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