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101. EPCO-09. LONGITUDINAL ANALYSIS OF DIFFUSE GLIOMA REVEALS CELL STATE DYNAMICS AT RECURRENCE ASSOCIATED WITH CHANGES IN GENETICS AND THE MICROENVIRONMENT

Author

Varn, Frederick, primary, Johnson, Kevin, additional, Wade, Taylor, additional, Malta, Tathiane, additional, Sabedot, Thais, additional, Barthel, Floris, additional, Kim, Hoon, additional, Ahmed, Nazia, additional, Datta, Indrani, additional, Barnholtz-Sloan, Jill, additional, Bakas, Spyridon, additional, D'Angelo, Fulvio, additional, Gan, Hui, additional, Garofano, Luciano, additional, Huse, Jason, additional, Khasraw, Mustafa, additional, Kocakavuk, Emre, additional, Migliozzi, Simona, additional, Ormond, David, additional, Paek, Sun Ha, additional, Van Meir, Erwin, additional, Walenkamp, Annemiek, additional, Watts, Colin, additional, Weller, Michael, additional, Weiss, Tobias, additional, Wesseling, Pieter, additional, Stead, Lucy, additional, Poisson, Laila, additional, Noushmehr, Houtan, additional, Iavarone, Antonio, additional, and Verhaak, Roel, additional

Published
2021
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103. OTME-5. Meningioma liquid biopsy specimens exhibit contrasting immune-cell landscapes across methylation-subtypes and estimated recurrence risk subgroups

Author

Herrgott, Grayson, primary, She, Ruicong, additional, Sabedot, Thais, additional, Wells, Michael, additional, Asmaro, Karam, additional, Malta, Tathiane, additional, Mosella, Maritza, additional, Nelson, Kevin, additional, deCarvalho, Ana, additional, Poisson, Laila, additional, Mukherjee, Abir, additional, Cazacu, Simona, additional, Robin, Adam, additional, Lee, Ian, additional, Snyder, James, additional, Walbert, Tobias, additional, Rosenblum, Mark, additional, Mikkelsen, Tom, additional, Kalkanis, Steven, additional, Rock, Jack, additional, Noushmehr, Houtan, additional, and Castro, Ana Valeria, additional

Published
2021
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104. Loss of H3K27me3 in meningiomas

Author

Nassiri, Farshad, Wang, Justin Z, Dimeco, Francesco, Yip, Stephen, Gao, Andrew, Aldape, Kenneth D, Zadeh, Gelareh, Aldape, Kenneth, Au, Karolyn, Barnholtz-Sloan, Jill, Behling, Felix, Singh, Olivia, Brastianos, Priscilla, Butowski, Nicholas, Brodie, Chaya, Cohen-Gadol, Aaron, Couce, Marta, Drummond, Kate, Dunn, Ian, Galanis, Eva, Karimi, Shirin, Galldiks, Norbert, Giannini, Caterina, Goldbrunner, Roland, Hanemann, Oliver, Herold-Mende, Christel, Horbinski, Craig, Huang, Raymond, Javadpour, Mohsen, Jenkinson, Michael, Jungk, Christine, Dalcourt, Tatyana, Kaufmann, Timothy, Krischek, Boris, Kurz, Sylvia, Lachance, Daniel, Lafougere, Christian, Lamszus, Katrin, Lee, Ian, Malta, Tathiana, Makarenko, Serge, Mawrin, Christian, Ijad, Nazanin, McDermott, Michael, Millward, Christopher, Moliterno-Gunel, Jennifer, Morokoff, Andrew, Ng, H. K., Noushmehr, Houtan, Perry, Arie, Poisson, Laila, Pollo, Bianco, Pirouzmand, Neda, Ragunathan, Aditya, Raleigh, David, Renovanz, Mirjam, Ricklefs, Franz, Sahm, Felix, Saladino, Andrea, Santacroce, Antonio, Santarius, Thomas, Schichor, Christian, Schimdt, Nils, Ng, Ho-Keung, Schittenhelm, Jens, Selman, Warren, Shih, Helen, Snyder, Jim, Snuderl, Matja, Sloan, Andrew, Suppiah, Suganth, Sulman, Erik, Tabatabai, Ghazaleh, Tatagiba, Marcos, Timmer, Marcos, Tonn, Joerg-Christian, Von Deimling, Andreas, Vogelbaum, Michael, Walbert, Tobias, Wang, Justin, Wen, Patrick, Westphal, Manfred, Pollo, Bianca, and Bi, Wenya

Subjects
Oncology, Cancer Research, medicine.medical_specialty, macromolecular substances, Meningioma, Histones, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Meningeal Neoplasms, Medicine, Humans, Meningeal Neoplasm, ddc:610, 030304 developmental biology, 0303 health sciences, REPRODUTIBILIDADE DE RESULTADOS, business.industry, Proportional hazards model, Editorials, Cancer, Reproducibility of Results, medicine.disease, Prognosis, Staining, 030220 oncology & carcinogenesis, Cohort, Immunohistochemistry, Neurology (clinical), Neoplasm Recurrence, Local, business, Who classification
Abstract

Background There is a critical need for objective and reliable biomarkers of outcome in meningiomas beyond WHO classification. Loss of H3K27me3 has been reported as a prognostically unfavorable alteration in meningiomas. We sought to independently evaluate the reproducibility and prognostic value of H3K27me3 loss by immunohistochemistry (IHC) in a multicenter study. Methods IHC staining for H3K27me3 and analyses of whole slides from 181 meningiomas across three centers was performed. Staining was analyzed by dichotomization into loss and retained immunoreactivity, and using a 3-tiered scoring system in 151 cases with clear staining. Associations of grouping with outcome were performed using Kaplan-Meier survival estimates. Results A total of 21 of 151 tumors (13.9%) demonstrated complete loss of H3K27me3 staining in tumor with retained endothelial staining. Overall, loss of H3K27me3 portended a worse outcome with shorter times to recurrence in our cohort, particularly for WHO grade 2 tumors which were enriched in our study. There were no differences in recurrence-free survival (RFS) for WHO grade 3 patients with retained vs loss of H3K27me3. Scoring by a 3-tiered system did not add further insights into the prognostic value of this H3K27me3 loss. Overall, loss of H3K27me3 was not independently associated with RFS after controlling for WHO grade, extent of resection, sex, age, and recurrence status of tumor on multivariable Cox regression analysis. Conclusions Loss of H3K27me3 identifies a subset of WHO grade 2 and possibly WHO grade 1 meningiomas with increased recurrence risk. Pooled analyses of a larger cohort of samples with standardized reporting of clinical definitions and staining patterns are warranted.

Published
2021

105. Prognostic significance of genome-wide DNA methylation profiles within the randomized, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma

Author

Tesileanu, C. Mircea S., Van Den Bent, Martin J., Sanson, Marc, Wick, Wolfgang, Brandes, Alba A., Clement, Paul M., Erridge, Sara C., Vogelbaum, Michael A., Nowak, Anna K., Baurain, Jean F., Mason, Warren P., Wheeler, Helen, Chinot, Olivier L., Gill, Sanjeev, Griffin, Matthew, Rogers, Leland, Taal, Walter, Rudà, Roberta, Weller, Michael, McBain, Catherine, Van Linde, Myra E., Sabedot, Thais S., Hoogstrate, Youri, Von Deimling, Andreas, De Heer, Iris, Van Ijcken, Wilfred F.J., Brouwer, Rutger W.W., Aldape, Kenneth, Jenkins, Robert B., Dubbink, Hendrikus J., Kros, Johan M., Wesseling, Pieter, Cheung, Kin Jip, Golfinopoulos, Vassilis, Baumert, Brigitta G., Gorlia, Thierry, Noushmehr, Houtan, French, Pim J., Tesileanu, C. Mircea S., Van Den Bent, Martin J., Sanson, Marc, Wick, Wolfgang, Brandes, Alba A., Clement, Paul M., Erridge, Sara C., Vogelbaum, Michael A., Nowak, Anna K., Baurain, Jean F., Mason, Warren P., Wheeler, Helen, Chinot, Olivier L., Gill, Sanjeev, Griffin, Matthew, Rogers, Leland, Taal, Walter, Rudà, Roberta, Weller, Michael, McBain, Catherine, Van Linde, Myra E., Sabedot, Thais S., Hoogstrate, Youri, Von Deimling, Andreas, De Heer, Iris, Van Ijcken, Wilfred F.J., Brouwer, Rutger W.W., Aldape, Kenneth, Jenkins, Robert B., Dubbink, Hendrikus J., Kros, Johan M., Wesseling, Pieter, Cheung, Kin Jip, Golfinopoulos, Vassilis, Baumert, Brigitta G., Gorlia, Thierry, Noushmehr, Houtan, and French, Pim J.

Abstract

Background: Survival in patients with IDH1/2-mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients. Methods: The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumor classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using 1 of the 2 glioma-tailored NGS panels. The primary endpoint was overall survival measured from the date of randomization.Results: Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumors. Of these, 432 tumors were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazard model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations, and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication. Conclusion: Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification.

