MC1R and melanoma risk: what's the pathway?

(look at all the greek author names!!)
This paper examines the association between melanoma and MC1R variants in 123 melanoma patients and 155 control subjects from Greece. In general, MC1R variants were associated with higher melanoma risk, yet it's still not known what kind of pathway is operating here (through pigment related pathway, or another pathway that MC1R may be involved in).

There is also a commentary by Jonathan Rees that accompanies this paper, with this interesting passage:

Even though we may be uncertain as to the nature of the pathways linking MC1Rwith cancer risk, surprising though it may seem, it is still possible to assess the relative quantitative contributions of such alternative pathways. In a critical study, Dwyer and colleagues studied a group of patients with melanoma and control subjects, and, besides carrying out MC1R sequencing, they also assayed the pigmentary phenotype by measuring skin reflectance on the upper inner arm (Dwyer et al., 2004). They then used a now fairly standard receiver operating characteristic (ROC) curve analysis to estimate how much information sequencing provided over and above that provided by skin color. They found that the additional information provided by MC1R was greater for basal-cell carcinoma than for melanoma, but even for basal-cell carcinoma the amount of information provided was modest. So, if age and sex could predict 42 of the 640 cases of basal-cell carcinoma expected in a cohort of 10,000 over 10 years, skin reflectance allowed prediction of a further 14 cases (56 in total), and adding in MC1R sequence would only add another two cases (58 in total). Why is this important to our interpretation of the data presented by Stratigos et al. (2006)? First, it suggests that any putative pathways linking MC1R variation and cancer risk (beyond skin color) are numerically small. Second, and of much greater importance, it serves to remind us that although we may identify and report modest odds ratios between genes and a disease state, in many instances we are perhaps an order of magnitude out in our ability to provide predictions of a future disease state that are meaningful for individual patients. So whereas our accumulating knowledge might gradually allow screening for melanoma to be considered, one has the feeling that there is a whole chunk of pigmentary biology that is still invisible to us. It seems, therefore, that some chapters of this particular story remain to be written.

Melanocortin Receptor-1 Gene Polymorphisms and the Risk of Cutaneous Melanoma in a Low-Risk Southern European Population

Alexander J Stratigos, Gerasimos Dimisianos, Vasiliki Nikolaou, Mirto Poulou, Vana Sypsa, Irene Stefanaki, Othon Papadopoulos, Dorothea Polydorou, Michaela Plaka, Eleftheria Christofidou, Helen Gogas, Dimosthenis Tsoutsos, Ourania Kastana, Christina Antoniou, Angelos Hatzakis, Emmanouil Kanavakis and Andreas D Katsambas

Journal of Investigative Dermatology (2006) 126, 1842–1849. doi:10.1038/sj.jid.5700292; published online 6 April 2006

Abstract: Individuals with melanocortin 1 receptor (MC1R) gene variants have been shown to carry an increased risk for the development of melanoma. In this study, we investigated the relationship of MC1R gene variants and the risk of melanoma in 123 melanoma patients and 155 control subjects from Greece. The entire MC1R gene was sequenced for polymorphisms and the results were correlated with host factors and pigmentary characteristics. MC1R polymorphisms were present in 59.4% of melanoma patients compared to 37.5% of controls, yielding an odds ratio (OR) of 2.43 (95% confidence interval (CI)=1.50–3.96, P<0.001) or="6.97;" ci="1.86–26.12,">P=0.004). Only the Val60Leu, Arg142His, and Arg151Cys variants were significantly associated with melanoma risk. In stratified analysis, the risk of melanoma among MC1R carriers was not influenced by skin phototype, skin color, or hair color. No association was found between MC1R genotype and the age of onset of melanoma, the tumor location, or the tumor thickness. In conclusion, MC1R polymorphisms are a predisposing factor of melanoma in a southern European population with a relatively low incidence of the disease.