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Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study.
J Natl Cancer Inst 2010; 102(20):1568-83JNCI

Abstract

BACKGROUND

Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited.

METHODS

We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided.

RESULTS

Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10(-6) ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; P(trend) = 1.86 × 10(-8)). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10(-6) ≤ P ≤ .02).

CONCLUSION

Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.

Authors+Show Affiliations

INSERM U946, Fondation Jean-Dausset-CEPH , 27 rue Juliette Dodu, 75010 Paris, France. florence.demenais@inserm.frNo 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 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
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20876876

Citation

Demenais, F, et al. "Association of MC1R Variants and Host Phenotypes With Melanoma Risk in CDKN2A Mutation Carriers: a GenoMEL Study." Journal of the National Cancer Institute, vol. 102, no. 20, 2010, pp. 1568-83.
Demenais F, Mohamdi H, Chaudru V, et al. Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study. J Natl Cancer Inst. 2010;102(20):1568-83.
Demenais, F., Mohamdi, H., Chaudru, V., Goldstein, A. M., Newton Bishop, J. A., Bishop, D. T., ... Gruis, N. (2010). Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study. Journal of the National Cancer Institute, 102(20), pp. 1568-83. doi:10.1093/jnci/djq363.
Demenais F, et al. Association of MC1R Variants and Host Phenotypes With Melanoma Risk in CDKN2A Mutation Carriers: a GenoMEL Study. J Natl Cancer Inst. 2010 Oct 20;102(20):1568-83. PubMed PMID: 20876876.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study. AU - Demenais,F, AU - Mohamdi,H, AU - Chaudru,V, AU - Goldstein,A M, AU - Newton Bishop,J A, AU - Bishop,D T, AU - Kanetsky,P A, AU - Hayward,N K, AU - Gillanders,E, AU - Elder,D E, AU - Avril,M F, AU - Azizi,E, AU - van Belle,P, AU - Bergman,W, AU - Bianchi-Scarrà,G, AU - Bressac-de Paillerets,B, AU - Calista,D, AU - Carrera,C, AU - Hansson,J, AU - Harland,M, AU - Hogg,D, AU - Höiom,V, AU - Holland,E A, AU - Ingvar,C, AU - Landi,M T, AU - Lang,J M, AU - Mackie,R M, AU - Mann,G J, AU - Ming,M E, AU - Njauw,C J, AU - Olsson,H, AU - Palmer,J, AU - Pastorino,L, AU - Puig,S, AU - Randerson-Moor,J, AU - Stark,M, AU - Tsao,H, AU - Tucker,M A, AU - van der Velden,P, AU - Yang,X R, AU - Gruis,N, AU - ,, Y1 - 2010/09/28/ PY - 2010/9/30/entrez PY - 2010/9/30/pubmed PY - 2010/11/3/medline SP - 1568 EP - 83 JF - Journal of the National Cancer Institute JO - J. Natl. Cancer Inst. VL - 102 IS - 20 N2 - BACKGROUND: Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited. METHODS: We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided. RESULTS: Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10(-6) ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; P(trend) = 1.86 × 10(-8)). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10(-6) ≤ P ≤ .02). CONCLUSION: Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings. SN - 1460-2105 UR - https://www.unboundmedicine.com/medline/citation/20876876/Association_of_MC1R_variants_and_host_phenotypes_with_melanoma_risk_in_CDKN2A_mutation_carriers:_a_GenoMEL_study_ L2 - https://academic.oup.com/jnci/article-lookup/doi/10.1093/jnci/djq363 DB - PRIME DP - Unbound Medicine ER -