Published
2021

106. Identification and characterization of functional risk variants for colorectal cancer mapping to chromosome 11q23.1

Author

Biancolella, Michela, Fortini, Barbara K., Tring, Stephanie, Plummer, Sarah J., Mendoza-Fandino, Gustavo A., Hartiala, Jaana, Hitchler, Michael J., Yan, Chunli, Schumacher, Fredrick R., Conti, David V., Edlund, Christopher K., Noushmehr, Houtan, Coetzee, Simon G., Bresalier, Robert S., Ahnen, Dennis J., Barry, Elizabeth L., Berman, Benjamin P., Rice, Judd C., Coetzee, Gerhard A., and Casey, Graham

Published
2014
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107. Prognostic significance of genome-wide DNA methylation profiles within the randomized, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma

Author

Tesileanu, C Mircea S, primary, van den Bent, Martin J, additional, Sanson, Marc, additional, Wick, Wolfgang, additional, Brandes, Alba A, additional, Clement, Paul M, additional, Erridge, Sara C, additional, Vogelbaum, Michael A, additional, Nowak, Anna K, additional, Baurain, Jean F, additional, Mason, Warren P, additional, Wheeler, Helen, additional, Chinot, Olivier L, additional, Gill, Sanjeev, additional, Griffin, Matthew, additional, Rogers, Leland, additional, Taal, Walter, additional, Rudà, Roberta, additional, Weller, Michael, additional, McBain, Catherine, additional, van Linde, Myra E, additional, Sabedot, Thais S, additional, Hoogstrate, Youri, additional, von Deimling, Andreas, additional, de Heer, Iris, additional, van IJcken, Wilfred F J, additional, Brouwer, Rutger W W, additional, Aldape, Kenneth, additional, Jenkins, Robert B, additional, Dubbink, Hendrikus J, additional, Kros, Johan M, additional, Wesseling, Pieter, additional, Cheung, Kin Jip, additional, Golfinopoulos, Vassilis, additional, Baumert, Brigitta G, additional, Gorlia, Thierry, additional, Noushmehr, Houtan, additional, and French, Pim J, additional

Published
2021
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109. Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus

Author

Buckley, Melissa A, Woods, Nicholas T, Tyrer, Jonathan P, Mendoza-Fandiño, Gustavo, Lawrenson, Kate, Hazelett, Dennis J, Najafabadi, Hamed S, Gjyshi, Anxhela, Carvalho, Renato S, Lyra, Paulo C, Coetzee, Simon G, Shen, Howard C, Yang, Ally W, Earp, Madalene A, Yoder, Sean J, Risch, Harvey, Chenevix-Trench, Georgia, Ramus, Susan J, Phelan, Catherine M, Coetzee, Gerhard A, Noushmehr, Houtan, Hughes, Timothy R, Sellers, Thomas A, Goode, Ellen L, Pharoah, Paul D, Gayther, Simon A, Monteiro, Alvaro NA, Ovarian Cancer Association Consortium, Lawrenson, Kate [0000-0002-6469-2515], Hazelett, Dennis J [0000-0003-0749-9935], Najafabadi, Hamed S [0000-0003-2735-4231], Coetzee, Simon G [0000-0003-4267-5930], Yoder, Sean J [0000-0003-0005-7798], Coetzee, Gerhard A [0000-0003-4267-5930], Noushmehr, Houtan [0000-0003-4051-8114], and Apollo - University of Cambridge Repository

Subjects
Ovarian Cancer Association Consortium, Oncology and Carcinogenesis, Cystadenocarcinoma, Cell Cycle Proteins, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, Chromosomes, Linkage Disequilibrium, Cell Line, Rare Diseases, Ovarian Epithelial, Cell Line, Tumor, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Polymorphism, Aetiology, Cancer, Ovarian Neoplasms, Tumor, Base Sequence, Prevention, Carcinoma, Human Genome, Serous, Chromosome Mapping, DNA, Single Nucleotide, DNA, Neoplasm, Ovarian Cancer, Cystadenocarcinoma, Serous, DNA-Binding Proteins, HEK293 Cells, Neoplasm, Female, Chromosomes, Human, Pair 9, Human, Pair 9, Biotechnology, Genome-Wide Association Study
Abstract

Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. SIGNIFICANCE: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene.See related commentary by Choi and Brown, p. 439.

Published
2018
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110. Exploring the cancer methylome

Author

Berman Benjamin P, Weisenberger Daniel J, Hinoue Toshinori, Noushmehr Houtan, Liu Yaping, Aman Joseph F, Shen Hui, Malik Simeen, Mahurkar Swapna, Triche Timothy, Ramjan Zachary, Nicolet Charles M, Van Den Berg David, Cope Leslie, Herman James G, Baylin Stephen B, and Laird Peter W

Subjects
Medicine, Science
Published
2012
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111. An early requirement for maternal FoxH1 during zebrafish gastrulation

Author

Pei, Wuhong, Noushmehr, Houtan, Costa, Justin, Ouspenskaia, Maia V., Elkahloun, Abdel G., and Feldman, Benjamin

Subjects
Keratin, Knowledge-based system, Biological sciences
Abstract

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2007.07.011 Byline: Wuhong Pei, Houtan Noushmehr, Justin Costa, Maia V. Ouspenskaia, Abdel G. Elkahloun, Benjamin Feldman Keywords: FoxH1; Gastrulation; Enveloping layer; Keratin Abstract: The Forkhead Box H1 (FoxH1) protein is a co-transcription factor recruited by phosphorylated Smad2 downstream of several TGF[beta]s, including Nodal-related proteins. We have reassessed the function of zebrafish FoxH1 using antisense morpholino oligonucleotides (MOs). MOs targeting translation of foxH1 disrupt embryonic epiboly movements during gastrulation and cause death on the first day of development. The FoxH1 morphant phenotype is much more severe than that of zebrafish carrying foxh1/schmalspur (sur) DNA-binding domain mutations, FoxH1 splice-blocking morphants or other Nodal pathway mutants, and it cannot be altered by concomitant perturbations in Nodal signaling. Apart from disrupting epiboly, FoxH1 MO treatment disrupts convergence and internalization movements. Late gastrula-stage FoxH1 morphants exhibit delayed mesoderm and endoderm marker gene expression and failed patterning of the central nervous system. Probing FoxH1 morphant RNA by microarray, we identified a cohort of five keratin genes - cyt1, cyt2, krt4, krt8 and krt18 - that are normally transcribed in the embryo's enveloping layer (EVL) and which have significantly reduced expression in FoxH1-depleted embryos. Simultaneously disrupting these keratins with a mixture of MOs reproduces the FoxH1 morphant phenotype. Our studies thus point to an essential role for maternal FoxH1 and downstream keratins during gastrulation that is epistatic to Nodal signaling. Author Affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, 9000 Rockville Pike, Building 35, Room 1B 205, Bethesda, MD 20892, USA Article History: Received 15 September 2006; Revised 26 June 2007; Accepted 11 July 2007

Published
2007

112. Cartography of opportunistic pathogens and antibiotic resistance genes in a tertiary hospital environment

Author

Chng, Kern Rei, Li, Chenhao, Bertrand, Denis, Ng, Amanda Hui Qi, Kwah, Junmei Samantha, Low, Hwee Meng, Tong, Chengxuan, Natrajan, Maanasa, Zhang, Michael Hongjie, Xu, Licheng, Ko, Karrie Kwan Ki, Ho, Eliza Xin Pei, Av-Shalom, Tamar, Teo, Jeanette Woon Pei, Khor, Chiea Chuen, Chen, Swaine L., Mason, Christopher E., Ng, Oon Tek, Marimuthu, Kalisvar, Ang, Brenda, Nagarajan, Niranjan, Danko, David, Bezdan, Daniela, Afshinnekoo, Ebrahim, Ahsanuddin, Sofia, Bhattacharya, Chandrima, Butler, Daniel J., De Filippis, Francesca, Hecht, Jochen, Kahles, Andre, Karasikov, Mikhail, Kyrpides, Nikos C., Leung, Marcus H. Y., Meleshko, Dmitry, Mustafa, Harun, Mutai, Beth, Neches, Russell Y., Ng, Amanda, Nieto-Caballero, Marina, Nikolayeva, Olga, Nikolayeva, Tatyana, Png, Eileen, Sanchez, Jorge L., Shaaban, Heba, Sierra, Maria A., Tong, Xinzhao, Young, Ben, Alicea, Josue, Bhattacharyya, Malay, Blekhman, Ran, Castro-Nallar, Eduardo, Canas, Ana M., Chatziefthimiou, Aspassia D., Crawford, Robert W., Deng, Youping, Desnues, Christelle, Dias-Neto, Emmanuel, Donnellan, Daisy, Dybwad, Marius, Elhaik, Eran, Ercolini, Danilo, Frolova, Alina, Graf, Alexandra B., Green, David C., Hajirasouliha, Iman, Hernandez, Mark, Iraola, Gregorio, Jang, Soojin, Jones, Angela, Kelly, Frank J., Knights, Kaymisha, Labaj, Pawel P., Lee, Patrick K. H., Shawn, Levy, Ljungdahl, Per, Lyons, Abigail, Mason-Buck, Gabriella, McGrath, Ken, Mongodin, Emmanuel F., Moraes, Milton Ozorio, Noushmehr, Houtan, Oliveira, Manuela, Ossowski, Stephan, Osuolale, Olayinka O., Ozcan, Orhan, Paez-Espino, David, Rascovan, Nicolas, Richard, Hugues, Raetsch, Gunnar, Schriml, Lynn M., Semmler, Torsten, Sezerman, Osman U., Shi, Leming, Song, Le Huu, Suzuki, Haruo, Court, Denise Syndercombe, Thomas, Dominique, Tighe, Scott W., Udekwu, Klas, Ugalde, Juan A., Valentine, Brandon, Vassilev, Dimitar, Vayndorf, Elena, Velavan, Thirumalaisamy P., Zambrano, Maria M., Zhu, Jifeng, Zhu, Sibo, Chng, Kern Rei, Li, Chenhao, Bertrand, Denis, Ng, Amanda Hui Qi, Kwah, Junmei Samantha, Low, Hwee Meng, Tong, Chengxuan, Natrajan, Maanasa, Zhang, Michael Hongjie, Xu, Licheng, Ko, Karrie Kwan Ki, Ho, Eliza Xin Pei, Av-Shalom, Tamar, Teo, Jeanette Woon Pei, Khor, Chiea Chuen, Chen, Swaine L., Mason, Christopher E., Ng, Oon Tek, Marimuthu, Kalisvar, Ang, Brenda, Nagarajan, Niranjan, Danko, David, Bezdan, Daniela, Afshinnekoo, Ebrahim, Ahsanuddin, Sofia, Bhattacharya, Chandrima, Butler, Daniel J., De Filippis, Francesca, Hecht, Jochen, Kahles, Andre, Karasikov, Mikhail, Kyrpides, Nikos C., Leung, Marcus H. Y., Meleshko, Dmitry, Mustafa, Harun, Mutai, Beth, Neches, Russell Y., Ng, Amanda, Nieto-Caballero, Marina, Nikolayeva, Olga, Nikolayeva, Tatyana, Png, Eileen, Sanchez, Jorge L., Shaaban, Heba, Sierra, Maria A., Tong, Xinzhao, Young, Ben, Alicea, Josue, Bhattacharyya, Malay, Blekhman, Ran, Castro-Nallar, Eduardo, Canas, Ana M., Chatziefthimiou, Aspassia D., Crawford, Robert W., Deng, Youping, Desnues, Christelle, Dias-Neto, Emmanuel, Donnellan, Daisy, Dybwad, Marius, Elhaik, Eran, Ercolini, Danilo, Frolova, Alina, Graf, Alexandra B., Green, David C., Hajirasouliha, Iman, Hernandez, Mark, Iraola, Gregorio, Jang, Soojin, Jones, Angela, Kelly, Frank J., Knights, Kaymisha, Labaj, Pawel P., Lee, Patrick K. H., Shawn, Levy, Ljungdahl, Per, Lyons, Abigail, Mason-Buck, Gabriella, McGrath, Ken, Mongodin, Emmanuel F., Moraes, Milton Ozorio, Noushmehr, Houtan, Oliveira, Manuela, Ossowski, Stephan, Osuolale, Olayinka O., Ozcan, Orhan, Paez-Espino, David, Rascovan, Nicolas, Richard, Hugues, Raetsch, Gunnar, Schriml, Lynn M., Semmler, Torsten, Sezerman, Osman U., Shi, Leming, Song, Le Huu, Suzuki, Haruo, Court, Denise Syndercombe, Thomas, Dominique, Tighe, Scott W., Udekwu, Klas, Ugalde, Juan A., Valentine, Brandon, Vassilev, Dimitar, Vayndorf, Elena, Velavan, Thirumalaisamy P., Zambrano, Maria M., Zhu, Jifeng, and Zhu, Sibo

