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7 results on '"Panagiotis Katsonis"'

1. Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

Author

Felix Marbach, Georgi Stoyanov, Florian Erger, Constantine A. Stratakis, Nikolaos Settas, Edra London, Jill A. Rosenfeld, Erin Torti, Chad Haldeman-Englert, Evgenia Sklirou, Elena Kessler, Sophia Ceulemans, Stanley F. Nelson, Julian A. Martinez-Agosto, Christina G.S. Palmer, Rebecca H. Signer, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennett, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Daya, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Susan Korrick, Mary Kozuira, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Joel B. Krier, Grace L. LaMoure, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Calum A. MacRae, Ellen F. Macnamara, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Paolo Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, David R. Murdock, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Deepak A. Rao, Wendy Raskind, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, C. Ron Scott, Daryl A. Scott, Vandana Shashi, Jimann Shin, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, null Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, Marisa V. Andrews, Dorothy K. Grange, Rebecca Willaert, Richard Person, Aida Telegrafi, Aaron Sievers, Magdalena Laugsch, Susanne Theiß, YuZhu Cheng, Olivier Lichtarge, Panagiotis Katsonis, Amber Stocco, and Christian P. Schaaf

Subjects
0301 basic medicine, Apraxias, Autism Spectrum Disorder, Pain, Biology, Apraxia, Article, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Pregnancy, Intellectual Disability, Intellectual disability, medicine, Humans, Missense mutation, Global developmental delay, Genetics (clinical), Genetics, medicine.disease, Phenotype, Human genetics, 030104 developmental biology, Neurodevelopmental Disorders, Autism spectrum disorder, Cyclic AMP-Dependent Protein Kinase RIbeta Subunit, Female, 030217 neurology & neurosurgery
Abstract

Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

Published
2021

2. Structure and evolutionary trace-assisted screening of a residue swapping the substrate ambiguity and chiral specificity in an esterase

Author

Olivier Lichtarge, Julia Sanz-Aparicio, Rafael Bargiela, Peter N. Golyshin, Cristina Coscolín, Panagiotis Katsonis, Manuel Ferrer, Isabel Cea-Rama, European Commission, Ministerio de Economía y Competitividad (España), Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Biotechnology and Biological Sciences Research Council (UK), Welsh Government, National Institutes of Health (US), and ALBA Synchrotron

Subjects
Stereochemistry, Biophysics, Esterase, Biochemistry, Serine, 03 medical and health sciences, 0302 clinical medicine, Stereospecificity, Structural Biology, Genetics, 14. Life underwater, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Crystal structure, Evolutionary trace, Substrate (chemistry), Protein engineering, Promiscuity, Computer Science Applications, Amino acid, chemistry, 030220 oncology & carcinogenesis, Crystal structures, Mutation (genetic algorithm), Specificity, Isoleucine, TP248.13-248.65, Biotechnology
Abstract

11 pags., 6figs., 3 pags., Our understanding of enzymes with high substrate ambiguity remains limited because their large active sites allow substrate docking freedom to an extent that seems incompatible with stereospecificity. One possibility is that some of these enzymes evolved a set of evolutionarily fitted sequence positions that stringently allow switching substrate ambiguity and chiral specificity. To explore this hypothesis, we targeted for mutation a serine ester hydrolase (EH) that exhibits an impressive 71-substrate repertoire but is not stereospecific (e.e. 50%). We used structural actions and the computational evolutionary trace method to explore specificity-swapping sequence positions and hypothesized that position I244 was critical. Driven by evolutionary action analysis, this position was substituted to leucine, which together with isoleucine appears to be the amino acid most commonly present in the closest homologous sequences (max. identity, ca. 67.1%), and to phenylalanine, which appears in distant homologues. While the I244L mutation did not have any functional consequences, the I244F mutation allowed the esterase to maintain a remarkable 53-substrate range while gaining stereospecificity properties (e.e. 99.99%). These data support the possibility that some enzymes evolve sequence positions that control the substrate scope and stereospecificity. Such residues, which can be evolutionarily screened, may serve as starting points for further designing substrate-ambiguous, yet chiral-specific, enzymes that are greatly appreciated in biotechnology and synthetic chemistry., MF acknowledges the grant ‘INMARE’ from the EuropeanUnion’s Horizon 2020 (grant agreement no. 634486), the grantsPCIN-2017-078 (within the Marine Biotechnology ERA-NET) and BIO2017-85522-R from the Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI), Fondo Eur-opeo de Desarrollo Regional (FEDER) and the European Union (EU),and the grant 2020AEP061 from the Agencia Estatal CSIC. J.S-A.acknowledges grant PID2019-105838RB-C33 from the Ministeriode Ciencia e Innovación, Agencia Estatal de Investigación (AEI),Fondo Europeo de Desarrollo Regional (FEDER) and the EuropeanUnion (EU). P.N.G. acknowledges the support of the Era-Net IB Pro-ject MetaCat funded through UK Biotechnology and BiologicalSciences Research Council (BBSRC), grant No. BB/M029085/1, andthe Centre for Environmental Biotechnology Project, co-fundedby European Regional Development Fund (ERDF) via the WelshGovernment (WEFO); R.B. acknowledges the Supercomputing Wales project, co-funded by ERDF via WEFO. OL and PK were sup-ported by the National Institutes of Health (NIH) grants 5R01AG061105, 5R01GM066099, and 5R01GM079656. C. Coscolínthanks the Ministerio de Economía y Competitividad and FEDER fora PhD fellowship (Grant BES-2015-073829). Staff of the Synchrotron Radiation Source at Alba (Barcelona, Spain) for assistance at the BL13-XALOC beamline

