|Publication Type||Journal Article|
|Year of Publication||2012|
|Authors||Berger, MF, Hodis, E, Heffernan, TP, Deribe, YL, Lawrence, MS, Protopopov, A, Ivanova, E, Watson, IR, Nickerson, E, Ghosh, P, Zhang, H, Zeid, R, Ren, X, Cibulskis, K, Sivachenko, AY, Wagle, N, Sucker, A, Sougnez, C, Onofrio, R, Ambrogio, L, Auclair, D, Fennell, T, Carter, SL, Drier, Y, Stojanov, P, Singer, MA, Voet, D, Jing, R, Saksena, G, Barretina, J, Ramos, AH, Pugh, TJ, Stransky, N, Parkin, M, Winckler, W, Mahan, S, Ardlie, K, Baldwin, J, Wargo, J, Schadendorf, D, Meyerson, M, Gabriel, SB, Golub, TR, Wagner, SN, Lander, ES, Getz, G, Chin, L, Garraway, LA|
Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. 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--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.