Abstract

Although disinfection is key to infection control, the colonization patterns and resistomes of hospital-environment microbes remain underexplored. We report the first extensive genomic characterization of microbiomes, pathogens and antibiotic resistance cassettes in a tertiary-care hospital, from repeated sampling (up to 1.5 years apart) of 179 sites associated with 45 beds. Deep shotgun metagenomics unveiled distinct ecological niches of microbes and antibiotic resistance genes characterized by biofilm-forming and human-microbiome-influenced environments with corresponding patterns of spatiotemporal divergence. Quasi-metagenomics with nanopore sequencing provided thousands of high-contiguity genomes, phage and plasmid sequences (>60% novel), enabling characterization of resistome and mobilome diversity and dynamic architectures in hospital environments. Phylogenetics identified multidrug-resistant strains as being widely distributed and stably colonizing across sites. Comparisons with clinical isolates indicated that such microbes can persist in hospitals for extended periods (>8 years), to opportunistically infect patients. These findings highlight the importance of characterizing antibiotic resistance reservoirs in hospitals and establish the feasibility of systematic surveys to target resources for preventing infections. Spatiotemporal characterization of microbial diversity and antibiotic resistance in a tertiary-care hospital reveals broad distribution and persistence of antibiotic-resistant organisms that could cause opportunistic infections in a healthcare setting.

Published
2020
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113. Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology.

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Integrative Cell Signalling (Skupin Group) [research center], Departmanet of Life Sciences and Medicine [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Neuropathology (Mittelbronn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Interventional Neuroscience (Hertel Group) [research center], n°7.4615.18/Télévie-FNRS [sponsor], n°7.4632.17/Télévie-FNRS [sponsor], 766069/H2020 Marie Skłodowska-Curie Actions [sponsor], Pan-RTK/Fondation Cancer Luxembourg [sponsor], PEARL award - P16/BM/11192868/Fonds National de la Recherche Luxembourg [sponsor], C17/BM/11664971 FNR [sponsor], Golebiewska, Anna, Hau, Ann-Christin, Oudin, Anaïs, Stieber, Daniel, Yabo, Yahaya A., Baus, Virginie, Barthelemy, Vanessa, Klein, Eliane, Bougnaud, Sébastien, Keunen, Olivier, Wantz, May, Michelucci, Alessandro, Neirinckx, Virginie, Muller, Arnaud, Kaoma, Tony, Nazarov, Petr V., Azuaje, Francisco, De Falco, Alfonso, Flies, Ben, Richart, Lorraine, Poovathingal, Suresh, Arns, Thais, Grzyb, Kamil, Mock, Andreas, Herold-Mende, Christel, Steino, Anne, Brown, Dennis, May, Patrick, Miletic, Hrvoje, Malta, Tathiane M., Noushmehr, Houtan, Kwon, Yong-Jun, Jahn, Winnie, Klink, Barbara, Tanner, Georgette, Stead, Lucy F., Mittelbronn, Michel, Skupin, Alexander, Hertel, Frank, Bjerkvig, Rolf, Niclou, Simone, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Integrative Cell Signalling (Skupin Group) [research center], Departmanet of Life Sciences and Medicine [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Neuropathology (Mittelbronn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Interventional Neuroscience (Hertel Group) [research center], n°7.4615.18/Télévie-FNRS [sponsor], n°7.4632.17/Télévie-FNRS [sponsor], 766069/H2020 Marie Skłodowska-Curie Actions [sponsor], Pan-RTK/Fondation Cancer Luxembourg [sponsor], PEARL award - P16/BM/11192868/Fonds National de la Recherche Luxembourg [sponsor], C17/BM/11664971 FNR [sponsor], Golebiewska, Anna, Hau, Ann-Christin, Oudin, Anaïs, Stieber, Daniel, Yabo, Yahaya A., Baus, Virginie, Barthelemy, Vanessa, Klein, Eliane, Bougnaud, Sébastien, Keunen, Olivier, Wantz, May, Michelucci, Alessandro, Neirinckx, Virginie, Muller, Arnaud, Kaoma, Tony, Nazarov, Petr V., Azuaje, Francisco, De Falco, Alfonso, Flies, Ben, Richart, Lorraine, Poovathingal, Suresh, Arns, Thais, Grzyb, Kamil, Mock, Andreas, Herold-Mende, Christel, Steino, Anne, Brown, Dennis, May, Patrick, Miletic, Hrvoje, Malta, Tathiane M., Noushmehr, Houtan, Kwon, Yong-Jun, Jahn, Winnie, Klink, Barbara, Tanner, Georgette, Stead, Lucy F., Mittelbronn, Michel, Skupin, Alexander, Hertel, Frank, Bjerkvig, Rolf, and Niclou, Simone

Abstract

Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology.

Published
2020

114. Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

Author

Luxembourg Institute of Health - LIH [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Integrative Cell Signalling (Skupin Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Télévie-FNRS (Grants n°7.4632.17, 4615.18) [sponsor], Fondation Cancer Luxembourg (Pan-RTK Targeting) [sponsor], FNR; CORE Junior C17/BM/11664971/DEMICS [sponsor], GLIOTRAIN ITN funded by the European Union’s Horizon 2020 [sponsor], Marie Skłodowska-Curie grant agreement No 766069 [sponsor], FNR PEARL P16/BM/11192868 grant [sponsor], Golebiewska, Anna, Hau, Ann-Christin, Oudin, Anais, Stieber, Daniel, Yabo, Yahaya A., Baus, Virginie, Barthelemy, Vanessa, Klein, Eliane, Bougnaud, Sebastien, Keunen, Olivier, Wantz, May, Michelucci, Alessandro, Neirinckx, Virginie, Muller, Arnaud, Kaoma, Tony, Nazarov, Petr V., Azuaje, Francisco, De Falco, Alfonso, Flies, Ben, Richart, Lorraine, Poovathingal, Suresh, Arns, Thais, Grzyb, Kamil, Mock, Andreas, Herold-Mende, Christel, Steino, Anne, Brown, Dennis, May, Patrick, Miletic, Hrvoje, Malta, Tathiane M., Noushmehr, Houtan, Kwon, Yong-Jun, Jahn, Winnie, Klink, Barbara, Tanner, Georgette, Stead, Lucy F., Mittelbronn, Michel, Skupin, Alexander, Hertel, Frank, Bjerkvig, Rolf, Niclou, Simone, Luxembourg Institute of Health - LIH [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Integrative Cell Signalling (Skupin Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Télévie-FNRS (Grants n°7.4632.17, 4615.18) [sponsor], Fondation Cancer Luxembourg (Pan-RTK Targeting) [sponsor], FNR; CORE Junior C17/BM/11664971/DEMICS [sponsor], GLIOTRAIN ITN funded by the European Union’s Horizon 2020 [sponsor], Marie Skłodowska-Curie grant agreement No 766069 [sponsor], FNR PEARL P16/BM/11192868 grant [sponsor], Golebiewska, Anna, Hau, Ann-Christin, Oudin, Anais, Stieber, Daniel, Yabo, Yahaya A., Baus, Virginie, Barthelemy, Vanessa, Klein, Eliane, Bougnaud, Sebastien, Keunen, Olivier, Wantz, May, Michelucci, Alessandro, Neirinckx, Virginie, Muller, Arnaud, Kaoma, Tony, Nazarov, Petr V., Azuaje, Francisco, De Falco, Alfonso, Flies, Ben, Richart, Lorraine, Poovathingal, Suresh, Arns, Thais, Grzyb, Kamil, Mock, Andreas, Herold-Mende, Christel, Steino, Anne, Brown, Dennis, May, Patrick, Miletic, Hrvoje, Malta, Tathiane M., Noushmehr, Houtan, Kwon, Yong-Jun, Jahn, Winnie, Klink, Barbara, Tanner, Georgette, Stead, Lucy F., Mittelbronn, Michel, Skupin, Alexander, Hertel, Frank, Bjerkvig, Rolf, and Niclou, Simone

Abstract

Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors and represent clinically relevant patient avatars. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1, which retained histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models recapitulate the limited genetic evolution of gliomas observed in patient tumors following treatment. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. Dianhydrogalactitol, a bifunctional alkylating agent, showed promising potential against glioblastoma. Our study underlines the clinical relevance of glioma PDOX models for translational research and personalized treatment studies.

