A Landscape of Driver Mutations in Melanoma

被引：1968

作者：

Hodis, Eran ^{[1
,2
]}

Watson, Ian R. ^{[3
,11
]}

Kryukov, Gregory V. ^{[1
,2
,13
]}

Arold, Stefan T. ^{[4
,5
]}

Imielinski, Marcin ^{[1
]}

Theurillat, Jean-Philippe ^{[1
]}

Nickerson, Elizabeth ^{[1
]}

Auclair, Daniel ^{[1
]}

Li, Liren ^{[3
,11
]}

Place, Chelsea ^{[11
]}

DiCara, Daniel ^{[1
]}

Ramos, Alex H. ^{[1
,2
]}

Lawrence, Michael S. ^{[1
]}

Cibulskis, Kristian ^{[1
]}

Sivachenko, Andrey ^{[1
]}

Voet, Douglas ^{[1
]}

Saksena, Gordon ^{[1
]}

Stransky, Nicolas ^{[1
]}

Onofrio, Robert C. ^{[1
]}

Winckler, Wendy ^{[1
]}

Ardlie, Kristin ^{[1
]}

Wagle, Nikhil ^{[1
,2
]}

Wargo, Jennifer ^{[14
]}

Chong, Kelly ^{[15
]}

Morton, Donald L. ^{[16
]}

Stemke-Hale, Katherine ^{[6
]}

Chen, Guo ^{[7
]}

Noble, Michael ^{[1
]}

Meyerson, Matthew ^{[1
,2
,11
,12
]}

Ladbury, John E. ^{[4
,5
]}

Davies, Michael A. ^{[6
,7
]}

Gershenwald, Jeffrey E. ^{[8
,9
]}

Wagner, Stephan N. ^{[17
,18
]}

Hoon, Dave S. B. ^{[15
]}

Schadendorf, Dirk ^{[19
]}

Lander, Eric S. ^{[1
,20
]}

Gabriel, Stacey B. ^{[1
]}

Getz, Gad ^{[1
]}

Garraway, Levi A. ^{[1
,2
,11
,12
]}

Chin, Lynda ^{[1
,2
,3
,10
,11
]}

机构：

[1] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[2] Harvard Univ, Sch Med, Boston, MA 02115 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Ctr Biomol Struct & Funct, Houston, TX 77030 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

[10] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA

[11] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[12] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[13] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

[14] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA

[15] John Wayne Canc Inst, Dept Mol Oncol, Santa Monica, CA 90404 USA

[16] John Wayne Canc Inst, Melanoma Dept, Santa Monica, CA 90404 USA

[17] Med Univ Vienna, Div Immunol Allergy & Infect Dis, Dept Dermatol, A-1090 Vienna, Austria

[18] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria

[19] Univ Hosp Essen, Dept Dermatol, D-45122 Essen, Germany

[20] Whitehead Inst Biomed Res, Cambridge Ctr 9, Cambridge, MA 02142 USA

来源：

CELL | 2012年 / 150卷 / 02期

基金：

奥地利科学基金会; 瑞士国家科学基金会; 加拿大健康研究院;

关键词：

SOMATIC MUTATIONS; HUMAN CANCER; PROTEIN COMPLEX; GENOME; RAS; AURORA; DISCOVERY; CATALOG;

D O I：

10.1016/j.cell.2012.06.024

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic UV light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2), three of which-RAC1, PPP6C, and STK19-harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis.

引用

页码：251 / 263

页数：13

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