© The Author 2006. Published by Oxford University Press.
CORRESPONDENCE |
RESPONSE: Re: MC1R, ASIP, and DNA Repair in Sporadic and Familial Melanoma in a Mediterranean Population
Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD (MTL, AG, RP); University of Pennsylvania Medical School, Philadelphia, PA (PK)
Correspondence to: Maria Teresa Landi, MD, PhD, Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, 6120 Executive Blvd., EPS 7114, Bethesda, MD 20892–7236 (e-mail: landim{at}mail.nih.gov).
We welcomed the correspondence by Fargnoli et al., which confirmed our findings that variant alleles in the melanocortin-1 receptor (MC1R) gene are associated with melanoma risk, with number of nevi, with pigmentation characteristics, and with melanoma thickness in an independent sample of Italian subjects. Overall, the results observed by Fargnoli et al. were remarkably similar to ours and strongly support the evidence of an important role of MC1R in the pathogenesis of melanoma. Indeed, consistency of inference across two or more independent studies is a key factor for interpreting research data (1) and is one of the guidelines used to judge whether an association is causal or not (2).
The slightly different estimates for melanoma risk and pigmentation among subjects carrying any variant or nonred hair color (NRHC) variants could be due to sample variability or differences in the categorization scheme used for pigmentation characteristics (e.g., for eye color). Because MC1R was not directly sequenced by Fargnoli et al., misclassification of MC1R allele status could have occurred, resulting in an underestimation of the odds ratios (ORs). For example, in our case–control population, 14 of 162 melanoma case patients and eight of 167 control subjects carrying any MC1R variant allele would have been misclassified if we had genotyped only the six variant alleles genotyped by Fargnoli et al. The odds ratio estimating the association between any MC1R variant and melanoma risk would have decreased from 2.12 (95% confidence interval [CI] = 1.2 to 3.6, P = .005) to 1.73 (95% CI = 1.0 to 2.9, P = .04). The effect of this misclassification would have been larger if we had investigated the association between multiple MC1R variants and melanoma risk.
When we analyzed each individual red hair color variant as presented by Fargnoli et al., R151C was the most strongly associated with melanoma risk in our study (OR = 3.3, 95% CI = 1.7 to 6.2, P<.0002), whereas D294H was only moderately associated (OR = 1.9, 95% CI = 0.7 to 5.4, P<.2). Of note, only three control subjects had the D294H variant in Fargnoli et al.'s study, resulting in an unstable estimate with large confidence intervals. Finally, we observed no association between R160W and melanoma risk as reported by our colleagues.
Fargnoli et al. observed a statistically significant association between MC1R variants and thickness of melanoma. We find the confirmation of this association particularly important, because we could not differentiate whether the association we observed was due to a delay in melanoma diagnosis or to a more aggressive type of melanoma. The findings reported by Fargnoli et al., those from our study, and that of a recently published report linking MC1R and risk of multiple melanomas in subjects carrying CDKN2A mutations (3), taken together, suggest a possible role of MC1R in melanoma progression or in determining a more aggressive phenotype of melanoma that results in metastases and/or multiple primary melanoma lesions. Additional, larger studies in different populations are needed to determine whether MC1R could be a predictor of melanoma prognosis. The association between MC1R and risk of melanoma or progression of melanoma appears to extend beyond its association with phenotypic pigmentation in our study, as well as in other studies (4,5). This association may involve different pathways, such as DNA repair (6) or signal transduction, and a more in depth understanding of this mechanism is crucial.
REFERENCES
(1) Rebbeck TR, Martinez ME, Sellers TA, Shields PG, Wild CP, Potter JD. Genetic variation and cancer: improving the environment for publication of association studies. Cancer Epidemiol Biomarkers Prev 2004;13:1985–6.
(2) Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965;58:295–300.[Web of Science][Medline]
(3) Goldstein AM, Landi MT, Tsang S, Fraser MC, Munroe DJ, Tucker MA. Association of MC1R variants and risk of melanoma in melanoma-prone families with CDKN2A mutations. Cancer Epidemiol Biomarkers Prev 2005;14:2208–12.
(4) Palmer JS, Duffy DL, Box NF, Aitken JF, O'Gorman LE, Green AC, et al. Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype? Am J Hum Genet 2000;66:176–86.[CrossRef][Web of Science][Medline]
(5) Kennedy C, ter Huurne J, Berkhout M, Gruis N, Bastiaens M, Bergman W, et al. Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color. J Invest Dermatol 2001;117:294–300.[CrossRef][Web of Science][Medline]
(6) Kadekaro AL, Kavanagh R, Kanto H, Terzieva S, Hauser J, Kobayashi N, et al. 
-Melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in human melanocytes. Cancer Res 2005;65:4292–9.
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J Natl Cancer Inst 2006 98: 144-145.
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