Published
2020

115. DNA methylation-based signatures classify sporadic pituitary tumors according to clinicopathological features

Author

Mosella, Maritza S, primary, Sabedot, Thais S, additional, Silva, Tiago C, additional, Malta, Tathiane M, additional, Dezem, Felipe Segato, additional, Asmaro, Karam P, additional, Wells, Michael, additional, Mukherjee, Abir, additional, Poisson, Laila M, additional, Snyder, James, additional, deCarvalho, Ana C, additional, Walbert, Tobias, additional, Aho, Todd, additional, Kalkanis, Steven, additional, Elias, Paula C, additional, Antonini, Sonir R, additional, Rock, Jack, additional, Noushmehr, Houtan, additional, Castro, Margaret, additional, and Castro, Ana Valeria, additional

Published
2021
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116. A serum-based DNA methylation assay provides accurate detection of glioma

Author

Sabedot, Thais S, primary, Malta, Tathiane M, additional, Snyder, James, additional, Nelson, Kevin, additional, Wells, Michael, additional, deCarvalho, Ana C, additional, Mukherjee, Abir, additional, Chitale, Dhananjay A, additional, Mosella, Maritza S, additional, Sokolov, Artem, additional, Asmaro, Karam P, additional, Robin, Adam, additional, Rosenblum, Mark L, additional, Mikkelsen, Tom, additional, Rock, Jack, additional, Poisson, Laila M, additional, Lee, Ian, additional, Walbert, Tobias, additional, Kalkanis, Steven, additional, Iavarone, Antonio, additional, Castro, Ana Valeria, additional, and Noushmehr, Houtan, additional

Published
2021
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117. The Pituitary Epigenetic Liquid Biopsy for the Peripheral Detection and Classification of Pituitary Adenomas

Author

Asmaro, Karam P, primary, Wells, Michael, additional, Sabedot, Thais, additional, Mosella, Maritza S, additional, Malta, Tathiane, additional, Nelson, Kevin, additional, Snyder, James, additional, Robin, Adam M, additional, Kalkanis, Steven N, additional, Rock, Jack P, additional, Noushmehr, Houtan, additional, and Castro, Anavaleria, additional

Published
2020
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121. PATH-11. PROGNOSTIC SIGNIFICANCE OF EPIGENETIC SUBTYPES AND CpGs ASSOCIATED WITH PROGRESSION TO G-CIMP LOW IN THE EORTC RANDOMIZED PHASE III INTERGROUP CATNON

Author

Tesileanu, C Mircea S, primary, van den Bent, Martin, additional, Sabedot, Thais, additional, Sanson, Marc, additional, Brandes, Alba, additional, Wick, Wolfgang, additional, Clement, Paul, additional, Erridge, Sarah, additional, Vogelbaum, Michael, additional, Nowak, Anna, additional, Baurain, Jean, additional, Mason, Warren, additional, Wheeler, Helen, additional, Weller, Michael, additional, de Heer, Iris, additional, Dubbink, Hendrikus, additional, Kros, Johan M, additional, Aldape, Kenneth, additional, Wesseling, Pieter, additional, Golfinopoulos, Vassilis, additional, Gorlia, Thierry, additional, Baumert, Brigitta, additional, Noushmehr, Houtan, additional, and French, Pim, additional

Published
2020
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122. PATH-23. GENOMIC LANDSCAPE OF IDH-MUTANT PRIMARY GLIOBLASTOMAS SHOWS DISTINCT CLINICAL AND MOLECULAR FEATURES AND THAT CDKN2A SHOULD BE SUPPLEMENTED WITH MGMTp AND G-CIMP FOR PRECISE PROGNOSTICATION

Author

Wong, Queenie Hoi-Wing, primary, Wong, Gabriel Chun-Hei, additional, Chan, Aden Ka-Yin, additional, Poon, Wai Sang, additional, Chan, Danny Tat-Ming, additional, Chen, Hong, additional, Zhang, Zhen-yu, additional, Noushmehr, Houtan, additional, Jones, Chris, additional, Grabovska, Yura, additional, Mackay, Alan, additional, Chow, Chit, additional, Kwan, Johnny Sheung Him, additional, Chung, Nellie Yuk-Fei, additional, Huang, Queenie Junqi, additional, Poon, Manix Fung-Man, additional, Shi, Zhi-feng, additional, Li, Kay Ka-Wai, additional, and Ng, Ho-Keung, additional

Published
2020
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125. Abstract A30: Super-enhancer-associated long noncoding RNA UCA1 interacts directly with AMOT to inhibit Hippo signaling pathway in epithelial ovarian cancer

Author

Lin, Xianzhi, primary, Spindler, Tassja J., additional, de Souza Fonseca, Marcos A, additional, Corona, Rosario I., additional, Seo, Ji-Heui, additional, Dezem, Felipe S, additional, Li, Lewyn, additional, Lee, Janet M., additional, Long, Henry W., additional, Sellers, Thomas A., additional, Karlan, Beth Y., additional, Noushmehr, Houtan, additional, Freedman, Matthew L., additional, Gayther, Simon A., additional, and Lawrenson, Kate, additional

Published
2020
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127. Abstract A10: Glioma cell-free DNA methylation marker for diagnosis and monitoring

Author

Sabedot, Thais, primary, Malta, Tathiane, additional, Snyder, James, additional, Nelson, Kevin, additional, Wells, Michael, additional, deCarvalho, Ana, additional, Mukherjee, Abir, additional, Chitale, Dhan, additional, Mosella, Maritza, additional, Asmaro, Karam, additional, Robin, Adam, additional, Rosenblum, Mark, additional, Mikkelsen, Tom, additional, Rock, Jack, additional, Poisson, Laila, additional, Lee, Ian, additional, Walbert, Tobias, additional, Kalkanis, Steven, additional, Castro, Ana Valeria, additional, and Noushmehr, Houtan, additional

Published
2020
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128. Abstract A11: Serum cell-free DNA methylome-based signatures distinguish pituitary tumor from other neoplasias and by clinicopathologic features

Author

Wells, Michael, primary, Asmaro, Karam, additional, Rock, Jack, additional, Sabedot, Thais, additional, Mosella, Maritza, additional, Malta, Tathiane, additional, Nelson, Kevin, additional, Snyder, James, additional, Kalkanis, Steven, additional, Castro, Ana Valeria, additional, and Noushmehr, Houtan, additional

Published
2020
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129. Detection of Circulating Tumor-specific DNA Methylation Markers in the Blood of Patients with Pituitary Tumors

Author

Wells, Michael, primary, Asmaro, Karam P., additional, Sabedot, Thais S., additional, Malta, Tathiane M., additional, Mosella, Maritza S., additional, Nelson, Kevin, additional, Snyder, James, additional, deCarvalho, Ana, additional, Mukherjee, Abir, additional, Chitale, Dhananjay, additional, Robin, Adam, additional, Rosenblum, Mark, additional, Mikkelsen, Thomas, additional, Poisson, Laila M., additional, Lee, Ian Y., additional, Walbert, Tobias, additional, Bhan, Arti, additional, Kalkanis, Steven, additional, Rock, Jack, additional, Noushmehr, Houtan, additional, and Castro, Ana Valeria, additional

Published
2020
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130. Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling

Author

Chen, Jian, primary, Mitra, Abhisek, additional, Li, Shulin, additional, Song, Shumei, additional, Nguyen, Bao-Ngoc, additional, Chen, Jiun-Sheng, additional, Shin, Ji-Hyun, additional, Gough, Nancy R., additional, Lin, Paul, additional, Obias, Vincent, additional, He, Aiwu Ruth, additional, Yao, Zhixing, additional, Malta, Tathiane M., additional, Noushmehr, Houtan, additional, Latham, Patricia S., additional, Su, Xiaoping, additional, Rashid, Asif, additional, Mishra, Bibhuti, additional, Wu, Ray-Chang, additional, and Mishra, Lopa, additional

Published
2020
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131. DNA Methylation-based Signatures Classify Sporadic Pituitary Tumors According to Clinicopathological Features

Author

Mosella, Maritza S., primary, Sabedot, Thais S., additional, Silva, Tiago C., additional, Malta, Tathiane M., additional, Segato, Felipe D., additional, Asmaro, Karam P., additional, Wells, Michael, additional, Mukherjee, Abir, additional, Poisson, Laila M., additional, Snyder, James, additional, deCarvalho, Ana C., additional, Walbert T, Tobias, additional, Aho, Todd, additional, Kalkanis, Steven, additional, Elias, Paula C., additional, Antonini, Sonir R., additional, Rock, Jack, additional, Noushmehr, Houtan, additional, Castro, Margaret, additional, and Castro, Ana Valeria, additional

Published
2020
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132. Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

Author

Golebiewska, Anna, primary, Hau, Ann-Christin, additional, Oudin, Anaïs, additional, Stieber, Daniel, additional, Yabo, Yahaya A., additional, Baus, Virginie, additional, Barthelemy, Vanessa, additional, Klein, Eliane, additional, Bougnaud, Sébastien, additional, Keunen, Olivier, additional, Wantz, May, additional, Michelucci, Alessandro, additional, Neirinckx, Virginie, additional, Muller, Arnaud, additional, Kaoma, Tony, additional, Nazarov, Petr V., additional, Azuaje, Francisco, additional, De Falco, Alfonso, additional, Flies, Ben, additional, Richart, Lorraine, additional, Poovathingal, Suresh, additional, Arns, Thais, additional, Grzyb, Kamil, additional, Mock, Andreas, additional, Herold-Mende, Christel, additional, Steino, Anne, additional, Brown, Dennis, additional, May, Patrick, additional, Miletic, Hrvoje, additional, Malta, Tathiane M., additional, Noushmehr, Houtan, additional, Kwon, Yong-Jun, additional, Jahn, Winnie, additional, Klink, Barbara, additional, Tanner, Georgette, additional, Stead, Lucy F., additional, Mittelbronn, Michel, additional, Skupin, Alexander, additional, Hertel, Frank, additional, Bjerkvig, Rolf, additional, and Niclou, Simone P., additional

