title: A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.
abstract: So far, two genes associated with familial melanoma have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds. Here we report the whole-genome sequencing of probands from several melanoma families, which we performed in order to identify other genes associated with familial melanoma. We identify one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log of odds (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case-control sample. Likewise, it was similarly associated in an independent case-control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.
authors.affiliation: Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Massachusetts 02114, USA.
authors.forename: Satoru
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Susan L
authors.initials: SL
authors.lastname: Woods
authors.forename: Glen M
authors.initials: GM
authors.lastname: Boyle
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Aoude
authors.forename: Stuart
authors.initials: S
authors.lastname: MacGregor
authors.forename: Victoria
authors.initials: V
authors.lastname: Zismann
authors.forename: Michael
authors.initials: M
authors.lastname: Gartside
authors.forename: Anne E
authors.initials: AE
authors.lastname: Cust
authors.forename: Rizwan
authors.initials: R
authors.lastname: Haq
authors.forename: Mark
authors.initials: M
authors.lastname: Harland
authors.forename: John C
authors.initials: JC
authors.lastname: Taylor
authors.forename: David L
authors.initials: DL
authors.lastname: Duffy
authors.forename: Kelly
authors.initials: K
authors.lastname: Holohan
authors.forename: Ken
authors.initials: K
authors.lastname: Dutton-Regester
authors.forename: Jane M
authors.initials: JM
authors.lastname: Palmer
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bonazzi
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Stark
authors.forename: Judith
authors.initials: J
authors.lastname: Symmons
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Law
authors.forename: Christopher
authors.initials: C
authors.lastname: Schmidt
authors.forename: Cathy
authors.initials: C
authors.lastname: Lanagan
authors.forename: Linda
authors.initials: L
authors.lastname: O'Connor
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Holland
authors.forename: Helen
authors.initials: H
authors.lastname: Schmid
authors.forename: Judith A
authors.initials: JA
authors.lastname: Maskiell
authors.forename: Jodie
authors.initials: J
authors.lastname: Jetann
authors.forename: Megan
authors.initials: M
authors.lastname: Ferguson
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Armstrong
authors.forename: Joanne F
authors.initials: JF
authors.lastname: Aitken
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: David C
authors.initials: DC
authors.lastname: Whiteman
authors.forename: Paul D
authors.initials: PD
authors.lastname: Pharoah
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
authors.forename: Julia A
authors.initials: JA
authors.lastname: Newton-Bishop
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.forename: Hensin
authors.initials: H
authors.lastname: Tsao
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Trent
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brown
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D058207:Sumoylation / Q000235:genetics; D055815:Young Adult
chemical_list: C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor
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