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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.

journal_name

Nature

journal_title

Nature

authors

Yokoyama S,Woods SL,Boyle GM,Aoude LG,MacGregor S,Zismann V,Gartside M,Cust AE,Haq R,Harland M,Taylor JC,Duffy DL,Holohan K,Dutton-Regester K,Palmer JM,Bonazzi V,Stark MS,Symmons J,Law MH,Schmidt C,Lanagan C,O'C

doi

10.1038/nature10630

subject

Has Abstract

pub_date

2011-11-13 00:00:00

pages

99-103

issue

7375

eissn

0028-0836

issn

1476-4687

pii

nature10630

journal_volume

480

pub_type

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A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.