Published
2020
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133. OR32-03 Serum Cell-Free Methylation-Based Signatures Distinguishes Pituitary Tumors According to Functional Status and from Other Neoplasia: A Liquid Biopsy Approach

Author

Wells, Michael, primary, Asmaro, Karam P, primary, Sabedot, Thais S, primary, Mosella, Maritza S, primary, Malta, PharmD, Tathiane M, primary, Nelson, Kevin, primary, Snyder, James, primary, deCarvalho, Ana, primary, Mukherjee, Abir, primary, Chitale, Dan, primary, Robin, Adam, primary, Rosenblum, Mark L, primary, Mikkelsen, Tom, primary, Poisson, Laila, primary, Lee, Ian, primary, Walbert, Tobias, primary, Bhan, Arti, primary, Kalkanis, Steven, primary, Rock, Jack, primary, Noushmehr, Houtan, primary, and Castro, Ana Valeria, primary

Published
2020
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134. Mutated CEACAMs Disrupt Transforming Growth Factor Beta Signaling and Alter the Intestinal Microbiome to Promote Colorectal Carcinogenesis

Author

Gu, Shoujun, primary, Zaidi, Sobia, additional, Hassan, Md Imtaiyaz, additional, Mohammad, Taj, additional, Malta, Tathiane M., additional, Noushmehr, Houtan, additional, Nguyen, Bryan, additional, Crandall, Keith A., additional, Srivastav, Jigisha, additional, Obias, Vincent, additional, Lin, Paul, additional, Nguyen, Bao-Ngoc, additional, Yao, Michael, additional, Yao, Ren, additional, King, Charles Hadley, additional, Mazumder, Raja, additional, Mishra, Bibhuti, additional, Rao, Shuyun, additional, and Mishra, Lopa, additional

Published
2020
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136. Advances in multidisciplinary therapy for meningiomas

Author

Brastianos, Priscilla K., Galanis, Evanthia, Butowski, Nicholas, Chan, Jason W., Dunn, Ian F., Goldbrunner, Roland, Herold-Mende, Christel, Ippen, Franziska M., Mawrin, Christian, McDermott, Michael W., Sloan, Andrew, Snyder, James, Tabatabai, Ghazaleh, Tatagiba, Marcos, Tonn, Joerg C., Wen, Patrick Y., Aldape, Kenneth, Nassiri, Farshad, Zadeh, Gelareh, Jenkinson, Michael D., Raleigh, David R., Au, Karolyn, Barnhartz-Sloan, Jill, Bi, Wenya Linda, Carlotti, Carlos, Cusimano, Michael D., DiMeco, Francesco, Drummond, Katharine, Giannini, Caterina, Griffith, Brent, Hashizume, Rintaro, Hanemann, C. Oliver, Horbinski, Craig, Huang, Raymond Y., James, David, Jungk, Christine, Kaufman, Timothy J., Krischek, Boris, Lachance, Daniel, Lafougere, Christian, Lee, Ian, Liu, Jeff C., Mamatjan, Yasin, Mansouri, Alireza, McDermott, Michael, Munoz, David, Noushmehr, Houtan, Ng, Ho-Keung, Perry, Arie, Pirouzmand, Farhad, Poisson, Laila M., Pollo, Bianca, Raleigh, David, Sahm, Felix, Saladino, Andrea, Santarius, Thomas, Schichor, Christian, Schultz, David, Schmidt, Nils O., Selman, Warren, Spears, Julian, Suppiah, Suganth, Tirapelli, Daniela, Tsang, Derek, Vogelbaum, Michael A., von Deimling, Andreas, Walbert, Tobias, Westphal, Manfred, Workewych, Adriana M., Brastianos, Priscilla K., Galanis, Evanthia, Butowski, Nicholas, Chan, Jason W., Dunn, Ian F., Goldbrunner, Roland, Herold-Mende, Christel, Ippen, Franziska M., Mawrin, Christian, McDermott, Michael W., Sloan, Andrew, Snyder, James, Tabatabai, Ghazaleh, Tatagiba, Marcos, Tonn, Joerg C., Wen, Patrick Y., Aldape, Kenneth, Nassiri, Farshad, Zadeh, Gelareh, Jenkinson, Michael D., Raleigh, David R., Au, Karolyn, Barnhartz-Sloan, Jill, Bi, Wenya Linda, Carlotti, Carlos, Cusimano, Michael D., DiMeco, Francesco, Drummond, Katharine, Giannini, Caterina, Griffith, Brent, Hashizume, Rintaro, Hanemann, C. Oliver, Horbinski, Craig, Huang, Raymond Y., James, David, Jungk, Christine, Kaufman, Timothy J., Krischek, Boris, Lachance, Daniel, Lafougere, Christian, Lee, Ian, Liu, Jeff C., Mamatjan, Yasin, Mansouri, Alireza, McDermott, Michael, Munoz, David, Noushmehr, Houtan, Ng, Ho-Keung, Perry, Arie, Pirouzmand, Farhad, Poisson, Laila M., Pollo, Bianca, Raleigh, David, Sahm, Felix, Saladino, Andrea, Santarius, Thomas, Schichor, Christian, Schultz, David, Schmidt, Nils O., Selman, Warren, Spears, Julian, Suppiah, Suganth, Tirapelli, Daniela, Tsang, Derek, Vogelbaum, Michael A., von Deimling, Andreas, Walbert, Tobias, Westphal, Manfred, and Workewych, Adriana M.

Abstract

Surgery has long been established as the first-line treatment for the majority of symptomatic and enlarging meningiomas, and evidence for its success is derived from retrospective case series. Despite surgical resection, a subset of meningiomas display aggressive behavior with early recurrences that are difficult to treat. The decision to radically resect meningiomas and involved structures is balanced against the risk for neurological injury in patients. Radiation therapy has largely been used as a complementary and safe therapeutic strategy in meningiomas with evidence primarily stemming from retrospective, single-institution reports. Two of the first cooperative group studies (RTOG 0539 and EORTC 22042) evaluating the outcomes of adjuvant radiation therapy in higher-risk meningiomas have shown promising preliminary results. Historically, systemic therapy has resulted in disappointing results in meningiomas. However, several clinical trials are under way evaluating the efficacy of chemotherapies, such as trabectedin, and novel molecular agents targeting Smoothened, AKT1, and focal adhesion kinase in patients with recurrent meningiomas.

Published
2019

137. Super-Enhancer-Associated LncRNA UCA1 Interacts Directly with AMOT to Activate YAP Target Genes in Epithelial Ovarian Cancer.

Author

Lin, Xianzhi, Lin, Xianzhi, Spindler, Tassja J, de Souza Fonseca, Marcos Abraão, Corona, Rosario I, Seo, Ji-Heui, Dezem, Felipe Segato, Li, Lewyn, Lee, Janet M, Long, Henry W, Sellers, Thomas A, Karlan, Beth Y, Noushmehr, Houtan, Freedman, Matthew L, Gayther, Simon A, Lawrenson, Kate, Lin, Xianzhi, Lin, Xianzhi, Spindler, Tassja J, de Souza Fonseca, Marcos Abraão, Corona, Rosario I, Seo, Ji-Heui, Dezem, Felipe Segato, Li, Lewyn, Lee, Janet M, Long, Henry W, Sellers, Thomas A, Karlan, Beth Y, Noushmehr, Houtan, Freedman, Matthew L, Gayther, Simon A, and Lawrenson, Kate

Abstract

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of tumorigenesis, and yet their mechanistic roles remain challenging to characterize. Here, we integrate functional proteomics with lncRNA-interactome profiling to characterize Urothelial Cancer Associated 1 (UCA1), a candidate driver of ovarian cancer development. Reverse phase protein array (RPPA) analysis indicates that UCA1 activates transcription coactivator YAP and its target genes. In vivo RNA antisense purification (iRAP) of UCA1 interacting proteins identified angiomotin (AMOT), a known YAP regulator, as a direct binding partner. Loss-of-function experiments show that AMOT mediates YAP activation by UCA1, as UCA1 enhances the AMOT-YAP interaction to promote YAP dephosphorylation and nuclear translocation. Together, we characterize UCA1 as a lncRNA regulator of Hippo-YAP signaling and highlight the UCA1-AMOT-YAP signaling axis in ovarian cancer development.

