Scientific Publications

Melanoma genome sequencing reveals frequent PREX2 mutations.

Publication TypeJournal Article
AuthorsBerger, MF, Hodis E., Heffernan TP, Deribe YL, 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 T. R., Wagner SN, Lander E. S., Getz G., Chin L., and Garraway LA
AbstractMelanoma 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 Publication2012
JournalNature
Volume485
Issue7399
Pages502-6
Date Published (YYYY/MM/DD)2012/05/09
ISSN Number0028-0836
DOI10.1038/nature11071
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/22622578?dopt=Abstract