Dataset Information

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

ABSTRACT:

We conducted whole-genome sequencing of probands from several melanoma families, identifying one individual carrying a novel germline variant (c.G1075A, NM_000248.3; p.E318K, NP_000239.1; rs149617956) in the melanoma lineage-specific oncogene MITF. While the variant cosegregated with melanoma in some, but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a LOD score of 2.7 under a dominant model, suggesting E318K as a possible intermediate risk variant. Consistent with this, E318K was significantly associated with melanoma in a large Australian case-control sample, giving an odds ratio (OR) of 2.33, 95% CI 1.21-4.70 (case and control carrier frequency, 0.0165 and 0.0072, respectively; P=0.008). Likewise, it was similarly associated in an independent case-control sample from the United Kingdom (UK P=0.012; combined P=0.0003, OR 2.19, 95% CI 1.41-3.45). In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma (OR 2.95, 95% CI 1.23-6.92), multiple primary melanomas (OR 4.22, 95% CI 1.52-10.91), or both (OR 8.37, 95% CI 2.58-23.80). The variant allele was also associated with increased nevus count (combined P=0.002, OR 2.54, 95% CI 1.42-4.55) and non-blue eye color (combined P=0.008, OR 2.01, 95% CI 1.11-3.81). 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 highlights the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.

OTHER RELATED OMICS DATASETS IN: PRJNA146135

PROVIDER: phs000419.v1.p1 | EGA |

REPOSITORIES: EGA

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

Yokoyama Satoru S Woods Susan L SL Boyle Glen M GM Aoude Lauren G LG MacGregor Stuart S Zismann Victoria V Gartside Michael M Cust Anne E AE Haq Rizwan R Harland Mark M Taylor John C JC Duffy David L DL Holohan Kelly K Dutton-Regester Ken K Palmer Jane M JM Bonazzi Vanessa V Stark Mitchell S MS Symmons Judith J Law Matthew H MH Schmidt Christopher C Lanagan Cathy C O'Connor Linda L Holland Elizabeth A EA Schmid Helen H Maskiell Judith A JA Jetann Jodie J Ferguson Megan M Jenkins Mark A MA Kefford Richard F RF Giles Graham G GG Armstrong Bruce K BK Aitken Joanne F JF Hopper John L JL Whiteman David C DC Pharoah Paul D PD Easton Douglas F DF Dunning Alison M AM Newton-Bishop Julia A JA Montgomery Grant W GW Martin Nicholas G NG Mann Graham J GJ Bishop D Timothy DT Tsao Hensin H Trent Jeffrey M JM Fisher David E DE Hayward Nicholas K NK Brown Kevin M KM

Nature 20111113 7375

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 ca ...[more]

PMID: 22080950

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Dataset Information

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

Publications

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

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