Published
2019

138. Longitudinal molecular trajectories of diffuse glioma in adults.

Author

Barthel, Floris P, Barthel, Floris P, Johnson, Kevin C, Varn, Frederick S, Moskalik, Anzhela D, Tanner, Georgette, Kocakavuk, Emre, Anderson, Kevin J, Abiola, Olajide, Aldape, Kenneth, Alfaro, Kristin D, Alpar, Donat, Amin, Samirkumar B, Ashley, David M, Bandopadhayay, Pratiti, Barnholtz-Sloan, Jill S, Beroukhim, Rameen, Bock, Christoph, Brastianos, Priscilla K, Brat, Daniel J, Brodbelt, Andrew R, Bruns, Alexander F, Bulsara, Ketan R, Chakrabarty, Aruna, Chakravarti, Arnab, Chuang, Jeffrey H, Claus, Elizabeth B, Cochran, Elizabeth J, Connelly, Jennifer, Costello, Joseph F, Finocchiaro, Gaetano, Fletcher, Michael N, French, Pim J, Gan, Hui K, Gilbert, Mark R, Gould, Peter V, Grimmer, Matthew R, Iavarone, Antonio, Ismail, Azzam, Jenkinson, Michael D, Khasraw, Mustafa, Kim, Hoon, Kouwenhoven, Mathilde CM, LaViolette, Peter S, Li, Meihong, Lichter, Peter, Ligon, Keith L, Lowman, Allison K, Malta, Tathiane M, Mazor, Tali, McDonald, Kerrie L, Molinaro, Annette M, Nam, Do-Hyun, Nayyar, Naema, Ng, Ho Keung, Ngan, Chew Yee, Niclou, Simone P, Niers, Johanna M, Noushmehr, Houtan, Noorbakhsh, Javad, Ormond, D Ryan, Park, Chul-Kee, Poisson, Laila M, Rabadan, Raul, Radlwimmer, Bernhard, Rao, Ganesh, Reifenberger, Guido, Sa, Jason K, Schuster, Michael, Shaw, Brian L, Short, Susan C, Smitt, Peter A Sillevis, Sloan, Andrew E, Smits, Marion, Suzuki, Hiromichi, Tabatabai, Ghazaleh, Van Meir, Erwin G, Watts, Colin, Weller, Michael, Wesseling, Pieter, Westerman, Bart A, Widhalm, Georg, Woehrer, Adelheid, Yung, WK Alfred, Zadeh, Gelareh, Huse, Jason T, De Groot, John F, Stead, Lucy F, Verhaak, Roel GW, GLASS Consortium, Barthel, Floris P, Barthel, Floris P, Johnson, Kevin C, Varn, Frederick S, Moskalik, Anzhela D, Tanner, Georgette, Kocakavuk, Emre, Anderson, Kevin J, Abiola, Olajide, Aldape, Kenneth, Alfaro, Kristin D, Alpar, Donat, Amin, Samirkumar B, Ashley, David M, Bandopadhayay, Pratiti, Barnholtz-Sloan, Jill S, Beroukhim, Rameen, Bock, Christoph, Brastianos, Priscilla K, Brat, Daniel J, Brodbelt, Andrew R, Bruns, Alexander F, Bulsara, Ketan R, Chakrabarty, Aruna, Chakravarti, Arnab, Chuang, Jeffrey H, Claus, Elizabeth B, Cochran, Elizabeth J, Connelly, Jennifer, Costello, Joseph F, Finocchiaro, Gaetano, Fletcher, Michael N, French, Pim J, Gan, Hui K, Gilbert, Mark R, Gould, Peter V, Grimmer, Matthew R, Iavarone, Antonio, Ismail, Azzam, Jenkinson, Michael D, Khasraw, Mustafa, Kim, Hoon, Kouwenhoven, Mathilde CM, LaViolette, Peter S, Li, Meihong, Lichter, Peter, Ligon, Keith L, Lowman, Allison K, Malta, Tathiane M, Mazor, Tali, McDonald, Kerrie L, Molinaro, Annette M, Nam, Do-Hyun, Nayyar, Naema, Ng, Ho Keung, Ngan, Chew Yee, Niclou, Simone P, Niers, Johanna M, Noushmehr, Houtan, Noorbakhsh, Javad, Ormond, D Ryan, Park, Chul-Kee, Poisson, Laila M, Rabadan, Raul, Radlwimmer, Bernhard, Rao, Ganesh, Reifenberger, Guido, Sa, Jason K, Schuster, Michael, Shaw, Brian L, Short, Susan C, Smitt, Peter A Sillevis, Sloan, Andrew E, Smits, Marion, Suzuki, Hiromichi, Tabatabai, Ghazaleh, Van Meir, Erwin G, Watts, Colin, Weller, Michael, Wesseling, Pieter, Westerman, Bart A, Widhalm, Georg, Woehrer, Adelheid, Yung, WK Alfred, Zadeh, Gelareh, Huse, Jason T, De Groot, John F, Stead, Lucy F, Verhaak, Roel GW, and GLASS Consortium

Abstract

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

Published
2019

139. A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants.

Author

Gusev, Alexander, Gusev, Alexander, Lawrenson, Kate, Lin, Xianzhi, Lyra, Paulo C, Kar, Siddhartha, Vavra, Kevin C, Segato, Felipe, Fonseca, Marcos AS, Lee, Janet M, Pejovic, Tanya, Liu, Gang, Ovarian Cancer Association Consortium, Karlan, Beth Y, Freedman, Matthew L, Noushmehr, Houtan, Monteiro, Alvaro N, Pharoah, Paul DP, Pasaniuc, Bogdan, Gayther, Simon A, Gusev, Alexander, Gusev, Alexander, Lawrenson, Kate, Lin, Xianzhi, Lyra, Paulo C, Kar, Siddhartha, Vavra, Kevin C, Segato, Felipe, Fonseca, Marcos AS, Lee, Janet M, Pejovic, Tanya, Liu, Gang, Ovarian Cancer Association Consortium, Karlan, Beth Y, Freedman, Matthew L, Noushmehr, Houtan, Monteiro, Alvaro N, Pharoah, Paul DP, Pasaniuc, Bogdan, and Gayther, Simon A

Abstract

We sought to identify susceptibility genes for high-grade serous ovarian cancer (HGSOC) by performing a transcriptome-wide association study of gene expression and splice junction usage in HGSOC-relevant tissue types (N = 2,169) and the largest genome-wide association study available for HGSOC (N = 13,037 cases and 40,941 controls). We identified 25 transcriptome-wide association study significant genes, 7 at the junction level only, including LRRC46 at 19q21.32, (P = 1 × 10-9), CHMP4C at 8q21 (P = 2 × 10-11) and a PRC1 junction at 15q26 (P = 7 × 10-9). In vitro assays for CHMP4C showed that the associated variant induces allele-specific exon inclusion (P = 0.0024). Functional screens in HGSOC cell lines found evidence of essentiality for three of the new genes we identified: HAUS6, KANSL1 and PRC1, with the latter comparable to MYC. Our study implicates at least one target gene for 6 out of 13 distinct genome-wide association study regions, identifying 23 new candidate susceptibility genes for HGSOC.

Published
2019

140. Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women.

Author

Lawrenson, Kate, Lawrenson, Kate, Song, Fengju, Hazelett, Dennis J, Kar, Siddhartha P, Tyrer, Jonathan, Phelan, Catherine M, Corona, Rosario I, Rodríguez-Malavé, Norma I, Seo, Ji-Hei, Adler, Emily, Coetzee, Simon G, Segato, Felipe, Fonseca, Marcos AS, Amos, Christopher I, Carney, Michael E, Chenevix-Trench, Georgia, Choi, Jiyeob, Doherty, Jennifer A, Jia, Weihua, Jin, Gang J, Kim, Byoung-Gie, Le, Nhu D, Lee, Juyeon, Li, Lian, Lim, Boon K, Adenan, Noor A, Mizuno, Mika, Park, Boyoung, Pearce, Celeste L, Shan, Kang, Shi, Yongyong, Shu, Xiao-Ou, Sieh, Weiva, Australian Ovarian Cancer Study Group, Thompson, Pamela J, Wilkens, Lynne R, Wei, Qingyi, Woo, Yin L, Yan, Li, Karlan, Beth Y, Freedman, Matthew L, Noushmehr, Houtan, Goode, Ellen L, Berchuck, Andrew, Sellers, Thomas A, Teo, Soo-Hwang, Zheng, Wei, Matsuo, Keitaro, Park, Sue, Chen, Kexin, Pharoah, Paul DP, Gayther, Simon A, Goodman, Marc T, Lawrenson, Kate, Lawrenson, Kate, Song, Fengju, Hazelett, Dennis J, Kar, Siddhartha P, Tyrer, Jonathan, Phelan, Catherine M, Corona, Rosario I, Rodríguez-Malavé, Norma I, Seo, Ji-Hei, Adler, Emily, Coetzee, Simon G, Segato, Felipe, Fonseca, Marcos AS, Amos, Christopher I, Carney, Michael E, Chenevix-Trench, Georgia, Choi, Jiyeob, Doherty, Jennifer A, Jia, Weihua, Jin, Gang J, Kim, Byoung-Gie, Le, Nhu D, Lee, Juyeon, Li, Lian, Lim, Boon K, Adenan, Noor A, Mizuno, Mika, Park, Boyoung, Pearce, Celeste L, Shan, Kang, Shi, Yongyong, Shu, Xiao-Ou, Sieh, Weiva, Australian Ovarian Cancer Study Group, Thompson, Pamela J, Wilkens, Lynne R, Wei, Qingyi, Woo, Yin L, Yan, Li, Karlan, Beth Y, Freedman, Matthew L, Noushmehr, Houtan, Goode, Ellen L, Berchuck, Andrew, Sellers, Thomas A, Teo, Soo-Hwang, Zheng, Wei, Matsuo, Keitaro, Park, Sue, Chen, Kexin, Pharoah, Paul DP, Gayther, Simon A, and Goodman, Marc T

Abstract

ObjectiveGenome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women.MethodsGenotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations.ResultsAt chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP <10%). At chromosome 20q11.22, rs74272064 was associated with HGSOC risk (OR = 1.27, P = 9.0 × 10-8). Overall EOC risk was associated with rs10260419 at chromosome 7p21.3 (OR = 1.33, P = 1.2 × 10-7) and rs74917072 at chromosome 2q37.3 (OR = 1.25, P = 4.7 × 10-7). At 2q37.3, expression quantitative trait locus analysis in 404 HGSOC tissues identified ESPNL as a putative candidate susceptibility gene (P = 1.2 × 10-7).ConclusionWhile some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.

Published
2019

141. Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus.

Author

Buckley, Melissa A, Buckley, Melissa A, Woods, Nicholas T, Tyrer, Jonathan P, Mendoza-Fandiño, Gustavo, Lawrenson, Kate, Hazelett, Dennis J, Najafabadi, Hamed S, Gjyshi, Anxhela, Carvalho, Renato S, Lyra, Paulo C, Coetzee, Simon G, Shen, Howard C, Yang, Ally W, Earp, Madalene A, Yoder, Sean J, Risch, Harvey, Chenevix-Trench, Georgia, Ramus, Susan J, Phelan, Catherine M, Coetzee, Gerhard A, Noushmehr, Houtan, Hughes, Timothy R, Sellers, Thomas A, Goode, Ellen L, Pharoah, Paul D, Gayther, Simon A, Monteiro, Alvaro NA, Ovarian Cancer Association Consortium, Buckley, Melissa A, Buckley, Melissa A, Woods, Nicholas T, Tyrer, Jonathan P, Mendoza-Fandiño, Gustavo, Lawrenson, Kate, Hazelett, Dennis J, Najafabadi, Hamed S, Gjyshi, Anxhela, Carvalho, Renato S, Lyra, Paulo C, Coetzee, Simon G, Shen, Howard C, Yang, Ally W, Earp, Madalene A, Yoder, Sean J, Risch, Harvey, Chenevix-Trench, Georgia, Ramus, Susan J, Phelan, Catherine M, Coetzee, Gerhard A, Noushmehr, Houtan, Hughes, Timothy R, Sellers, Thomas A, Goode, Ellen L, Pharoah, Paul D, Gayther, Simon A, Monteiro, Alvaro NA, and Ovarian Cancer Association Consortium

Abstract

Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. SIGNIFICANCE: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene.See related commentary by Choi and Brown, p. 439.

