期刊
JOURNAL OF MEDICAL GENETICS
卷 50, 期 4, 页码 264-U82出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jmedgenet-2012-101455
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资金
- European Commission [LSHC-CT-2006-018702]
- Cancer Research UK [C588/A4994, C588/A10589, C8216/A6129]
- US National Institutes of Health (NIH) [CA83115]
- University of Bergen
- INSERM Research Fellowship
- INCA
- Norwegian Cancer Society [71512-PR-2006-0356]
- Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics
- Leeds Cancer Research UK Centre [C37059/A11941]
- Latvian Council of Science [10.0010.8]
- National Health and Medical Research Council of Australia
- Italian Ministry of Health
- PRIN
- Sapienza University of Rome
- Institut National du Cancer PHRC [AOM 07, 195, N107004]
- Lyon 1 University
- Hospices Civils de Lyon
- Ligue Contre le Cancer du Rhone
- NIH [K24 CA149202]
- Cancer Research UK [10589] Funding Source: researchfish
Background CDKN2A and CDK4 are high risk susceptibility genes for cutaneous malignant melanoma. Melanoma families with CDKN2A germline mutations have been extensively characterised, whereas CDK4 families are rare and lack a systematic investigation of their phenotype. Methods All known families with CDK4 germline mutations (n=17) were recruited for the study by contacting the authors of published papers or by requests via the Melanoma Genetics Consortium (GenoMEL). Phenotypic data related to primary melanoma and pigmentation characteristics were collected. The CDK4 exon 2 and the complete coding region of the MC1R gene were sequenced. Results Eleven families carried the CDK4 R24H mutation whereas six families had the R24C mutation. The total number of subjects with verified melanoma was 103, with a median age at first melanoma diagnosis of 39 years. Forty-three (41.7%) subjects had developed multiple primary melanomas (MPM). A CDK4 mutation was found in 89 (including 62 melanoma cases) of 209 tested subjects. CDK4 positive family members (both melanoma cases and unaffected subjects) were more likely to have clinically atypical nevi than CDK4 negative family members (p<0.001). MPM subjects had a higher frequency of MC1R red hair colour variants compared with subjects with one tumour (p=0.010). Conclusion Our study shows that families with CDK4 germline mutations cannot be distinguished phenotypically from CDKN2A melanoma families, which are characterised by early onset of disease, increased occurrence of clinically atypical nevi, and development of MPM. In a clinical setting, the CDK4 gene should therefore always be examined when a melanoma family tests negative for CDKN2A mutation.
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