Melanoma genome sequencing reveals frequent PREX2 mutations.
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Abstract | 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. |
Year of Publication | 2012
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Journal | Nature
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Volume | 485
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Issue | 7399
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Pages | 502-6
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Date Published | 2012 May 09
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ISSN | 1476-4687
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URL | |
DOI | 10.1038/nature11071
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PubMed ID | 22622578
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PubMed Central ID | PMC3367798
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Grant list | R33 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
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