Published
2021

3. FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance

Author

Abdulaziz Al-Saman, Mohammed Almannai, Matthew A. Lines, Amal Alhashem, Panagiotis Katsonis, Yaser I. Aljadhai, Julia Wang, Brahim Tabarki, Ayman W. El-Hattab, Mohammed A. Saleh, Adel A H Mahmoud, Ruba Benini, Dorothy K. Grange, Ali H Alwadei, Eissa Faqeih, Lee-Jun C. Wong, Hongzheng Dai, Ali Al Asmari, and Olivier Lichtarge

Subjects
Adult, Male, 0301 basic medicine, Mitochondrial Diseases, Adolescent, Phenylalanine, Endocrinology, Diabetes and Metabolism, Mitochondrion, Biology, Biochemistry, Amino Acyl-tRNA Synthetases, Mitochondrial Proteins, Structure-Activity Relationship, Young Adult, 03 medical and health sciences, Endocrinology, Genetics, Humans, Protein Isoforms, Missense mutation, Child, Molecular Biology, Loss function, Paraplegia, chemistry.chemical_classification, Evolutionary significance, Phenotype, Mitochondria, Amino acid, 030104 developmental biology, chemistry, Child, Preschool, Mutation, Transfer RNA, Female, Phenylalanine-tRNA Ligase, Trans-acting, Gene Deletion
Abstract

An increasing number of mitochondrial diseases are found to be caused by pathogenic variants in nuclear encoded mitochondrial aminoacyl-tRNA synthetases. FARS2 encodes mitochondrial phenylalanyl-tRNA synthetase (mtPheRS) which transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, a total of 21 subjects with FARS2 deficiency have been reported to date with a spectrum of disease severity that falls between two phenotypes; early onset epileptic encephalopathy and a less severe phenotype characterized by spastic paraplegia. In this report, we present an additional 15 individuals from 12 families who are mostly Arabs homozygous for the pathogenic variant Y144C, which is associated with the more severe early onset phenotype. The total number of unique pathogenic FARS2 variants known to date is 21 including three different partial gene deletions reported in four individuals. Except for the large deletions, all variants but two (one in-frame deletion of one amino acid and one splice-site variant) are missense. All large deletions and the single splice-site variant are in trans with a missense variant. This suggests that complete loss of function may be incompatible with life. In this report, we also review structural, functional, and evolutionary significance of select FARS2 pathogenic variants reported here.

Published
2018

4. Gnathodiaphyseal dysplasia: Severe atypical presentation with novel heterozygous mutation of the anoctamin gene (ANO5)

Author

Ghada A. Otaify, Marina Stolina, Marwan Shinawi, Olivier Lichtarge, Abby S. Hollander, Wei-Shen Chen, Samir K. El-Mofty, J. Eric Gordon, Albert S. Woo, Gary S. Gottesman, Michael P. Whyte, Marisa V. Andrews, William H. McAlister, Panagiotis Katsonis, Fan Zhang, and Deborah V. Veis

