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Please use this identifier to cite or link to this item: http://hdl.handle.net/1959.14/294852
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- Title
- A Novel recurrent mutation in MITF predisposes to familial and sporadic melanoma
- Related
- Nature, Vol. 480, No. 7375, (2011), p.99-103
- DOI
- 10.1038/nature10630
- Publisher
- Nature Publishing Group
- Date
- 2011
- Author/Creator
- Yokoyama, Satoru
- Author/Creator
- Woods, Susan L
- Author/Creator
- Taylor, John C
- Author/Creator
- Duffy, David L
- Author/Creator
- Holohan, Kelly
- Author/Creator
- Dutton-Regester, Ken
- Author/Creator
- Palmer, Jane M
- Author/Creator
- Bonazzi, Vanessa
- Author/Creator
- Stark, Mitchell S
- Author/Creator
- Symmons, Judith
- Author/Creator
- Law, Matthew H
- Author/Creator
- Schmidt, Christopher
- Author/Creator
- Boyle, Glen M
- Author/Creator
- Lanagan, Cathy
- Author/Creator
- O'Connor, Linda
- Author/Creator
- Holland, Elizabeth A
- Author/Creator
- Schmid, Helen
- Author/Creator
- Maskiell, Judith A
- Author/Creator
- Jetann, Jodie
- Author/Creator
- Ferguson, Megan
- Author/Creator
- Jenkins, Mark A
- Author/Creator
- Kefford, Richard F
- Author/Creator
- Giles, Graham G
- Author/Creator
- Aoude, Lauren G
- Author/Creator
- Armstrong, Bruce K
- Author/Creator
- Aitken, Joanne F
- Author/Creator
- Hopper, John L
- Author/Creator
- Whiteman, David C
- Author/Creator
- Pharoah, Paul D
- Author/Creator
- Easton, Douglas F
- Author/Creator
- Dunning, Alison M
- Author/Creator
- Newton-Bishop, Julia A
- Author/Creator
- Montgomery, Grant W
- Author/Creator
- Martin, Nicholas G
- Author/Creator
- MacGregor, Stuart
- Author/Creator
- Mann, Graham J
- Author/Creator
- Bishop, D. Timothy
- Author/Creator
- Tsao, Hensin
- Author/Creator
- Trent, Jeffrey M
- Author/Creator
- Fisher, David E
- Author/Creator
- Hayward, Nicholas K
- Author/Creator
- Brown, Kevin M
- Author/Creator
- Zismann, Victoria
- Author/Creator
- Gartside, Michael
- Author/Creator
- Cust, Anne E
- Author/Creator
- Haq, Rizwan
- Author/Creator
- Harland, Mark
- Description
- 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.
- Description
- 5 page(s)
- Subject Keyword
- 110300 Clinical Sciences
- Subject Keyword
- 111200 Oncology and Carcinogenesis
- Resource Type
- journal article
- Organisation
- Macquarie University. Australian School of Advanced Medicine
- Identifier
- http://hdl.handle.net/1959.14/294852
- Identifier
- mq:31818
- Identifier
- ISSN:0028-0836
- Identifier
- mq-rm-2013003385
- Identifier
- mq_res-ext-2-s2.0-82555187007
- Language
- eng
- Reviewed
Macquarie University ResearchOnline
