Genomic Classification of Cutaneous Melanoma

Rehan Akbani; Kadir C. Akdemir; B. Arman Aksoy; Monique Albert; Adrian Ally; Samirkumar B. Amin; Harindra Arachchi; Arshi Arora; J. Todd Auman; Brenda Ayala; Julien Baboud; Miruna Balasundaram; Saianand Balu; Nandita Barnabas; John Bartlett; Pam Bartlett; Boris C. Bastian; Stephen B. Baylin; Madhusmita Behera; Dmitry Belyaev; Christopher Benz; Brady Bernard; Rameen Beroukhim; Natalie Bir; Aaron D. Black; Tom Bodenheimer; Lori Boice; Genevieve M. Boland; Riccardo Bono; Moiz S. Bootwalla; Marcus Bosenberg; Jay Bowen; Reanne Bowlby; Christopher A. Bristow; Laura Brockway-Lunardi; Denise Brooks; Jakub Brzezinski; Wiam Bshara; Elizabeth Buda; William R. Burns; Yaron S.N. Butterfield; Michael Button; Tiffany Calderone; Giancarlo Antonini Cappellini; Candace Carter; Scott L. Carter; Lynn Cherney; Andrew D. Cherniack; Aaron Chevalier; Lihua Zou; The Cancer Genome Atlas Network

doi:10.1016/j.cell.2015.05.044

Genomic Classification of Cutaneous Melanoma

Rehan Akbani, Kadir C. Akdemir, B. Arman Aksoy, Monique Albert, Adrian Ally, Samirkumar B. Amin, Harindra Arachchi, Arshi Arora, J. Todd Auman, Brenda Ayala, Julien Baboud, Miruna Balasundaram, Saianand Balu, Nandita Barnabas, John Bartlett, Pam Bartlett, Boris C. Bastian, Stephen B. Baylin, Madhusmita Behera, Dmitry BelyaevChristopher Benz, Brady Bernard, Rameen Beroukhim, Natalie Bir, Aaron D. Black, Tom Bodenheimer, Lori Boice, Genevieve M. Boland, Riccardo Bono, Moiz S. Bootwalla, Marcus Bosenberg, Jay Bowen, Reanne Bowlby, Christopher A. Bristow, Laura Brockway-Lunardi, Denise Brooks, Jakub Brzezinski, Wiam Bshara, Elizabeth Buda, William R. Burns, Yaron S.N. Butterfield, Michael Button, Tiffany Calderone, Giancarlo Antonini Cappellini, Candace Carter, Scott L. Carter, Lynn Cherney, Andrew D. Cherniack, Aaron Chevalier, Lihua Zou, The Cancer Genome Atlas Network

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

2321 Scopus citations

Abstract

Summary We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.

Original language	English (US)
Pages (from-to)	1681-1696
Number of pages	16
Journal	Cell
Volume	161
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2015.05.044
State	Published - Jun 20 2015

Funding

We thank all patients and families who contributed to this study. We are grateful to Chris Gunter for manuscript editing and Ina Felau and Margi Sheth for project management. This article is dedicated to the memory of Donald L. Morton, M.D., a pioneer in melanoma oncology, who passed away on January 10, 2014. This study was supported by NIH grants: 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, and P30 CA016672. A.D.C. and M.M. receive research funding from Bayer AG. M.M. is a founder of, equity holder in, and consultant for Foundation Medicine, a next-generation sequencing-based cancer diagnostics company. L.A.G. received a commercial research grant from Novartis and is a consultant/advisory board member for Novartis, Foundation Medicine, and Boehringer Ingelheim. L.A.G. also has equity interest in Foundation Medicine. D.J.W. is a consultant for Zymo Research Corporation, which distributes commercially available products for DNA methylation-based experiments. Zymo Research neither supported this work nor has an interest in the outcome of this research. O.P and O.V. are co-founders and shareholders of Cureline, Inc., which received a contract payment from the NIH for this work. J.E.G. is an advisory board member for Merck.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2015.05.044

Cite this

Akbani, R., Akdemir, K. C., Aksoy, B. A., Albert, M., Ally, A., Amin, S. B., Arachchi, H., Arora, A., Auman, J. T., Ayala, B., Baboud, J., Balasundaram, M., Balu, S., Barnabas, N., Bartlett, J., Bartlett, P., Bastian, B. C., Baylin, S. B., Behera, M., ... The Cancer Genome Atlas Network (2015). Genomic Classification of Cutaneous Melanoma. Cell, 161(7), 1681-1696. https://doi.org/10.1016/j.cell.2015.05.044