Subjects
Male, 0301 basic medicine, Diaphyseal sclerosis, Pathology, medicine.medical_specialty, Histology, Physiology, Gnathodiaphyseal dysplasia, Endocrinology, Diabetes and Metabolism, Mutation, Missense, Anoctamins, Article, 03 medical and health sciences, Exon, medicine, Humans, Missense mutation, Genetics, business.industry, Osteogenesis Imperfecta, Debulking, medicine.disease, Cherubism, Phenotype, 030104 developmental biology, Child, Preschool, Maxilla, Mutation (genetic algorithm), business
Abstract

Gnathodiaphyseal dysplasia (GDD; OMIM #166260) is an ultra-rare autosomal dominant disorder caused by heterozygous mutation in the anoctamin 5 (ANO5) gene and features fibro-osseous lesions of the jawbones, bone fragility with recurrent fractures, and bowing/sclerosis of tubular bones. The physiologic role of ANO5 is unknown. We report a 5-year-old boy with a seemingly atypical and especially severe presentation of GDD and unique ANO5 mutation. Severe osteopenia was associated with prenatal femoral fractures, recurrent postnatal fractures, and progressive bilateral enlargement of his maxilla and mandible beginning at ~ 2 months-of-age that interfered with feeding and speech and required four debulking operations. Histopathological analysis revealed benign fibro-osseous lesions resembling cemento-ossifying fibromas of the jaw without psammomatoid bodies. A novel, de novo, heterozygous, missense mutation was identified in exon 15 of ANO5 (c.1553G>A; p.Gly518Glu). Our findings broaden the phenotypic and molecular spectra of GDD. Fractures early in life with progressive facial swelling are key features. We assessed his response to a total of 7 pamidronate infusions commencing at age 15 months. Additional reports must further elucidate the phenotype, explore any genotype-phenotype correlation, and evaluate treatments.

Published
2018

5. Prediction and redesign of protein–protein interactions

Author

Angela D. Wilkins, Anbu Karani Adikesavan, David C. Marciano, Panagiotis Katsonis, Olivier Lichtarge, and Rhonald C. Lua

Subjects
Genetics, Protein function, Protein design, Biophysics, Computational Biology, Proteins, Computational biology, Biology, Article, Protein protein interaction network, Substrate Specificity, Protein–protein interaction, Functional annotation, Molecular evolution, Protein Interaction Mapping, Humans, Human genome, Molecular Biology
Abstract

Understanding the molecular basis of protein function remains a central goal of biology, with the hope to elucidate the role of human genes in health and in disease, and to rationally design therapies through targeted molecular perturbations. We review here some of the computational techniques and resources available for characterizing a critical aspect of protein function – those mediated by protein–protein interactions (PPI). We describe several applications and recent successes of the Evolutionary Trace (ET) in identifying molecular events and shapes that underlie protein function and specificity in both eukaryotes and prokaryotes. ET is a part of analytical approaches based on the successes and failures of evolution that enable the rational control of PPI.

