This case-control study was planned to investigate the link of solar radiation with gene damage, host factors, including also genetic variants, and DNA repair proficiency in cutaneous malignant melanoma (CMM) risk. The hypothesis was that impaired DNA repair proficiency is associated with an increased risk of CMM due to unrepaired DNA damage, particularly in subjects with dysplastic nevi, poor tanning ability or genetic susceptibility.

The study was reviewed and funded as an R01 Grant from the National Cancer Institute in 1995. Subject enrollment, which included clinical evaluation, epidemiologic questionnaires, and skin and blood sample collection, was completed in 1999 on approximately 180 melanoma cases and 180 controls identified in Italy. The study protocol and consent form both included the measurement of genetic and biochemical factors, and DNA repair capacity. DNA repair proficiency was measured in lymphocytes by the host cell reactivation assay, and sun exposure was evaluated by means of a detailed questionnaire. Photographs of the back of the subjects were taken to allow nevi count. Minimal erythemal dosage was measured in all subjects to estimate skin sun sensitivity 24 hours after skin's UV-irradiation. Skin color was ascertained on the inner side of the forearm by means of a Minolta chromometer.

The aim of this protocol is to continue analysis of the biological samples already collected, as originally outlined in the study protocol. In particular, we measured polymorphisms in genes that may lead to susceptibility to melanoma by altering the repair of damaged DNA. In addition, we investigated the role of pigmentation genes, including MC1R, ASIP and AGRP in melanogenesis, and their interaction with sun exposure and DNA repair. We have found that variants in the MCIR gene are associated with risk of developing melanoma, and in particular, the type of melanomas that arise on skin with no marked signs of chronic solar damage and that bears mutations in the BRAF oncogene. We are currently analyzing other genes in the pigmentation pathway. We have also completed the laboratory analyses of the protein pattern in plasma of all subjects and we are conducting the related statistical analyses, to investigate whether they differ by case-status, presence of dysplastic nevi, gene polymorphisms or DNA repair proficiency. Moreover, we are studying the effect of variants in KIR genes and protection against melanoma risk.