Published
2019

142. Molecular and translational advances in meningiomas.

Author

Suppiah, Suganth, Suppiah, Suganth, Nassiri, Farshad, Bi, Wenya Linda, Dunn, Ian F, Hanemann, Clemens Oliver, Horbinski, Craig M, Hashizume, Rintaro, James, Charles David, Mawrin, Christian, Noushmehr, Houtan, Perry, Arie, Sahm, Felix, Sloan, Andrew, Von Deimling, Andreas, Wen, Patrick Y, Aldape, Kenneth, Zadeh, Gelareh, International Consortium on Meningiomas, Suppiah, Suganth, Suppiah, Suganth, Nassiri, Farshad, Bi, Wenya Linda, Dunn, Ian F, Hanemann, Clemens Oliver, Horbinski, Craig M, Hashizume, Rintaro, James, Charles David, Mawrin, Christian, Noushmehr, Houtan, Perry, Arie, Sahm, Felix, Sloan, Andrew, Von Deimling, Andreas, Wen, Patrick Y, Aldape, Kenneth, Zadeh, Gelareh, and International Consortium on Meningiomas

Abstract

Meningiomas are the most common primary intracranial neoplasm. The current World Health Organization (WHO) classification categorizes meningiomas based on histopathological features, but emerging molecular data demonstrate the importance of genomic and epigenomic factors in the clinical behavior of these tumors. Treatment options for symptomatic meningiomas are limited to surgical resection where possible and adjuvant radiation therapy for tumors with concerning histopathological features or recurrent disease. At present, alternative adjuvant treatment options are not available in part due to limited historical biological analysis and clinical trial investigation on meningiomas. With advances in molecular and genomic techniques in the last decade, we have witnessed a surge of interest in understanding the genomic and epigenomic landscape of meningiomas. The field is now at the stage to adopt this molecular knowledge to refine meningioma classification and introduce molecular algorithms that can guide prediction and therapeutics for this tumor type. Animal models that recapitulate meningiomas faithfully are in critical need to test new therapeutics to facilitate rapid-cycle translation to clinical trials. Here we review the most up-to-date knowledge of molecular alterations that provide insight into meningioma behavior and are ready for application to clinical trial investigation, and highlight the landscape of available preclinical models in meningiomas.

Published
2019

143. A Study of High-Grade Serous Ovarian Cancer Origins Implicates the SOX18 Transcription Factor in Tumor Development

Author

Lawrenson, Kate, Lawrenson, Kate, Fonseca, Marcos AS, Liu, Annie Y, Dezem, Felipe Segato, Lee, Janet M, Lin, Xianzhi, Corona, Rosario I, Abbasi, Forough, Vavra, Kevin C, Dinh, Huy Q, Gill, Navjot Kaur, Seo, Ji-Heui, Coetzee, Simon, Lin, Yvonne G, Pejovic, Tanja, Mhawech-Fauceglia, Paulette, Rowat, Amy C, Drapkin, Ronny, Karlan, Beth Y, Hazelett, Dennis J, Freedman, Matthew L, Gayther, Simon A, Noushmehr, Houtan, Lawrenson, Kate, Lawrenson, Kate, Fonseca, Marcos AS, Liu, Annie Y, Dezem, Felipe Segato, Lee, Janet M, Lin, Xianzhi, Corona, Rosario I, Abbasi, Forough, Vavra, Kevin C, Dinh, Huy Q, Gill, Navjot Kaur, Seo, Ji-Heui, Coetzee, Simon, Lin, Yvonne G, Pejovic, Tanja, Mhawech-Fauceglia, Paulette, Rowat, Amy C, Drapkin, Ronny, Karlan, Beth Y, Hazelett, Dennis J, Freedman, Matthew L, Gayther, Simon A, and Noushmehr, Houtan

Abstract

Fallopian tube secretory epithelial cells (FTSECs) are likely the main precursor cell type of high-grade serous ovarian cancers (HGSOCs), but these tumors may also arise from ovarian surface epithelial cells (OSECs). We profiled global landscapes of gene expression and active chromatin to characterize molecular similarities between OSECs (n = 114), FTSECs (n = 74), and HGSOCs (n = 394). A one-class machine learning algorithm predicts that most HGSOCs derive from FTSECs, with particularly high FTSEC scores in mesenchymal-type HGSOCs (padj < 8 × 10-4). However, a subset of HGSOCs likely derive from OSECs, particularly HGSOCs of the proliferative type (padj < 2 × 10-4), suggesting a dualistic model for HGSOC origins. Super-enhancer (SE) landscapes were also more similar between FTSECs and HGSOCs than between OSECs and HGSOCs (p < 2.2 × 10-16). The SOX18 transcription factor (TF) coincided with a HGSOC-specific SE, and ectopic overexpression of SOX18 in FTSECs caused epithelial-to-mesenchymal transition, indicating that SOX18 plays a role in establishing the mesenchymal signature of fallopian-derived HGSOCs.

Published
2019

144. The Immune Landscape of Cancer

Author

Thorsson, Vésteinn, Thorsson, Vésteinn, Gibbs, David L, Brown, Scott D, Wolf, Denise, Bortone, Dante S, Yang, Tai-Hsien Ou, Porta-Pardo, Eduard, Gao, Galen F, Plaisier, Christopher L, Eddy, James A, Ziv, Elad, Culhane, Aedin C, Paull, Evan O, Sivakumar, IK Ashok, Gentles, Andrew J, Malhotra, Raunaq, Farshidfar, Farshad, Colaprico, Antonio, Parker, Joel S, Mose, Lisle E, Vo, Nam Sy, Liu, Jianfang, Liu, Yuexin, Rader, Janet, Dhankani, Varsha, Reynolds, Sheila M, Bowlby, Reanne, Califano, Andrea, Cherniack, Andrew D, Anastassiou, Dimitris, Bedognetti, Davide, Mokrab, Younes, Newman, Aaron M, Rao, Arvind, Chen, Ken, Krasnitz, Alexander, Hu, Hai, Malta, Tathiane M, Noushmehr, Houtan, Pedamallu, Chandra Sekhar, Bullman, Susan, Ojesina, Akinyemi I, Lamb, Andrew, Zhou, Wanding, Shen, Hui, Choueiri, Toni K, Weinstein, John N, Guinney, Justin, Saltz, Joel, Holt, Robert A, Rabkin, Charles S, Network, The Cancer Genome Atlas Research, Caesar-Johnson, Samantha J, Demchok, John A, Felau, Ina, Kasapi, Melpomeni, Ferguson, Martin L, Hutter, Carolyn M, Sofia, Heidi J, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean C, Zhang, Jiashan, Chudamani, Sudha, Liu, Jia, Lolla, Laxmi, Naresh, Rashi, Pihl, Todd, Sun, Qiang, Wan, Yunhu, Wu, Ye, Cho, Juok, DeFreitas, Timothy, Frazer, Scott, Gehlenborg, Nils, Getz, Gad, Heiman, David I, Kim, Jaegil, Lawrence, Michael S, Lin, Pei, Meier, Sam, Noble, Michael S, Saksena, Gordon, Voet, Doug, Zhang, Hailei, Bernard, Brady, Chambwe, Nyasha, Knijnenburg, Theo, Kramer, Roger, Leinonen, Kalle, Miller, Michael, Reynolds, Sheila, Shmulevich, Ilya, Thorsson, Vesteinn, Zhang, Wei, Akbani, Rehan, Broom, Bradley M, Thorsson, Vésteinn, Thorsson, Vésteinn, Gibbs, David L, Brown, Scott D, Wolf, Denise, Bortone, Dante S, Yang, Tai-Hsien Ou, Porta-Pardo, Eduard, Gao, Galen F, Plaisier, Christopher L, Eddy, James A, Ziv, Elad, Culhane, Aedin C, Paull, Evan O, Sivakumar, IK Ashok, Gentles, Andrew J, Malhotra, Raunaq, Farshidfar, Farshad, Colaprico, Antonio, Parker, Joel S, Mose, Lisle E, Vo, Nam Sy, Liu, Jianfang, Liu, Yuexin, Rader, Janet, Dhankani, Varsha, Reynolds, Sheila M, Bowlby, Reanne, Califano, Andrea, Cherniack, Andrew D, Anastassiou, Dimitris, Bedognetti, Davide, Mokrab, Younes, Newman, Aaron M, Rao, Arvind, Chen, Ken, Krasnitz, Alexander, Hu, Hai, Malta, Tathiane M, Noushmehr, Houtan, Pedamallu, Chandra Sekhar, Bullman, Susan, Ojesina, Akinyemi I, Lamb, Andrew, Zhou, Wanding, Shen, Hui, Choueiri, Toni K, Weinstein, John N, Guinney, Justin, Saltz, Joel, Holt, Robert A, Rabkin, Charles S, Network, The Cancer Genome Atlas Research, Caesar-Johnson, Samantha J, Demchok, John A, Felau, Ina, Kasapi, Melpomeni, Ferguson, Martin L, Hutter, Carolyn M, Sofia, Heidi J, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean C, Zhang, Jiashan, Chudamani, Sudha, Liu, Jia, Lolla, Laxmi, Naresh, Rashi, Pihl, Todd, Sun, Qiang, Wan, Yunhu, Wu, Ye, Cho, Juok, DeFreitas, Timothy, Frazer, Scott, Gehlenborg, Nils, Getz, Gad, Heiman, David I, Kim, Jaegil, Lawrence, Michael S, Lin, Pei, Meier, Sam, Noble, Michael S, Saksena, Gordon, Voet, Doug, Zhang, Hailei, Bernard, Brady, Chambwe, Nyasha, Knijnenburg, Theo, Kramer, Roger, Leinonen, Kalle, Miller, Michael, Reynolds, Sheila, Shmulevich, Ilya, Thorsson, Vesteinn, Zhang, Wei, Akbani, Rehan, and Broom, Bradley M

Abstract

(Immunity 48, 812–830.e1–e14; April 17, 2018) In the originally published version of this article, the authors neglected to include Younes Mokrab and Aaron M. Newman as co-authors and misspelled the names of authors Charles S. Rabkin and Ilya Shmulevich. The author names have been corrected here and online. In addition, the concluding sentence of the subsection “Immune Signature Compilation” in the Method Details in the original published article was deemed unclear because it did not specify differences among the gene set scoring methods. The concluding sentences now reads “Gene sets from Bindea et al., Senbabaoglu et al., and the MSigDB C7 collection were scored using single-sample gene set enrichment (ssGSEA) analysis (Barbie et al., 2009), as implemented in the GSVA R package (Hänzelmann et al., 2013). All other signatures were scored using methods found in the associated citations.”

