Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

A. Gordon Robertson,Juliann Shih,Christina Yau, Ewan A. Gibb,Junna Oba,Karen Mungall,Julian M. Hess,Vladislav Uzunangelov,Vonn Walter,Ludmila Danilova,Tara M. Lichtenberg,Melanie H. Kucherlapati,Patrick K. Kimes,Ming Tang, A. Penson,Özgün Babur,Rehan Akbani, Christopher A. Bristow,Katherine A. Hoadley, Lisa Iype,Matthew T. Chang,Andrew D. Cherniack, Christopher C. Benz,Gordon B. Mills,Roel G.W. Verhaak,Klaus G. Griewank,Ina Felau, Jean C. Zenklusen, Jeffrey E. Gershenwald,Lynn Schoenfield, Alexander J. Lazar,Mohamed H. Abdel‐Rahman, Sergio Roman‐Roman,Marc‐Henri Stern,Colleen M. Cebulla,Michelle D. Williams,Martine J. Jager,Sarah E. Coupland,Bita Esmaeli,Cyriac Kandoth,Scott E. Woodman,Adrian Ally,J. Todd Auman, Miruna Balasundaram, Saianand Balu,Rameen Beroukhim,İnanç Birol,Tom Bodenheimer,Jay Bowen,Reanne Bowlby,Denise Brooks, Rebecca Carlsen,Lynda Chin, Juok Cho,Eric Chuah, Sudha Chudamani,Carrie Cibulskis,Kristian Cibulskis,Leslie Cope, Timothy Defreitas, John A. Demchok,Laurence Desjardins,Noreen Dhalla,Martin L. Ferguson, Scott Frazer,Stacey Gabriel,Julie M. Gastier‐Foster,Nils Gehlenborg,Mark Gerken, Gad Getz,Elizabeth A. Grimm,D. Neil Hayes,Apurva M. Hegde,David I. Heiman, Carmen Helsel, Shital Hobensack,Robert A. Holt,Alan P. Hoyle, Xin Hu,Carolyn M. Hutter,Stuart R. Jefferys,Corbin D. Jones,Steven Jones,Katayoon Kasaian,Jaegil Kim,Raju Kucherlapati,Eric S. Lander,Michael S. Lawrence, Semin Lee,Kristen Leraas,Pei Lin,Jia Liu, Wenbin Liu,Laxmi Lolla,Yiling Lu,Yussanne Ma,Harshad S. Mahadeshwar,Odette Mariani,Marco A. Marra,Michael Mayo, Sam Meier,Shaowu Meng,Matthew Meyerson,Piotr A. Mieczkowski, Richard A. Moore,Lisle E. Mose,Andrew J. Mungall,Bradley A. Murray, Rashi Naresh, Michael S. Noble,Angeliki Pantazi,Michael Parfenov,Peter J. Park,Joel S. Parker,Charles M. Perou, Todd Pihl,Robert Pilarski,Alexei Protopopov, Amie Radenbaugh,Karan Rai,Nilsa C. Ramirez,Xiaojia Ren,Sheila M. Reynolds,Jeffrey Roach, Jason Roszik,Sara Sadeghi,Gordon Saksena,Xavier Sastre,Dirk Schadendorf,Jacqueline E. Schein,Steven E. Schumacher,Jonathan G. Seidman,Sahil Seth,Geetika Sethi, Margi Sheth,Yan Shi,Carol L. Shields,Ilya Shmulevich, Janae V. Simons,Arun D. Singh,Payal Sipahimalani, Tara Skelly,Heidi J. Sofia,Matthew G. Soloway,Xingzhi Song,Joshua M. Stuart,Qiang Sun,Huandong Sun,Angela Tam,Donghui Tan,Jiabin Tang,Roy Tarnuzzer,Barry S. Taylor,Nina Thiessen, Vésteinn Thórsson,Kane Tse, Umadevi Veluvolu, Doug Voet,Yunhu Wan,Zhining Wang,John N. Weinstein, Matthew D. Wilkerson, Lisa Wise,Tina Wong,Ye Wu, Liming Yang,Lixing Yang,Jiashan Zhang, Erik Zmuda

Cancer cell（2017）

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摘要

Summary Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.

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