Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

A. Gordon Robertson, Juliann Shih, Christina Yau, Ewan A. Gibb, Junna Oba, Karen L. Mungall, Julian M. Hess, Vladislav Uzunangelov, Vonn Walter, Ludmila Danilova, Tara M. Lichtenberg, Melanie Kucherlapati, Patrick K. Kimes, Ming Tang, Alexander Penson, Ozgun Babur, Rehan Akbani, Christopher A. Bristow, Katherine A. Hoadley, Lisa IypeMatthew T. Chang, Mohamed H. Abdel-Rahman, Adrian Ally, J. Todd Auman, Miruna Balasundaram, Saianand Balu, Christopher Benz, Rameen Beroukhim, Inanc Birol, Tom Bodenheimer, Jay Bowen, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Colleen M. Cebulla, Andrew D. Cherniack, Lynda Chin, Juok Cho, Eric Chuah, Sudha Chudamani, Carrie Cibulskis, Kristian Cibulskis, Leslie Cope, Sarah E. Coupland, Timothy Defreitas, John A. Demchok, Laurence Desjardins, Noreen Dhalla, Bita Esmaeli, Ina Felau, Martin L. Ferguson, Scott Frazer, Stacey B. Gabriel, Julie M. Gastier-Foster, Nils Gehlenborg, Mark Gerken, Jeffrey E. Gershenwald, Gad Getz, Klaus G. Griewank, 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, Martine J. Jager, Stuart R. Jefferys, Corbin D. Jones, Steven J.M. Jones, Cyriac Kandoth, Katayoon Kasaian, Jaegil Kim, Raju Kucherlapati, Eric Lander, Michael S. Lawrence, Alexander J. Lazar, Semin Lee, Kristen M. 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, Gordon B. Mills, 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, Sergio Roman-Roman, Jason Roszik, Sara Sadeghi, Gordon Saksena, Xavier Sastre, Dirk Schadendorf, Jacqueline E. Schein, Lynn Schoenfield, Steven E. Schumacher, Jonathan Seidman, Sahil Seth, Geetika Sethi, Margi Sheth, Yan Shi, Carol Shields, Ilya Shmulevich, Janae V. Simons, Arun D. Singh, Payal Sipahimalani, Tara Skelly, Heidi Sofia, Matthew G. Soloway, Xingzhi Song, Marc Henri Stern, Joshua Stuart, Qiang Sun, Huandong Sun, Angela Tam, Donghui Tan, Jiabin Tang, Roy Tarnuzzer, Barry S. Taylor, Nina Thiessen, Vesteinn Thorsson, Kane Tse, Umadevi Veluvolu, Roel G.W. Verhaak, Doug Voet, Yunhu Wan, Zhining Wang, John N. Weinstein, Matthew D. Wilkerson, Michelle D. Williams, Lisa Wise, Scott E. Woodman, Tina Wong, Ye Wu, Liming Yang, Lixing Yang, Jean C. Zenklusen, Jiashan Zhang, Hailei Zhang, Erik Zmuda

Research output: Contribution to journalArticle

164 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)204-220.e15
JournalCancer Cell
Volume32
Issue number2
DOIs
StatePublished - Aug 14 2017

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Keywords

  • EIF1AX
  • GNA11
  • GNAQ
  • SF3B1
  • SRSF2
  • TCGA
  • molecular subtypes
  • monosomy 3
  • noncoding RNA
  • uveal melanoma

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Robertson, A. G., Shih, J., Yau, C., Gibb, E. A., Oba, J., Mungall, K. L., Hess, J. M., Uzunangelov, V., Walter, V., Danilova, L., Lichtenberg, T. M., Kucherlapati, M., Kimes, P. K., Tang, M., Penson, A., Babur, O., Akbani, R., Bristow, C. A., Hoadley, K. A., ... Zmuda, E. (2017). Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. Cancer Cell, 32(2), 204-220.e15. https://doi.org/10.1016/j.ccell.2017.07.003