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Cancer Cell. 2017 Aug 14;32(2):204-220.e15. doi: 10.1016/j.ccell.2017.07.003.

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma.

Collaborators (170)

Abdel-Rahman MH, Akbani R, Ally A, Auman JT, Babur O, Balasundaram M, Balu S, Benz C, Beroukhim R, Birol I, Bodenheimer T, Bowen J, Bowlby R, Bristow CA, Brooks D, Carlsen R, Cebulla CM, Chang MT, Cherniack AD, Chin L, Cho J, Chuah E, Chudamani S, Cibulskis C, Cibulskis K, Cope L, Coupland SE, Danilova L, 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, Gibb EA, Griewank KG, Grimm EA, Hayes DN, Hegde AM, Heiman DI, Helsel C, Hess JM, Hoadley KA, Hobensack S, Holt RA, Hoyle AP, Hu X, Hutter CM, Jager MJ, Jefferys SR, Jones CD, Jones SJM, Kandoth C, Kasaian K, Kim J, Kimes PK, Kucherlapati M, Kucherlapati R, Lander E, Lawrence MS, Lazar AJ, Lee S, Leraas KM, Lichtenberg TM, Lin P, Liu J, Liu W, Lolla L, Lu Y, Iype L, 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, Mungall KL, Murray BA, Naresh R, Noble MS, Oba J, Pantazi A, Parfenov M, Park PJ, Parker JS, Penson A, Perou CM, Pihl T, Pilarski R, Protopopov A, Radenbaugh A, Rai K, Ramirez NC, Ren X, Reynolds SM, Roach J, Robertson AG, 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, Shih J, 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 M, Tang J, Tarnuzzer R, Taylor BS, Thiessen N, Thorsson V, Tse K, Uzunangelov V, Veluvolu U, Verhaak RGW, Voet D, Walter V, Wan Y, Wang Z, Weinstein JN, Wilkerson MD, Williams MD, Wise L, Woodman SE, Wong T, Wu Y, Yang L, Yang L, Yau C, Zenklusen JC, Zhang J, Zhang H, Zmuda E.

Author information

1
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
2
The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3
Buck Institute for Research on Aging, Novato, CA 94945, USA.
4
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
6
Department of Biomolecular Engineering, Center for Biomolecular Sciences and Engineering, University of California, Santa Cruz, CA 95064, USA.
7
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Public Health Sciences, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
8
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA.
9
The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
10
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
11
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
12
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
13
Human Oncology and Pathogenesis Program, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
14
Molecular and Medical Genetics, Computational Biology, Oregon Health and Science University, Portland, OR 97239, USA.
15
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
16
Institute for Applied Cancer Science, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
17
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
18
Institute for Systems Biology, Seattle, WA 98109, USA.
19
Human Oncology and Pathogenesis Program, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Departments of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94122, USA.
20
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
21
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
22
Department of Dermatology, University Hospital Essen, 45157 Essen, Germany.
23
Center for Cancer Genomics, National Cancer Institute, Bethesda, MD 20892, USA.
24
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
25
Department of Pathology, The Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA.
26
Department of Pathology, Dermatology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
27
Departments of Ophthalmology and Internal Medicine, Division of Human Genetics, The Ohio State University, Columbus, OH 43210, USA.
28
Department of Translational Research, Institut Curie, PSL Research University, Paris 75248, France.
29
Havener Eye Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43212, USA.
30
Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
31
Department of Molecular & Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool L7 8TX, UK; Department of Cellular Pathology, Royal Liverpool University Hospital, Liverpool, L69 3GA, UK.
32
Orbital Oncology & Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: besmaeli@mdanderson.org.
33
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. Electronic address: kandothc@mskcc.org.
34
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: swoodman@mdanderson.org.

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

PMID:
28810145
PMCID:
PMC5619925
DOI:
10.1016/j.ccell.2017.07.003
[Indexed for MEDLINE]
Free PMC Article

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