title: Melanoma genome sequencing reveals frequent PREX2 mutations.
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.
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.forename: Eran
authors.initials: E
authors.lastname: Hodis
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffernan
authors.forename: Yonathan Lissanu
authors.initials: YL
authors.lastname: Deribe
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.forename: Alexei
authors.initials: A
authors.lastname: Protopopov
authors.forename: Elena
authors.initials: E
authors.lastname: Ivanova
authors.forename: Ian R
authors.initials: IR
authors.lastname: Watson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nickerson
authors.forename: Papia
authors.initials: P
authors.lastname: Ghosh
authors.forename: Hailei
authors.initials: H
authors.lastname: Zhang
authors.forename: Rhamy
authors.initials: R
authors.lastname: Zeid
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Ren
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Sivachenko
authors.forename: Nikhil
authors.initials: N
authors.lastname: Wagle
authors.forename: Antje
authors.initials: A
authors.lastname: Sucker
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.forename: Robert
authors.initials: R
authors.lastname: Onofrio
authors.forename: Lauren
authors.initials: L
authors.lastname: Ambrogio
authors.forename: Daniel
authors.initials: D
authors.lastname: Auclair
authors.forename: Timothy
authors.initials: T
authors.lastname: Fennell
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.forename: Yotam
authors.initials: Y
authors.lastname: Drier
authors.forename: Petar
authors.initials: P
authors.lastname: Stojanov
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Singer
authors.forename: Douglas
authors.initials: D
authors.lastname: Voet
authors.forename: Rui
authors.initials: R
authors.lastname: Jing
authors.forename: Gordon
authors.initials: G
authors.lastname: Saksena
authors.forename: Jordi
authors.initials: J
authors.lastname: Barretina
authors.forename: Alex H
authors.initials: AH
authors.lastname: Ramos
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Pugh
authors.forename: Nicolas
authors.initials: N
authors.lastname: Stransky
authors.forename: Melissa
authors.initials: M
authors.lastname: Parkin
authors.forename: Wendy
authors.initials: W
authors.lastname: Winckler
authors.forename: Scott
authors.initials: S
authors.lastname: Mahan
authors.forename: Kristin
authors.initials: K
authors.lastname: Ardlie
authors.forename: Jennifer
authors.initials: J
authors.lastname: Baldwin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wargo
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Stephan N
authors.initials: SN
authors.lastname: Wagner
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
mesh_terms: D056905:Chromosome Breakpoints / Q000528:radiation effects; D004249:DNA Damage; D004252:DNA Mutational Analysis; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D016296:Mutagenesis / Q000528:radiation effects; D009154:Mutation / Q000235:genetics* / Q000528:radiation effects; D009857:Oncogenes / Q000235:genetics; D013472:Sunlight / Q000009:adverse effects*; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C490712:PREX2 protein, human