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- Title
Melanoma genome sequencing reveals frequent PREX2 mutations.
- Authors
Berger, Michael F; Hodis, Eran; Heffernan, Timothy P; Deribe, Yonathan Lissanu; Lawrence, Michael S; Protopopov, Alexei; Ivanova, Elena; Watson, Ian R; Nickerson, Elizabeth; Ghosh, Papia; Zhang, Hailei; Zeid, Rhamy; Ren, Xiaojia; Cibulskis, Kristian; Sivachenko, Andrey Y; Wagle, Nikhil; Sucker, Antje; Sougnez, Carrie; Onofrio, Robert; Ambrogio, Lauren; Auclair, Daniel; Fennell, Timothy; Carter, Scott L; Drier, Yotam; Stojanov, Petar; Singer, Meredith A; Voet, Douglas; Jing, Rui; Saksena, Gordon; Barretina, Jordi; Ramos, Alex H; Pugh, Trevor J; Stransky, Nicolas; Parkin, Melissa; Winckler, Wendy; Mahan, Scott; Ardlie, Kristin; Baldwin, Jennifer; Wargo, Jennifer; Schadendorf, Dirk; Meyerson, Matthew; Gabriel, Stacey B; Golub, Todd R; Wagner, Stephan N; Lander, Eric S; Getz, Gad; Chin, Lynda; Garraway, Levi A
- 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.
- Publication
Nature, 2012, Vol 485, Issue 7399, p502
- ISSN
1476-4687
- Publication type
Journal Article
- DOI
10.1038/nature11071