis, Perciformes
Abstract: Coral reef fishes are expected to experience rising sea surface temperatures due to climate change. How well tropical reef fishes will respond to these increased temperatures and which genes are important in the response to elevated temperatures is not known. Microarray technology provides a powerful tool for gene discovery studies, but the development of microarrays for individual species can be expensive and time-consuming. In this study, we tested the suitability of a Danio rerio oligonucleotide microarray for application in a species with few genomic resources, the coral reef fish Pomacentrus moluccensis. Results from a comparative genomic hybridization experiment and direct sequence comparisons indicate that for most genes there is considerable sequence similarity between the two species, suggesting that the D. rerio array is useful for genomic studies of P. moluccensis. We employed this heterologous microarray approach to characterize the early transcriptional response to heat stress in P. moluccensis. A total of 111 gene loci, many of which are involved in protein processing, transcription, and cell growth, showed significant changes in transcript abundance following exposure to elevated temperatures. Changes in transcript abundance were validated for a selection of candidate genes using quantitative real-time polymerase chain reaction. This study demonstrates that heterologous microarrays can be successfully employed to study species for which specific microarrays have not yet been developed, and so have the potential to greatly enhance the utility of microarray technology to the field of environmental and functional genomics.
Published: 2007

47. Returning individual research results for genome sequences of pancreatic cancer

Author: Karin S. Kassahn, Anthony J. Gill, Jeremy L. Humphris, David K. Chang, Lesley Andrews, Andrew V. Biankin, David Miller, Amber L. Johns, Marina Pajic, Skye Simpson, Jaswinder S. Samra, Sean M. Grimmond, Katherine L. Tucker, Nicola Waddell, John V. Pearson, and Nikolajs Zeps
Subjects: medicine.medical_specialty, business.industry, Research, Alternative medicine, Context (language use), medicine.disease, Bioinformatics, Genome, Human genetics, Clinical pathway, Close relationship, Family medicine, Pancreatic cancer, Genetics, medicine, Molecular Medicine, Genetics(clinical), Risks and benefits, business, Molecular Biology, Genetics (clinical)
Abstract: Background:\ud Disclosure of individual results to participants in genomic research is a complex and contentious issue. There are many existing commentaries and opinion pieces on the topic, but little empirical data concerning actual cases describing how individual results have been returned. Thus, the real life risks and benefits of disclosing individual research results to participants are rarely if ever presented as part of this debate.\ud \ud Methods:\ud The Australian Pancreatic Cancer Genome Initiative (APGI) is an Australian contribution to the International Cancer Genome Consortium (ICGC), that involves prospective sequencing of tumor and normal genomes of study participants with pancreatic cancer in Australia. We present three examples that illustrate different facets of how research results may arise, and how they may be returned to individuals within an ethically defensible and clinically practical framework. This framework includes the necessary elements identified by others including consent, determination of the significance of results and which to return, delineation of the responsibility for communication and the clinical pathway for managing the consequences of returning results.\ud \ud Results:\ud Of 285 recruited patients, we returned results to a total of 25 with no adverse events to date. These included four that were classified as medically actionable, nine as clinically significant and eight that were returned at the request of the treating clinician. Case studies presented depict instances where research results impacted on cancer susceptibility, current treatment and diagnosis, and illustrate key practical challenges of developing an effective framework.\ud \ud Conclusions:\ud We suggest that return of individual results is both feasible and ethically defensible but only within the context of a robust framework that involves a close relationship between researchers and clinicians.
Published: 2014

