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 Iype; Matthew 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

doi:10.1016/j.ccell.2017.07.003

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 journal › Article › peer-review

432 Citations (Scopus)

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 language	English
Pages (from-to)	204-220.e15
Journal	Cancer Cell
Volume	32
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2017.07.003
Publication status	Published - 2017 Aug 14
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccell.2017.07.003

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

Robertson, AG, Shih, J, Yau, C, Gibb, EA, Oba, J, Mungall, KL, Hess, JM, Uzunangelov, V, Walter, V, Danilova, L, Lichtenberg, TM, Kucherlapati, M, Kimes, PK, Tang, M, Penson, A, Babur, O, Akbani, R, Bristow, CA, Hoadley, KA, Iype, L, Chang, MT, Abdel-Rahman, MH, Ally, A, Auman, JT, Balasundaram, M, Balu, S, Benz, C, Beroukhim, R, Birol, I, Bodenheimer, T, Bowen, J, Bowlby, R, Brooks, D, Carlsen, R, Cebulla, CM, Cherniack, AD, Chin, L, Cho, J, Chuah, E, Chudamani, S, Cibulskis, C, Cibulskis, K, Cope, L, Coupland, SE, Defreitas, T, Demchok, JA, Desjardins, L, Dhalla, N, Esmaeli, B, Felau, I, Ferguson, ML, Frazer, S, Gabriel, SB, Gastier-Foster, JM, Gehlenborg, N, Gerken, M, Gershenwald, JE, Getz, G, Griewank, KG, Grimm, EA, Hayes, DN, Hegde, AM, Heiman, DI, Helsel, C, Hobensack, S, Holt, RA, Hoyle, AP, Hu, X, Hutter, CM, Jager, MJ, Jefferys, SR, Jones, CD, Jones, SJM, Kandoth, C, Kasaian, K, Kim, J, Kucherlapati, R, Lander, E, Lawrence, MS, Lazar, AJ, Lee, S, Leraas, KM, Lin, P, Liu, J, Liu, W, Lolla, L, Lu, Y, Ma, Y, Mahadeshwar, HS, Mariani, O, Marra, MA, Mayo, M, Meier, S, Meng, S, Meyerson, M, Mieczkowski, PA, Mills, GB, Moore, RA, Mose, LE, Mungall, AJ, Murray, BA, Naresh, R, Noble, MS, Pantazi, A, Parfenov, M, Park, PJ, Parker, JS, Perou, CM, Pihl, T, Pilarski, R, Protopopov, A, Radenbaugh, A, Rai, K, Ramirez, NC, Ren, X, Reynolds, SM, Roach, J, Roman-Roman, S, Roszik, J, Sadeghi, S, Saksena, G, Sastre, X, Schadendorf, D, Schein, JE, Schoenfield, L, Schumacher, SE, Seidman, J, Seth, S, Sethi, G, Sheth, M, Shi, Y, Shields, C, Shmulevich, I, Simons, JV, Singh, AD, Sipahimalani, P, Skelly, T, Sofia, H, Soloway, MG, Song, X, Stern, MH, Stuart, J, Sun, Q, Sun, H, Tam, A, Tan, D, Tang, J, Tarnuzzer, R, Taylor, BS, Thiessen, N, Thorsson, V, Tse, K, Veluvolu, U, Verhaak, RGW, Voet, D, Wan, Y, Wang, Z, Weinstein, JN, Wilkerson, MD, Williams, MD, Wise, L, Woodman, SE, Wong, T, Wu, Y, Yang, L, Yang, L, Zenklusen, JC, Zhang, J, Zhang, H & Zmuda, E 2017, 'Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma', Cancer Cell, vol. 32, no. 2, pp. 204-220.e15. https://doi.org/10.1016/j.ccell.2017.07.003

@article{adc5c80ef5a948028bf8bb7af4c2c180,

title = "Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma",

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.",

keywords = "EIF1AX, GNA11, GNAQ, SF3B1, SRSF2, TCGA, molecular subtypes, monosomy 3, noncoding RNA, uveal melanoma",

