TY - JOUR
T1 - Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers
T2 - 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-Scarr, 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.
N1 - Funding Information:
European Community FP6 Network of Excellence Award (LSH-CT-2006-018702 to J.A.N.B. and N.G.); the National Institutes of Health (RO1 CA83115 to D.E.E., RO1 CA88363 to N.K.H., RO1 CA5558-01A2 to M.T.L.); the Ligue Nationale contre le Cancer (PRE05/FD and PRE09/FD to F.D.); the Programme Hospitalier de Recherche Clinique (PHRC 2007-AOM-07-195 to F.D. and M.F.A.); the French Institut National du Cancer (Melanoma Network RS Number 13 to BB-dP); the Intramural Research Program of the National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Institutes of Health to A.M.G, M.T.L., M.A.T and X.R.Y.; the Cancer Research UK Programme Award (C588/A4994 to J.A.N.B. and D.T.B.); the Australian National Health and Medical Research Council (to N.K.H. and to G.J.M.); the Cancer Councils of New South Wales, Victoria and Queensland to N.K.H. and G.J.M.; the Cancer Institute NSW to N.K.H. and G.J.M.; the Italian Ministry of Health (DGRST.4/4235-P1.9.A.B to G.B-S.); the Swedish Cancer Society to J.H.: the Radiumhemmet Research Funds to J.H.; the Swedish Research Council to J.H; the Swedish Cancer foundation to C.I and H.O.; the Regional funds in Skane to C.I and H.O.; the funds at the University Hospital in Lund to C.I and H.O.; and Fondo de Investigaciones Sanitarias, Spain (03/0019, 05/0302, 06/0265 to S.P.).
PY - 2010/10/20
Y1 - 2010/10/20
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]; Ptrend = 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). Conclusions 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.
AB - 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]; Ptrend = 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). Conclusions 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.
UR - http://www.scopus.com/inward/record.url?scp=77958609747&partnerID=8YFLogxK
U2 - 10.1093/jnci/djq363
DO - 10.1093/jnci/djq363
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AN - SCOPUS:77958609747
SN - 0027-8874
VL - 102
SP - 1568
EP - 1583
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 20
ER -
