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, TCGA Research Network, Andrew D Cherniack, Christopher 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, Mohamed H Abdel-Rahman, Rehan Akbani, Adrian Ally, J Todd Auman, Ozgun Babur, Miruna Balasundaram, Saianand Balu, Christopher Benz, Rameen Beroukhim, Inanc Birol, Tom Bodenheimer, Jay Bowen, Reanne Bowlby, Christopher A Bristow, Denise Brooks, Rebecca Carlsen, Colleen M Cebulla, Matthew T Chang, Andrew D Cherniack, Lynda Chin, Juok Cho, Eric Chuah, Sudha Chudamani, Carrie Cibulskis, Kristian Cibulskis, Leslie Cope, Sarah E Coupland, Ludmila Danilova, 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, Ewan A Gibb, Klaus G Griewank, Elizabeth A Grimm, D Neil Hayes, Apurva M Hegde, David I Heiman, Carmen Helsel, Julian M Hess, Katherine A Hoadley, 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, Patrick K Kimes, Melanie Kucherlapati, Raju Kucherlapati, Eric Lander, Michael S Lawrence, Alexander J Lazar, Semin Lee, Kristen M Leraas, Tara M Lichtenberg, Pei Lin, Jia Liu, Wenbin Liu, Laxmi Lolla, Yiling Lu, Lisa Iype, 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, Karen L Mungall, Bradley A Murray, Rashi Naresh, Michael S Noble, Junna Oba, Angeliki Pantazi, Michael Parfenov, Peter J Park, Joel S Parker, Alexander Penson, Charles M Perou, Todd Pihl, Robert Pilarski, Alexei Protopopov, Amie Radenbaugh, Karan Rai, Nilsa C Ramirez, Xiaojia Ren, Sheila M Reynolds, Jeffrey Roach, A Gordon Robertson, 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, Juliann Shih, 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, Ming Tang, Jiabin Tang, Roy Tarnuzzer, Barry S Taylor, Nina Thiessen, Vesteinn Thorsson, Kane Tse, Vladislav Uzunangelov, Umadevi Veluvolu, Roel G W Verhaak, Doug Voet, Vonn Walter, 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, Christina Yau, Jean C Zenklusen, Jiashan Zhang, Hailei Zhang, Erik Zmuda, 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, TCGA Research Network, Andrew D Cherniack, Christopher 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, Mohamed H Abdel-Rahman, Rehan Akbani, Adrian Ally, J Todd Auman, Ozgun Babur, Miruna Balasundaram, Saianand Balu, Christopher Benz, Rameen Beroukhim, Inanc Birol, Tom Bodenheimer, Jay Bowen, Reanne Bowlby, Christopher A Bristow, Denise Brooks, Rebecca Carlsen, Colleen M Cebulla, Matthew T Chang, Andrew D Cherniack, Lynda Chin, Juok Cho, Eric Chuah, Sudha Chudamani, Carrie Cibulskis, Kristian Cibulskis, Leslie Cope, Sarah E Coupland, Ludmila Danilova, 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, Ewan A Gibb, Klaus G Griewank, Elizabeth A Grimm, D Neil Hayes, Apurva M Hegde, David I Heiman, Carmen Helsel, Julian M Hess, Katherine A Hoadley, 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, Patrick K Kimes, Melanie Kucherlapati, Raju Kucherlapati, Eric Lander, Michael S Lawrence, Alexander J Lazar, Semin Lee, Kristen M Leraas, Tara M Lichtenberg, Pei Lin, Jia Liu, Wenbin Liu, Laxmi Lolla, Yiling Lu, Lisa Iype, 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, Karen L Mungall, Bradley A Murray, Rashi Naresh, Michael S Noble, Junna Oba, Angeliki Pantazi, Michael Parfenov, Peter J Park, Joel S Parker, Alexander Penson, Charles M Perou, Todd Pihl, Robert Pilarski, Alexei Protopopov, Amie Radenbaugh, Karan Rai, Nilsa C Ramirez, Xiaojia Ren, Sheila M Reynolds, Jeffrey Roach, A Gordon Robertson, 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, Juliann Shih, 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, Ming Tang, Jiabin Tang, Roy Tarnuzzer, Barry S Taylor, Nina Thiessen, Vesteinn Thorsson, Kane Tse, Vladislav Uzunangelov, Umadevi Veluvolu, Roel G W Verhaak, Doug Voet, Vonn Walter, 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, Christina Yau, Jean C Zenklusen, Jiashan Zhang, Hailei Zhang, Erik Zmuda
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.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
Figures
![Figure 1. Genomic Landscape of Primary UM](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5619925/bin/nihms895876f1.jpg)
![Figure 2. DNA Methylation Landscape in Primary…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5619925/bin/nihms895876f2.jpg)
![Figure 3. Gene Expression Patterns in UM](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5619925/bin/nihms895876f3.jpg)
Figure 4. Immune Gene Expression in M3-versus…
Figure 4. Immune Gene Expression in M3-versus D3-UM
Heatmap for 80 primary UM, highlighting mRNA…
Figure 5. Integrative Pathway Analysis of UM
Figure 5. Integrative Pathway Analysis of UM
(A) Heatmap of hierarchically clustered PARADIGM inferred pathway…
Figure 6. Pathway and Regulators that were…
Figure 6. Pathway and Regulators that were Differentially Active in Transcriptional Subtypes 3 and 4
Figure 7. Good-Prognosis D3-UM and Poor-Prognosis M3-UM…
Figure 7. Good-Prognosis D3-UM and Poor-Prognosis M3-UM Separate into Distinct Biological Subsets
(A) Kaplan-Meier plots…
![Figure 4. Immune Gene Expression in M3-versus…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5619925/bin/nihms895876f4.jpg)
![Figure 5. Integrative Pathway Analysis of UM](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5619925/bin/nihms895876f5.jpg)
![Figure 6. Pathway and Regulators that were…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5619925/bin/nihms895876f6.jpg)
![Figure 7. Good-Prognosis D3-UM and Poor-Prognosis M3-UM…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5619925/bin/nihms895876f7.jpg)
Source: PubMed