Melanoma genome sequencing reveals frequent PREX2 mutations

被引：565

作者：

Berger, Michael F. ^{[1
]}

Hodis, Eran ^{[1
]}

Heffernan, Timothy P. ^{[2
]}

Deribe, Yonathan Lissanu ^{[2
]}

Lawrence, Michael S. ^{[1
]}

Protopopov, Alexei ^{[2
]}

Ivanova, Elena ^{[2
]}

Watson, Ian R. ^{[2
]}

Nickerson, Elizabeth ^{[1
]}

Ghosh, Papia ^{[2
]}

Zhang, Hailei ^{[2
]}

Zeid, Rhamy ^{[2
]}

Ren, Xiaojia ^{[2
]}

Cibulskis, Kristian ^{[1
]}

Sivachenko, Andrey Y. ^{[1
]}

Wagle, Nikhil ^{[2
,3
]}

Sucker, Antje ^{[4
]}

Sougnez, Carrie ^{[1
]}

Onofrio, Robert ^{[1
]}

Ambrogio, Lauren ^{[1
]}

Auclair, Daniel ^{[1
]}

Fennell, Timothy ^{[1
]}

Carter, Scott L. ^{[1
]}

Drier, Yotam ^{[5
]}

Stojanov, Petar ^{[1
]}

Singer, Meredith A. ^{[2
]}

Voet, Douglas ^{[1
]}

Jing, Rui ^{[1
]}

Saksena, Gordon ^{[1
]}

Barretina, Jordi ^{[1
]}

Ramos, Alex H. ^{[1
,3
]}

Pugh, Trevor J. ^{[1
,2
,3
]}

Stransky, Nicolas ^{[1
]}

Parkin, Melissa ^{[1
]}

Winckler, Wendy ^{[1
]}

Mahan, Scott ^{[1
]}

Ardlie, Kristin ^{[1
]}

Baldwin, Jennifer ^{[1
]}

Wargo, Jennifer ^{[6
]}

Schadendorf, Dirk ^{[4
]}

Meyerson, Matthew ^{[1
,2
,3
,7
]}

Gabriel, Stacey B. ^{[1
]}

Golub, Todd R. ^{[1
,7
,8
,9
]}

Wagner, Stephan N. ^{[10
,11
]}

Lander, Eric S. ^{[1
,12
]}

Getz, Gad ^{[1
]}

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

Garraway, Levi A. ^{[1
,2
,3
,7
]}

机构：

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

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

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

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

[5] Weizmann Inst Sci, Dept Phys Complex Syst, IL-76100 Rehovot, Israel

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

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

[8] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[9] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

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

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

[12] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

来源：

NATURE | 2012年 / 485卷 / 7399期

基金：

奥地利科学基金会;

关键词：

HUMAN CANCER; MALIGNANT-MELANOMA; SOMATIC MUTATIONS; INHIBITION; PATTERNS; BRAF; REARRANGEMENTS; SPECIFICITY; ACTIVATION; SURVIVAL;

D O I：

10.1038/nature11071

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life(1). To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)-a PTEN-interacting protein and negative regulator of PTEN in breast cancer(2)-as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.

引用

页码：502 / 506

页数：5

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