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

note = "Funding Information: We are grateful to all patients and families who contributed to this study. We thank Dr. Jasmine Francis, Dr. Amy Schefler and Dr Helen Kalirai for following through with the requirements for sample submission. This work was supported by the following grants from the NIH: U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, P30 CA016672, P50 CA083639, and K08 EY022672 (C.M.C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. E.A.G. is an employee of GenomeDx Biosciences. A.D.C. declares research funding from Bayer AG. J.E.G. has an advisory role in Castle Biosciences and Merck. K.G.G. holds the patent for WO2011130691: GNA11 and GNAQ exon 4 mutations in melanoma. Publisher Copyright: {\textcopyright} 2017 The Authors",

year = "2017",

month = aug,

day = "14",

doi = "10.1016/j.ccell.2017.07.003",

language = "English",

volume = "32",

pages = "204--220.e15",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

AU - Robertson, A. Gordon

AU - Shih, Juliann

AU - Yau, Christina

AU - Gibb, Ewan A.

AU - Oba, Junna

AU - Mungall, Karen L.

AU - Hess, Julian M.

AU - Uzunangelov, Vladislav

AU - Walter, Vonn

AU - Danilova, Ludmila

AU - Lichtenberg, Tara M.

AU - Kucherlapati, Melanie

AU - Kimes, Patrick K.

AU - Tang, Ming

AU - Penson, Alexander

AU - Babur, Ozgun

AU - Akbani, Rehan

AU - Bristow, Christopher A.

AU - Hoadley, Katherine A.

AU - Iype, Lisa

AU - Chang, Matthew T.

AU - Abdel-Rahman, Mohamed H.

AU - Ally, Adrian

AU - Auman, J. Todd

AU - Balasundaram, Miruna

AU - Balu, Saianand

AU - Benz, Christopher

AU - Beroukhim, Rameen

AU - Birol, Inanc

AU - Bodenheimer, Tom

AU - Bowen, Jay

AU - Bowlby, Reanne

AU - Brooks, Denise

AU - Carlsen, Rebecca

AU - Cebulla, Colleen M.

AU - Cherniack, Andrew D.

AU - Chin, Lynda

AU - Cho, Juok

AU - Chuah, Eric

AU - Chudamani, Sudha

AU - Cibulskis, Carrie

AU - Cibulskis, Kristian

AU - Cope, Leslie

AU - Coupland, Sarah E.

AU - Defreitas, Timothy

AU - Demchok, John A.

AU - Desjardins, Laurence

AU - Dhalla, Noreen

AU - Esmaeli, Bita

AU - Felau, Ina

AU - Ferguson, Martin L.

AU - Frazer, Scott

AU - Gabriel, Stacey B.

AU - Gastier-Foster, Julie M.

AU - Gehlenborg, Nils

AU - Gerken, Mark

AU - Gershenwald, Jeffrey E.

AU - Getz, Gad

AU - Griewank, Klaus G.

AU - Grimm, Elizabeth A.

AU - Hayes, D. Neil

AU - Hegde, Apurva M.

AU - Heiman, David I.

AU - Helsel, Carmen

AU - Hobensack, Shital

AU - Holt, Robert A.

AU - Hoyle, Alan P.

AU - Hu, Xin

AU - Hutter, Carolyn M.

AU - Jager, Martine J.

AU - Jefferys, Stuart R.

AU - Jones, Corbin D.

AU - Jones, Steven J.M.

AU - Kandoth, Cyriac

AU - Kasaian, Katayoon

AU - Kim, Jaegil

AU - Kucherlapati, Raju

AU - Lander, Eric

AU - Lawrence, Michael S.

AU - Lazar, Alexander J.

AU - Lee, Semin

AU - Leraas, Kristen M.

AU - Lin, Pei

AU - Liu, Jia

AU - Liu, Wenbin

AU - Lolla, Laxmi

AU - Lu, Yiling

AU - Ma, Yussanne

AU - Mahadeshwar, Harshad S.

AU - Mariani, Odette

AU - Marra, Marco A.

