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Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants.
J Med Genet 2013; 50(4):264-70JM

Abstract

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.

Authors+Show Affiliations

Section for Pathology, The Gade Institute, University of Bergen, Haukeland University Hospital, N-5021 Bergen, Norway.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23384855

Citation

Puntervoll, Hanne Eknes, et al. "Melanoma Prone Families With CDK4 Germline Mutation: Phenotypic Profile and Associations With MC1R Variants." Journal of Medical Genetics, vol. 50, no. 4, 2013, pp. 264-70.
Puntervoll HE, Yang XR, Vetti HH, et al. Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. J Med Genet. 2013;50(4):264-70.
Puntervoll, H. E., Yang, X. R., Vetti, H. H., Bachmann, I. M., Avril, M. F., Benfodda, M., ... Molven, A. (2013). Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. Journal of Medical Genetics, 50(4), pp. 264-70. doi:10.1136/jmedgenet-2012-101455.
Puntervoll HE, et al. Melanoma Prone Families With CDK4 Germline Mutation: Phenotypic Profile and Associations With MC1R Variants. J Med Genet. 2013;50(4):264-70. PubMed PMID: 23384855.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. AU - Puntervoll,Hanne Eknes, AU - Yang,Xiaohong R, AU - Vetti,Hildegunn Høberg, AU - Bachmann,Ingeborg M, AU - Avril,Marie Françoise, AU - Benfodda,Meriem, AU - Catricalà,Caterina, AU - Dalle,Stéphane, AU - Duval-Modeste,Anne B, AU - Ghiorzo,Paola, AU - Grammatico,Paola, AU - Harland,Mark, AU - Hayward,Nicholas K, AU - Hu,Hui-Han, AU - Jouary,Thomas, AU - Martin-Denavit,Tanguy, AU - Ozola,Aija, AU - Palmer,Jane M, AU - Pastorino,Lorenza, AU - Pjanova,Dace, AU - Soufir,Nadem, AU - Steine,Solrun J, AU - Stratigos,Alexander J, AU - Thomas,Luc, AU - Tinat,Julie, AU - Tsao,Hensin, AU - Veinalde,Ruta, AU - Tucker,Margaret A, AU - Bressac-de Paillerets,Brigitte, AU - Newton-Bishop,Julia A, AU - Goldstein,Alisa M, AU - Akslen,Lars A, AU - Molven,Anders, Y1 - 2013/02/05/ PY - 2013/2/7/entrez PY - 2013/2/7/pubmed PY - 2013/9/4/medline SP - 264 EP - 70 JF - Journal of medical genetics JO - J. Med. Genet. VL - 50 IS - 4 N2 - 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. SN - 1468-6244 UR - https://www.unboundmedicine.com/medline/citation/23384855/Melanoma_prone_families_with_CDK4_germline_mutation:_phenotypic_profile_and_associations_with_MC1R_variants_ L2 - http://jmg.bmj.com/cgi/pmidlookup?view=long&amp;pmid=23384855 DB - PRIME DP - Unbound Medicine ER -