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

Yokoyama, Satoru, Woods, Susan L., Boyle, Glen M., Aoude, Lauren G., MacGregor, Stuart, Zismann, Victoria, Gartside, Michael, Cust, Anne E., Haq, Rizwan, Harland, Mark, Taylor, John C., Duffy, David L., Holohan, Kelly, Dutton-Regester, Ken, Palmer, Jane M., Bonazzi, Vanessa, Stark, Mitchell S., Symmons, Judith, Law, Matthew H., Schmidt, Christopher, Lanagan, Cathy, O'Connor, Linda, Holland, Elizabeth A., Schmid, Helen, Maskiell, Judith A., Jetann, Jodie, Ferguson, Megan, Jenkins, Mark A., Kefford, Richard F., Giles, Graham G., Armstrong, Bruce K., Aitken, Joanne F., Hopper, John L., Whiteman, David C., Pharoah, Paul D., Easton, Douglas F., Dunning, Alison M., Newton-Bishop, Julia A., Montgomery, Grant W., Martin, Nicholas G., Mann, Graham J., Bishop, D. Timothy, Tsao, Hensin, Trent, Jeffrey M., Fisher, David E., Hayward, Nicholas K. and Brown, Kevin M. (2011) A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature, 480 7375: 99-103. doi:10.1038/nature10630

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Author Yokoyama, Satoru
Woods, Susan L.
Boyle, Glen M.
Aoude, Lauren G.
MacGregor, Stuart
Zismann, Victoria
Gartside, Michael
Cust, Anne E.
Haq, Rizwan
Harland, Mark
Taylor, John C.
Duffy, David L.
Holohan, Kelly
Dutton-Regester, Ken
Palmer, Jane M.
Bonazzi, Vanessa
Stark, Mitchell S.
Symmons, Judith
Law, Matthew H.
Schmidt, Christopher
Lanagan, Cathy
O'Connor, Linda
Holland, Elizabeth A.
Schmid, Helen
Maskiell, Judith A.
Jetann, Jodie
Ferguson, Megan
Jenkins, Mark A.
Kefford, Richard F.
Giles, Graham G.
Armstrong, Bruce K.
Aitken, Joanne F.
Hopper, John L.
Whiteman, David C.
Pharoah, Paul D.
Easton, Douglas F.
Dunning, Alison M.
Newton-Bishop, Julia A.
Montgomery, Grant W.
Martin, Nicholas G.
Mann, Graham J.
Bishop, D. Timothy
Tsao, Hensin
Trent, Jeffrey M.
Fisher, David E.
Hayward, Nicholas K.
Brown, Kevin M.
Title A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma
Journal name Nature   Check publisher's open access policy
ISSN 0028-0836
Publication date 2011-12-01
Year available 2011
Sub-type Article (original research)
DOI 10.1038/nature10630
Open Access Status Not yet assessed
Volume 480
Issue 7375
Start page 99
End page 103
Total pages 5
Place of publication London, England, U.K.
Publisher Nature Publishing Group
Language eng
Subject 1000 General
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(1), and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds(2). 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.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID RSG-08-200-01
Institutional Status UQ

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Created: Fri, 16 Dec 2011, 01:36:26 EST by Matthew Lamb on behalf of School of Medicine