Published
2019

145. New functionalities in the TCGAbiolinks package for the study and integration of cancer data from GDC and GTEx

Author

Mounir, Mohamed, Lucchetta, Marta, Silva, Tiago C, Olsen, Catharina, Bontempi, Gianluca, Chen, Xi, Noushmehr, Houtan, Colaprico, Antonio, Papaleo, Elena, Mounir, Mohamed, Lucchetta, Marta, Silva, Tiago C, Olsen, Catharina, Bontempi, Gianluca, Chen, Xi, Noushmehr, Houtan, Colaprico, Antonio, and Papaleo, Elena

Abstract

The advent of Next-Generation Sequencing (NGS) technologies has opened new perspectives in deciphering the genetic mechanisms underlying complex diseases. Nowadays, the amount of genomic data is massive and substantial efforts and new tools are required to unveil the information hidden in the data. The Genomic Data Commons (GDC) Data Portal is a platform that contains different genomic studies including the ones from The Cancer Genome Atlas (TCGA) and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiatives, accounting for more than 40 tumor types originating from nearly 30000 patients. Such platforms, although very attractive, must make sure the stored data are easily accessible and adequately harmonized. Moreover, they have the primary focus on the data storage in a unique place, and they do not provide a comprehensive toolkit for analyses and interpretation of the data. To fulfill this urgent need, comprehensive but easily accessible computational methods for integrative analyses of genomic data that do not renounce a robust statistical and theoretical framework are required. In this context, the R/Bioconductor package TCGAbiolinks was developed, offering a variety of bioinformatics functionalities. Here we introduce new features and enhancements of TCGAbiolinks in terms of i) more accurate and flexible pipelines for differential expression analyses, ii) different methods for tumor purity estimation and filtering, iii) integration of normal samples from other platforms iv) support for other genomics datasets, exemplified here by the TARGET data. Evidence has shown that accounting for tumor purity is essential in the study of tumorigenesis, as these factors promote confounding behavior regarding differential expression analysis. With this in mind, we implemented these filtering procedures in TCGAbiolinks. Moreover, a limitation of some of the TCGA datasets is the unavailability or paucity of corresponding normal samples. We

Published
2019

147. Molecular landscape of IDH-mutant primary astrocytoma Grade IV/glioblastomas.

Author

Wong, Queenie Hoi-Wing, Li, Kay Ka-Wai, Wang, Wei-Wei, Malta, Tathiane M., Noushmehr, Houtan, Grabovska, Yura, Jones, Chris, Chan, Aden Ka-Yin, Kwan, Johnny Sheung-Him, Huang, Queenie Jun-Qi, Wong, Gabriel Chun-Hei, Li, Wen-Cai, Liu, Xian-Zhi, Chen, Hong, Chan, Danny Tat-Ming, Mao, Ying, Zhang, Zhen-Yu, Shi, Zhi-Feng, and Ng, Ho-Keung

Published
2021
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148. Multi-Tissue Transcriptome-Wide Association Study Identifies 26 Novel Candidate Susceptibility Genes for High Grade Serous Epithelial Ovarian Cancer

Author

Gusev, Alexander, Lawrenson, Kate, Segato, Felipe, Fonseca, Marcos A.S., Kar, Siddhartha, Vavra, Kevin C., Lee, Janet M, Pejovic, Tanya, Karlan, Beth Y., Freedman, Matthew L., Noushmehr, Houtan, Pharoah, Paul D.P., Pasaniuc, Bogdan, and Gayther, Simon A.

Subjects
Genetics, 0303 health sciences, Biology, 3. Good health, Transcriptome, 03 medical and health sciences, Exon, 0302 clinical medicine, 030220 oncology & carcinogenesis, Expression quantitative trait loci, Gene expression, RNA splicing, Gene, Genotyping, 030304 developmental biology, Genetic association
Abstract

Genome-wide association studies (GWASs) have identified about 30 different susceptibility loci associated with high grade serous ovarian cancer (HGSOC) risk. We sought to identify potential susceptibility genes by integrating the risk variants at these regions with genetic variants impacting gene expression and splicing of nearby genes. We compiled gene expression and genotyping data from 2,169 samples for 6 different HGSOC-relevant tissue types. We integrated these data with GWAS data from 13,037 HGSOC cases and 40,941 controls, and performed a transcriptome-wide association study (TWAS) across >70,000 significantly heritable gene/exon features. We identified 24 transcriptome-wide significant associations for 14 unique genes, plus 90 significant exon-level associations in 20 unique genes. We implicated multiple novel genes at risk loci, e.g.LRRC46at 19q21.32 (TWASP=1×10−9) and aPRC1splicing event (TWASP=9×10−8) which was splice-variant specific and exhibited no eQTL signal. Functional analyses in HGSOC cell lines found evidence of essentiality forGOSR2, INTS1, KANSL1andPRC1; with the latter gene showing levels of essentiality comparable to that ofMYC. Overall, gene expression and splicing events explained 41% of SNP-heritability for HGSOC (s.e. 11%,P=2.5×10−4), implicated at least one target gene for 6/13 distinct genome-wide significant regions and revealed 2 known and 26 novel candidate susceptibility genes for HGSOC.STATEMENT OF SIGNIFICANCEFor many ovarian cancer risk regions, the target genes regulated by germline genetic variants are unknown. Using expression data from >2,100 individuals, this study identified novel associations of genes and splicing variants with ovarian cancer risk; with transcriptional variation now explaining over one-third of the SNP-heritability for this disease.

Published
2018

149. The Immune Landscape of Cancer

Author

Thorsson, Vésteinn, Gibbs, David L., Brown, Scott D., Wolf, Denise, Bortone, Dante S., Ou Yang, Tai Hsien, Porta-Pardo, Eduard, Gao, Galen F., Plaisier, Christopher L., Eddy, James A., Ziv, Elad, Culhane, Aedin C., Paull, Evan O., Sivakumar, I. K.Ashok, Gentles, Andrew J., Malhotra, Raunaq, Farshidfar, Farshad, Colaprico, Antonio, Parker, Joel S., Mose, Lisle E., Vo, Nam Sy, Liu, Jianfang, Liu, Yuexin, Rader, Janet, Dhankani, Varsha, Reynolds, Sheila M., Bowlby, Reanne, Califano, Andrea, Cherniack, Andrew D., Anastassiou, Dimitris, Bedognetti, Davide, Rao, Arvind, Chen, Ken, Krasnitz, Alexander, Hu, Hai, Malta, Tathiane M., Noushmehr, Houtan, Pedamallu, Chandra Sekhar, Bullman, Susan, Ojesina, Akinyemi I., Lamb, Andrew, Zhou, Wanding, Shen, Hui, Choueiri, Toni K., Weinstein, John N., Guinney, Justin, Saltz, Joel, Holt, Robert, Zhang, Jiashan (Julia), de Krijger, Ronald, and The Cancer Genome Atlas Research Network

Subjects
cancer genomics, integrative network analysis, Infectious Diseases, Immunology, immune subtypes, tumor microenvironment, Immunology and Allergy, immunotherapy, tumor immunology, immuno-oncology, immunomodulatory
Abstract

We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes—wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant—characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field. Thorsson et al. present immunogenomics analyses of more than 10,000 tumors, identifying six immune subtypes that encompass multiple cancer types and are hypothesized to define immune response patterns impacting prognosis. This work provides a resource for understanding tumor-immune interactions, with implications for identifying ways to advance research on immunotherapy.

Published
2018

150. Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer

Author

Hoadley, Katherine A., Yau, Christina, Hinoue, Toshinori, Wolf, Denise M., Lazar, Alexander J., Drill, Esther, Shen, Ronglai, Taylor, Alison M., Cherniack, Andrew D., Thorsson, Vésteinn, Akbani, Rehan, Bowlby, Reanne, Wong, Christopher K., Wiznerowicz, Maciej, Sanchez-Vega, Francisco, Robertson, A. Gordon, Schneider, Barbara G., Lawrence, Michael S., Noushmehr, Houtan, Malta, Tathiane M., Caesar-Johnson, Samantha J., Demchok, John A., Felau, Ina, Kasapi, Melpomeni, Ferguson, Martin L., Hutter, Carolyn M., Sofia, Heidi J., Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean C., Zhang, Jiashan (Julia), Chudamani, Sudha, Liu, Jia, Lolla, Laxmi, Naresh, Rashi, Pihl, Todd, Sun, Qiang, Wan, Yunhu, Wu, Ye, Cho, Juok, DeFreitas, Timothy, Frazer, Scott, Gehlenborg, Nils, Getz, Gad, Heiman, David I., Kim, Jaegil, Lin, Pei, de Krijger, Ronald, and The Cancer Genome Atlas Network

Subjects
Biochemistry, Genetics and Molecular Biology(all), proteome, subtypes, cell-of-origin, cancer, tissues, methylome, TCGA, organs, genome, transcriptome
Abstract

We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development. Comprehensive, integrated molecular analysis identifies molecular relationships across a large diverse set of human cancers, suggesting future directions for exploring clinical actionability in cancer treatment.

Published
2018

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