Published
2014

6. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Author

Adrian Ally, Miruna Balasundaram, Rebecca Carlsen, Eric Chuah, Amanda Clarke, Noreen Dhalla, Robert A. Holt, Steven J.M. Jones, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Dorothy Cheung, Tina Wong, Denise Brooks, A. Gordon Robertson, Reanne Bowlby, Karen Mungall, Sara Sadeghi, Liu Xi, Kyle Covington, Eve Shinbrot, David A. Wheeler, Richard A. Gibbs, Lawrence A. Donehower, Linghua Wang, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Carmen Helsel, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Stacey B. Gabriel, Matthew Meyerson, Carrie Cibulskis, Bradley A. Murray, Juliann Shih, Rameen Beroukhim, Andrew D. Cherniack, Steven E. Schumacher, Gordon Saksena, Chandra Sekhar Pedamallu, Lynda Chin, Gad Getz, Michael Noble, Hailei Zhang, David Heiman, Juok Cho, Nils Gehlenborg, Douglas Voet, Pei Lin, Scott Frazer, Timothy Defreitas, Sam Meier, Michael Lawrence, Jaegil Kim, Chad J. Creighton, Donna Muzny, HarshaVardhan Doddapaneni, Jianhong Hu, Min Wang, Donna Morton, Viktoriya Korchina, Yi Han, Huyen Dinh, Lora Lewis, Michelle Bellair, Xiuping Liu, Jireh Santibanez, Robert Glenn, Sandra Lee, Walker Hale, Joel S. Parker, Matthew D. Wilkerson, D. Neil Hayes, Sheila M. Reynolds, Ilya Shmulevich, Wei Zhang, Yuexin Liu, Lisa Iype, Hala Makhlouf, Michael S. Torbenson, Sanjay Kakar, Matthew M. Yeh, Dhanpat Jain, David E. Kleiner, Renumathy Dhanasekaran, Hashem B. El-Serag, Sun Young Yim, John N. Weinstein, Lopa Mishra, Jianping Zhang, Rehan Akbani, Shiyun Ling, Zhenlin Ju, Xiaoping Su, Apurva M. Hegde, Gordon B. Mills, Yiling Lu, Jian Chen, Ju-Seog Lee, Bo Hwa Sohn, Jae Jun Shim, Pan Tong, Hiroyuki Aburatani, Shogo Yamamoto, Kenji Tatsuno, Wei Li, Zheng Xia, Nicolas Stransky, Eric Seiser, Federico Innocenti, Jianjiong Gao, Ritika Kundra, Hongxin Zhang, Zachary Heins, Angelica Ochoa, Chris Sander, Marc Ladanyi, Ronglai Shen, Arshi Arora, Francisco Sanchez-Vega, Nikolaus Schultz, Katayoon Kasaian, Amie Radenbaugh, Karl-Dimiter Bissig, David D. Moore, Yasushi Totoki, Hiromi Nakamura, Tatsuhiro Shibata, Christina Yau, Kiley Graim, Josh Stuart, David Haussler, Betty L. Slagle, Akinyemi I. Ojesina, Panagiotis Katsonis, Amanda Koire, Olivier Lichtarge, Teng-Kuei Hsu, Martin L. Ferguson, John A. Demchok, Ina Felau, Margi Sheth, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan Zhang, Carolyn M. Hutter, Heidi J. Sofia, Roel G.W. Verhaak, Siyuan Zheng, Frederick Lang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Ye Wu, Rashi Naresh, Todd Pihl, Charlie Sun, Yunhu Wan, Christopher Benz, Amy H. Perou, Leigh B. Thorne, Lori Boice, Mei Huang, W. Kimryn Rathmell, Houtan Noushmehr, Fabiano Pinto Saggioro, Daniela Pretti da Cunha Tirapelli, Carlos Gilberto Carlotti Junior, Enio David Mente, Orlando de Castro Silva, Felipe Amstalden Trevisan, Koo Jeong Kang, Keun Soo Ahn, Nasra H. Giama, Catherine D. Moser, Thomas J. Giordano, Michelle Vinco, Theodore H. Welling, Daniel Crain, Erin Curley, Johanna Gardner, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Robin Kelley, Joong-Won Park, Vishal S. Chandan, Lewis R. Roberts, Oliver F. Bathe, Curt H. Hagedorn, J. Todd Auman, Daniel R. O'Brien, Jean-Pierre A. Kocher, Corbin D. Jones, Piotr A. Mieczkowski, Charles M. Perou, Tara Skelly, Donghui Tan, Umadevi Veluvolu, Saianand Balu, Tom Bodenheimer, Alan P. Hoyle, Stuart R. Jefferys, Shaowu Meng, Lisle E. Mose, Yan Shi, Janae V. Simons, Matthew G. Soloway, Jeffrey Roach, Katherine A. Hoadley, Stephen B. Baylin, Hui Shen, Toshinori Hinoue, Moiz S. Bootwalla, David J. Van Den Berg, Daniel J. Weisenberger, Phillip H. Lai, Andrea Holbrook, Mario Berrios, and Peter W. Laird

Subjects
0301 basic medicine, Carcinoma, Hepatocellular, Genomics, Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, microRNA, medicine, Humans, CARCINOMA HEPATOCELULAR, Gene, Mutation, Liver Neoplasms, DNA Methylation, medicine.disease, Isocitrate Dehydrogenase, MicroRNAs, 030104 developmental biology, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, DNA methylation, Cancer research, Liver cancer
Abstract

Summary Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1 , EEF1A1 , SF3B1 , and SMARCA4 . Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming ( ALB , APOB , and CPS1 ) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.

Published
2017

7. 114 Expanding clinical spectrum of RRM2B mutations to include MNGIE

Author

Shulin Zhang, Lee-Jun C. Wong, Olivier Lichtarge, Marwan Shinawi, Aziz Shaibani, Oleg A. Shchelochkov, and Panagiotis Katsonis

Subjects
Physics, Molecular Medicine, Cell Biology, Computational biology, Molecular Biology, Spectrum (topology)
Published
2010

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