48. Somatic Point Mutation Calling in Low Cellularity Tumors

Author: Ivon Harliwong, Scott Wood, Felicity Newell, Peter Wilson, Andrew V. Biankin, Lynn Fink, Anthony J. Gill, Suzanne Manning, David K. Chang, Sarah Song, Marina Pajic, Darrin Taylor, Senel Idrisoglu, Ann-Marie Patch, Ehsan Nourbakhsh, Mark J. Cowley, Katia Nones, Anita L Steptoe, Nicola Waddell, Craig Nourse, John V. Pearson, Shivangi Wani, Amber L. Johns, Timothy J. C. Bruxner, Mark Pinese, Qinying Xu, Oliver Holmes, David Miller, Karin S. Kassahn, Angelika N. Christ, Conrad Leonard, Sean M. Grimmond, Matthew J. Anderson, and Jianmin Wu
Subjects: DNA Copy Number Variations, Somatic cell, lcsh:Medicine, Biology, Polymerase Chain Reaction, Germline, law.invention, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, law, Neoplasms, Humans, Point Mutation, Allele, lcsh:Science, Polymerase chain reaction, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Point mutation, lcsh:R, Computational Biology, High-Throughput Nucleotide Sequencing, 030220 oncology & carcinogenesis, Mutation, Mutation (genetic algorithm), lcsh:Q, Human genome, Software, Research Article
Abstract: Somatic mutation calling from next-generation sequencing data remains a challenge due to the difficulties of distinguishing true somatic events from artifacts arising from PCR, sequencing errors or mis-mapping. Tumor cellularity or purity, sub-clonality and copy number changes also confound the identification of true somatic events against a background of germline variants. We have developed a heuristic strategy and software (http://www.qcmg.org/bioinformatics/qsnp/) for somatic mutation calling in samples with low tumor content and we show the superior sensitivity and precision of our approach using a previously sequenced cell line, a series of tumor/normal admixtures, and 3,253 putative somatic SNVs verified on an orthogonal platform.
Published: 2013

49. qpure: A Tool to Estimate Tumor Cellularity from Genome-Wide Single-Nucleotide Polymorphism Profiles

Author: Nic Waddell, Qinying Xu, Mark J. Cowley, Andrew V. Biankin, Ivon Harliwong, Felicity Newell, Katia Nones, Scott Wood, Peter Wilson, Sean M. Grimmond, David Miller, Amber L. Johns, Marina Pajic, Jianmin Wu, Mark Pinese, Karin S. Kassahn, Sarah Song, Conrad Leonard, Oliver Holmes, Matthew J. Anderson, Lynn Fink, John V. Pearson, Anthony J. Gill, and Darrin Taylor
Subjects: Pathology, Loss of Heterozygosity, Genome-wide association study, medicine.disease_cause, Loss of heterozygosity, 0302 clinical medicine, Gene Frequency, Genome Sequencing, 0303 health sciences, Multidisciplinary, Statistics, Exons, Genomics, 3. Good health, 030220 oncology & carcinogenesis, Regression Analysis, Medicine, KRAS, Sequence Analysis, Algorithms, Molecular Pathology, Research Article, Biotechnology, SNP array, medicine.medical_specialty, Science, Copy number analysis, Single-nucleotide polymorphism, Biostatistics, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Germline mutation, Genome Analysis Tools, Diagnostic Medicine, Cell Line, Tumor, Genetics, Cancer Genetics, medicine, Humans, Allele frequency, 030304 developmental biology, Models, Statistical, Sequence Assembly Tools, Models, Genetic, Computational Biology, Sequence Analysis, DNA, Pancreatic Neoplasms, Gene Expression Regulation, Mutation, Genetic Polymorphism, Software, Population Genetics, Mathematics, Genome-Wide Association Study, General Pathology
Abstract: Tumour cellularity, the relative proportion of tumour and normal cells in a sample, affects the sensitivity of mutation detection, copy number analysis, cancer gene expression and methylation profiling. Tumour cellularity is traditionally estimated by pathological review of sectioned specimens; however this method is both subjective and prone to error due to heterogeneity within lesions and cellularity differences between the sample viewed during pathological review and tissue used for research purposes. In this paper we describe a statistical model to estimate tumour cellularity from SNP array profiles of paired tumour and normal samples using shifts in SNP allele frequency at regions of loss of heterozygosity (LOH) in the tumour. We also provide qpure, a software implementation of the method. Our experiments showed that there is a medium correlation 0.42 ([Formula: see text]-value=0.0001) between tumor cellularity estimated by qpure and pathology review. Interestingly there is a high correlation 0.87 ([Formula: see text]-value [Formula: see text] 2.2e-16) between cellularity estimates by qpure and deep Ion Torrent sequencing of known somatic KRAS mutations; and a weaker correlation 0.32 ([Formula: see text]-value=0.004) between IonTorrent sequencing and pathology review. This suggests that qpure may be a more accurate predictor of tumour cellularity than pathology review. qpure can be downloaded from https://sourceforge.net/projects/qpure/.
Published: 2012