@article{a1a700ebd42049559d5da0aa92a7918c,

title = "Genomic Classification of Cutaneous Melanoma",

abstract = "Summary We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.",

author = "Rehan Akbani and Akdemir, {Kadir C.} and Aksoy, {B. Arman} and Monique Albert and Adrian Ally and Amin, {Samirkumar B.} and Harindra Arachchi and Arshi Arora and Auman, {J. Todd} and Brenda Ayala and Julien Baboud and Miruna Balasundaram and Saianand Balu and Nandita Barnabas and John Bartlett and Pam Bartlett and Bastian, {Boris C.} and Baylin, {Stephen B.} and Madhusmita Behera and Dmitry Belyaev and Christopher Benz and Brady Bernard and Rameen Beroukhim and Natalie Bir and Black, {Aaron D.} and Tom Bodenheimer and Lori Boice and Boland, {Genevieve M.} and Riccardo Bono and Bootwalla, {Moiz S.} and Marcus Bosenberg and Jay Bowen and Reanne Bowlby and Bristow, {Christopher A.} and Laura Brockway-Lunardi and Denise Brooks and Jakub Brzezinski and Wiam Bshara and Elizabeth Buda and Burns, {William R.} and Butterfield, {Yaron S.N.} and Michael Button and Tiffany Calderone and Cappellini, {Giancarlo Antonini} and Candace Carter and Carter, {Scott L.} and Lynn Cherney and Cherniack, {Andrew D.} and Aaron Chevalier and Lihua Zou and {The Cancer Genome Atlas Network}",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = jun,

day = "20",

doi = "10.1016/j.cell.2015.05.044",

language = "English (US)",

volume = "161",

pages = "1681--1696",

journal = "Cell",

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Akbani, R, Akdemir, KC, Aksoy, BA, Albert, M, Ally, A, Amin, SB, Arachchi, H, Arora, A, Auman, JT, Ayala, B, Baboud, J, Balasundaram, M, Balu, S, Barnabas, N, Bartlett, J, Bartlett, P, Bastian, BC, Baylin, SB, Behera, M, Belyaev, D, Benz, C, Bernard, B, Beroukhim, R, Bir, N, Black, AD, Bodenheimer, T, Boice, L, Boland, GM, Bono, R, Bootwalla, MS, Bosenberg, M, Bowen, J, Bowlby, R, Bristow, CA, Brockway-Lunardi, L, Brooks, D, Brzezinski, J, Bshara, W, Buda, E, Burns, WR, Butterfield, YSN, Button, M, Calderone, T, Cappellini, GA, Carter, C, Carter, SL, Cherney, L, Cherniack, AD, Chevalier, A, Zou, L & The Cancer Genome Atlas Network 2015, 'Genomic Classification of Cutaneous Melanoma', Cell, vol. 161, no. 7, pp. 1681-1696. https://doi.org/10.1016/j.cell.2015.05.044

TY - JOUR

T1 - Genomic Classification of Cutaneous Melanoma

AU - Akbani, Rehan

AU - Akdemir, Kadir C.

AU - Aksoy, B. Arman

AU - Albert, Monique

AU - Ally, Adrian

AU - Amin, Samirkumar B.

AU - Arachchi, Harindra

AU - Arora, Arshi

AU - Auman, J. Todd

AU - Ayala, Brenda

AU - Baboud, Julien

AU - Balasundaram, Miruna

AU - Balu, Saianand

AU - Barnabas, Nandita

AU - Bartlett, John

AU - Bartlett, Pam

AU - Bastian, Boris C.

AU - Baylin, Stephen B.

AU - Behera, Madhusmita

AU - Belyaev, Dmitry

AU - Benz, Christopher

AU - Bernard, Brady

AU - Beroukhim, Rameen

AU - Bir, Natalie

AU - Black, Aaron D.

AU - Bodenheimer, Tom

AU - Boice, Lori

AU - Boland, Genevieve M.

AU - Bono, Riccardo

AU - Bootwalla, Moiz S.

AU - Bosenberg, Marcus

AU - Bowen, Jay

AU - Bowlby, Reanne

AU - Bristow, Christopher A.

AU - Brockway-Lunardi, Laura

AU - Brooks, Denise

AU - Brzezinski, Jakub

AU - Bshara, Wiam

AU - Buda, Elizabeth

AU - Burns, William R.

AU - Butterfield, Yaron S.N.

AU - Button, Michael

AU - Calderone, Tiffany

AU - Cappellini, Giancarlo Antonini

AU - Carter, Candace

AU - Carter, Scott L.

AU - Cherney, Lynn

AU - Cherniack, Andrew D.

AU - Chevalier, Aaron

AU - Zou, Lihua

AU - The Cancer Genome Atlas Network

PY - 2015/6/20

Y1 - 2015/6/20

N2 - Summary We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.

AB - Summary We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.

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UR - http://www.scopus.com/inward/citedby.url?scp=84935009372&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2015.05.044

DO - 10.1016/j.cell.2015.05.044

M3 - Article

C2 - 26091043

AN - SCOPUS:84935009372

SN - 0092-8674

VL - 161

SP - 1681

EP - 1696

JO - Cell

JF - Cell

IS - 7

ER -

Genomic Classification of Cutaneous Melanoma

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