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human cells

Melanoma genome sequencing reveals frequent PREX2 mutations

Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life

human cells

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Michael F. Berger, Eran Hodis, Timothy P. Heffernan, Yonathan Lissanu Deribe, Michael S. Lawrence, Alexei Protopopov, Elena Ivanova, Ian R. Watson, Elizabeth Nickerson, Papia Ghosh, Hailei Zhang, Rhamy Zeid, Xiaojia Ren, Kristian Cibulskis, Andrey Y. Sivachenko, Nikhil Wagle, Antje Sucker, Carrie Sougnez, Robert Onofrio, Lauren Ambrogio, Daniel Auclair, Timothy Fennell, Scott L. Carter, Yotam Drier, Petar Stojanov, Meredith A. Singer, Douglas Voet, Rui Jing, Gordon Saksena, Jordi Barretina, Alex H. Ramos, Trevor J. Pugh, Nicolas Stransky, Melissa Parkin, Wendy Winckler, Scott Mahan, Kristin Ardlie, Jennifer Baldwin, Jennifer Wargo, Dirk Schadendorf, Matthew Meyerson, Stacey B. Gabriel, Todd R. Golub, Stephan N. Wagner, Eric S. Lander, Gad Getz, Lynda Chin, Levi A. Garraway.

Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life1. 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 cancer2—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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