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Nature DOI:10.1038/nature11071

Melanoma genome sequencing reveals frequent PREX2 mutations.

Publication TypeJournal Article
Year of Publication2012
AuthorsBerger, MF, Hodis, E, Heffernan, TP, Deribe, YLissanu, 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
Date Published2012 May 09
KeywordsChromosome Breakpoints, DNA Damage, DNA Mutational Analysis, Gene Expression Regulation, Neoplastic, Genome, Human, Guanine Nucleotide Exchange Factors, Humans, Melanocytes, Melanoma, Mutagenesis, Mutation, Oncogenes, Sunlight, Ultraviolet Rays

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.


Alternate JournalNature
PubMed ID22622578
PubMed Central IDPMC3367798
Grant ListR33 CA126674-03 / CA / NCI NIH HHS / United States
R33 CA155554-01 / CA / NCI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
R33 CA126674-04 / CA / NCI NIH HHS / United States
DP2 OD002750 / OD / NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R33 CA126674 / CA / NCI NIH HHS / United States
R33 CA155554 / CA / NCI NIH HHS / United States
DP2 OD002750-01 / OD / NIH HHS / United States