Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: A GenoMEL study

Demenais, F., Mohamdi, H., Chaudru, V., Goldstein, A. M., Newton Bishop, J. A., Bishop, D. T., Kanetsky, P. A., Hayward, N. K., Gillanders, E., Elder, D. E., Avril, M. F., Azizi, E., van Belle, P., Bergman, W., Bianchi-Scarra, G., Brassac-de Paillerets, B., Calista, D., Carrera, C., Hansson, J., Harland, M., Hogg, D., Hoiom, V., Holland, E. A., Ingvar, C., Landi, M. T., Lang, J. M., Mackie, R. M., Mann, G. J., Ming, M. E., Njauw, C. J., Olsson, H., Palmer, J., Pastorino, L., Puig, S., Randerson-Moor, J., Stark, M., Tsao, H., Tucker, M. A., van der Velden, P., Yang, X. R., Gruis, N. and Melanoma Genetics Consortium (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: 1568-1583. doi:10.1093/jnci/djq363

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Author Demenais, F.
Mohamdi, H.
Chaudru, V.
Goldstein, A. M.
Newton Bishop, J. A.
Bishop, D. T.
Kanetsky, P. A.
Hayward, N. K.
Gillanders, E.
Elder, D. E.
Avril, M. F.
Azizi, E.
van Belle, P.
Bergman, W.
Bianchi-Scarra, G.
Brassac-de Paillerets, B.
Calista, D.
Carrera, C.
Hansson, J.
Harland, M.
Hogg, D.
Hoiom, V.
Holland, E. A.
Ingvar, C.
Landi, M. T.
Lang, J. M.
Mackie, R. M.
Mann, G. J.
Ming, M. E.
Njauw, C. J.
Olsson, H.
Palmer, J.
Pastorino, L.
Puig, S.
Randerson-Moor, J.
Stark, M.
Tsao, H.
Tucker, M. A.
van der Velden, P.
Yang, X. R.
Gruis, N.
Melanoma Genetics Consortium
Title Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: A GenoMEL study
Journal name Journal of the National Cancer Institute   Check publisher's open access policy
ISSN 0027-8874
Publication date 2010-10-20
Sub-type Article (original research)
DOI 10.1093/jnci/djq363
Volume 102
Issue 20
Start page 1568
End page 1583
Total pages 16
Place of publication Oxford, U.K.
Publisher Oxford University Press
Collection year 2011
Language eng
Formatted 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]; 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).

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.
Copyright © 2011 Oxford University Press

Keyword Cyclin-dependent kinase inhibitor p16
Risk assessment
Skin pigmentation
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( , which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 34 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 46 times in Scopus Article | Citations
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Created: Wed, 23 Mar 2011, 13:26:12 EST by Lisa Hennell on behalf of School of Medicine