期刊
NATURE
卷 485, 期 7399, 页码 502-506出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature11071
关键词
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资金
- National Human Genome Research Institute
- National Cancer Institute
- FWF-Austrian Science Fund
- NIH
- Melanoma Research Alliance
- Starr Cancer Consortium
- Burroughs-Wellcome Fund
- Austrian Science Fund (FWF) [L 590] Funding Source: researchfish
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.
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