期刊
NATURE
卷 480, 期 7375, 页码 99-U266出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature10630
关键词
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资金
- Melanoma Research Alliance
- American Cancer Society [RSG-08-200-01]
- National Institutes of Health (NIH) [AR043369-14, CA88363, K24CA149202, P50CA93683, R01 CA83115, CA-83115-01A2]
- Doris Duke Medical Foundation
- Dr Miriam and Sheldon G. Adelson Medical Research Foundation
- US-Israel Binational Science Foundation
- Division of Cancer Epidemiology and Genetics of the National Cancer Institute
- National Health and Medical Research Council of Australia (NHMRC)
- Cancer Australia [1011143]
- Cancer Research UK [C8216/A6129, C588/A4994, C588/A10589, C490/A11021, C8197/A10123]
- NHMRC [566946, 107359, 211172, 402761, 520018]
- Cancer Council New South Wales [77/00, 06/10]
- Cancer Council Victoria
- Cancer Council Queensland [371]
- Cancer Institute NSW [10/ECF/2-06]
- University of Sydney Medical Foundation
- Cancer Research UK [10118, 11022, 10589] Funding Source: researchfish
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.
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