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

Satoru Yokoyama, Susan L. Woods, Glen M. Boyle, Lauren G. Aoude, Stuart MacGregor, Victoria Zismann, Michael Gartside, Anne E. Cust, Rizwan Haq, Mark Harland, John C. Taylor, David L. Duffy, Kelly Holohan, Ken Dutton-Regester, Jane M. Palmer, Vanessa Bonazzi, Mitchell S. Stark, Judith Symmons, Matthew H. Law, Christopher Schmidt, Cathy Lanagan, Linda O’Connor, Elizabeth A. Holland, Helen Schmid, Judith A. Maskiell, Jodie Jetann, Megan Ferguson, Mark A. Jenkins, Richard F. Kefford, Graham G. Giles, Bruce K. Armstrong, Joanne F. Aitken, John L. Hopper, David C. Whiteman, Paul D. Pharoah, Douglas F. Easton, Alison M. Dunning, Julia A. Newton-Bishop, Grant W. Montgomery, Nicholas G. Martin, Graham J. Mann, D. Timothy Bishop, Hensin Tsao, Jeffrey M. Trent, David E. Fisher, Nicholas K. Hayward, Kevin M. 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.