MELANOCORTIN-1 RECEPTOR VARIANTS IN SKIN CARCINOGENESIS: A POOLED-ANALYSIS

Beside the known risk factors for melanoma (environmental UV radiation exposure, fair skin, family history of melanoma, high number of melanocytic nevi, light eye and hair pigmentation), melanocortin-1-receptor (MC1R) gene has been suggested to play a role in melanoma development because it determines skin pigmentation. The aim of my thesis was to create a data-bank of the available information on sporadic skin cancer cases and controls with genetic information on MC1R variants, and to perform a pooled-analysis on MC1R variants, skin cancer, and phenotypic characteristics (M-SKIP Project), using individual patient data. The possibility to perform stratified analysis and to deeply study MC1R-melanoma association would let find different pathways in melanoma development and identify at risk populations. An Advisory Committee of 10 investigators with great expertise in skin cancer and genetic research was established and the authors of appropriate papers were invited to provide their original published and unpublished data. Data collection started in May 2009 and was closed in December 2010. During this period, 43 investigators were contacted and invited to share data. Thirty-one (72%) agreed to participate and provided data on 28,998 subjects, including 13,511 skin cancer cases (10,182 melanomas) and 15,477 controls from 37 independent published and 2 unpublished studies. A two stage analysis and a multivariate adaptation of a new approach which took into account the different assessment of confounders in the enclosed studies, were performed to evaluate the main effect of MC1R variants on melanoma development. I found a significant association with melanoma for the five MC1R variants D84E, R142H, R151C, R160W, and D294H by using both the applied approaches. No significant association with melanoma was found for the two not functional MC1R variants V60L and R163Q. Results for the association with melanoma of V92M and I55T variant were still controversial and further investigations is warranted. In order to study gene-phenotype interaction, I applied logic regression, a method of statistical analysis recently proposed in the genetic field to select combinations of genes mostly associated with a disease. Within the M-SKIP project, I extend the application of this method to the study of both genetic and phenotypic factors, in order to find which combinations of MC1R variants and phenotypic characteristics are mostly associated with melanoma development. The first subgroup included subjects with either atypical naevi or MC1R D294H, who have a more than doubled risk of melanoma than subjects with none of these factors. The second subgroup of high risk subjects included those with either brown eye or more than 45 common naevi. In the validation analysis performed on a larger M-SKIP dataset, however, the association with melanoma for this subgroup of patients was not confirmed. The last high risk subgroup contained subjects with freckles or with intermediate skin type and brown hair or with intermediate skin type and at least one MC1R R151C variant, who had a triple risk of melanoma than subjects without this combination of phenotypic and genetic factors. In conclusion, among the MC1R variants associated with melanoma, the two variants D294H and R151C seemed the two ones that could indeed increase melanoma risk in combination with phenotypic characteristics and that are warranted to screen.