50. The mammalian PYHIN gene family: Phylogeny, evolution and expression

Author: Jasmyn A. Cridland, Matthew J. Sweet, Michelle N. Wykes, Kate Schroder, Eva Z. Curley, Mark A. Ragan, Katryn J. Stacey, Tara L. Roberts, and Karin S. Kassahn
Subjects: Evolution, Inflammasomes, Pseudogene, AIM2, Biology, cytosolic DNA, Pyrin domain, Genome, Evolution, Molecular, 03 medical and health sciences, Mice, 0302 clinical medicine, Phylogenetics, Gene duplication, QH359-425, Gene family, Animals, Humans, IFI16, Gene, Ecology, Evolution, Behavior and Systematics, Phylogeny, 030304 developmental biology, Genetics, Mammals, 0303 health sciences, PYHIN, Nuclear Proteins, Bayes Theorem, HIN-200, Rats, DNA-Binding Proteins, Mice, Inbred C57BL, Evolutionary biology, 030220 oncology & carcinogenesis, ALR, Transcriptome, Research Article
Abstract: Background Proteins of the mammalian PYHIN (IFI200/HIN-200) family are involved in defence against infection through recognition of foreign DNA. The family member absent in melanoma 2 (AIM2) binds cytosolic DNA via its HIN domain and initiates inflammasome formation via its pyrin domain. AIM2 lies within a cluster of related genes, many of which are uncharacterised in mouse. To better understand the evolution, orthology and function of these genes, we have documented the range of PYHIN genes present in representative mammalian species, and undertaken phylogenetic and expression analyses. Results No PYHIN genes are evident in non-mammals or monotremes, with a single member found in each of three marsupial genomes. Placental mammals show variable family expansions, from one gene in cow to four in human and 14 in mouse. A single HIN domain appears to have evolved in the common ancestor of marsupials and placental mammals, and duplicated to give rise to three distinct forms (HIN-A, -B and -C) in the placental mammal ancestor. Phylogenetic analyses showed that AIM2 HIN-C and pyrin domains clearly diverge from the rest of the family, and it is the only PYHIN protein with orthology across many species. Interestingly, although AIM2 is important in defence against some bacteria and viruses in mice, AIM2 is a pseudogene in cow, sheep, llama, dolphin, dog and elephant. The other 13 mouse genes have arisen by duplication and rearrangement within the lineage, which has allowed some diversification in expression patterns. Conclusions The role of AIM2 in forming the inflammasome is relatively well understood, but molecular interactions of other PYHIN proteins involved in defence against foreign DNA remain to be defined. The non-AIM2 PYHIN protein sequences are very distinct from AIM2, suggesting they vary in effector mechanism in response to foreign DNA, and may bind different DNA structures. The PYHIN family has highly varied gene composition between mammalian species due to lineage-specific duplication and loss, which probably indicates different adaptations for fighting infectious disease. Non-genomic DNA can indicate infection, or a mutagenic threat. We hypothesise that defence of the genome against endogenous retroelements has been an additional evolutionary driver for PYHIN proteins.
Published: 2012

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