AU - Mayo, Michael

AU - Meier, Sam

AU - Meng, Shaowu

AU - Meyerson, Matthew

AU - Mieczkowski, Piotr A.

AU - Mills, Gordon B.

AU - Moore, Richard A.

AU - Mose, Lisle E.

AU - Mungall, Andrew J.

AU - Murray, Bradley A.

AU - Naresh, Rashi

AU - Noble, Michael S.

AU - Pantazi, Angeliki

AU - Parfenov, Michael

AU - Park, Peter J.

AU - Parker, Joel S.

AU - Perou, Charles M.

AU - Pihl, Todd

AU - Pilarski, Robert

AU - Protopopov, Alexei

AU - Radenbaugh, Amie

AU - Rai, Karan

AU - Ramirez, Nilsa C.

AU - Ren, Xiaojia

AU - Reynolds, Sheila M.

AU - Roach, Jeffrey

AU - Roman-Roman, Sergio

AU - Roszik, Jason

AU - Sadeghi, Sara

AU - Saksena, Gordon

AU - Sastre, Xavier

AU - Schadendorf, Dirk

AU - Schein, Jacqueline E.

AU - Schoenfield, Lynn

AU - Schumacher, Steven E.

AU - Seidman, Jonathan

AU - Seth, Sahil

AU - Sethi, Geetika

AU - Sheth, Margi

AU - Shi, Yan

AU - Shields, Carol

AU - Shmulevich, Ilya

AU - Simons, Janae V.

AU - Singh, Arun D.

AU - Sipahimalani, Payal

AU - Skelly, Tara

AU - Sofia, Heidi

AU - Soloway, Matthew G.

AU - Song, Xingzhi

AU - Stern, Marc Henri

AU - Stuart, Joshua

AU - Sun, Qiang

AU - Sun, Huandong

AU - Tam, Angela

AU - Tan, Donghui

AU - Tang, Jiabin

AU - Tarnuzzer, Roy

AU - Taylor, Barry S.

AU - Thiessen, Nina

AU - Thorsson, Vesteinn

AU - Tse, Kane

AU - Veluvolu, Umadevi

AU - Verhaak, Roel G.W.

AU - Voet, Doug

AU - Wan, Yunhu

AU - Wang, Zhining

AU - Weinstein, John N.

AU - Wilkerson, Matthew D.

AU - Williams, Michelle D.

AU - Wise, Lisa

AU - Woodman, Scott E.

AU - Wong, Tina

AU - Wu, Ye

AU - Yang, Liming

AU - Yang, Lixing

AU - Zenklusen, Jean C.

AU - Zhang, Jiashan

AU - Zhang, Hailei

AU - Zmuda, Erik

N1 - Funding Information: We are grateful to all patients and families who contributed to this study. We thank Dr. Jasmine Francis, Dr. Amy Schefler and Dr Helen Kalirai for following through with the requirements for sample submission. This work was supported by the following grants from the NIH: U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, P30 CA016672, P50 CA083639, and K08 EY022672 (C.M.C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. E.A.G. is an employee of GenomeDx Biosciences. A.D.C. declares research funding from Bayer AG. J.E.G. has an advisory role in Castle Biosciences and Merck. K.G.G. holds the patent for WO2011130691: GNA11 and GNAQ exon 4 mutations in melanoma. Publisher Copyright: © 2017 The Authors

PY - 2017/8/14

Y1 - 2017/8/14

N2 - 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.

AB - 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.

KW - EIF1AX

KW - GNA11

KW - GNAQ

KW - SF3B1

KW - SRSF2

KW - TCGA

KW - molecular subtypes

KW - monosomy 3

KW - noncoding RNA

KW - uveal melanoma

UR - http://www.scopus.com/inward/record.url?scp=85026887361&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85026887361&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2017.07.003

DO - 10.1016/j.ccell.2017.07.003

M3 - Article

C2 - 28810145

AN - SCOPUS:85026887361

SN - 1535-6108

VL - 32

SP - 204-220.e15

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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