Melanocortin-1 receptor variant R151C modifies melanoma risk in Dutch families with melanoma

Germline mutations of the cell-cycle regulator p16 (also called "CDKN2A") i n kindreds with melanoma implicate this gene in susceptibility to malignant melanoma. Most families with familial atypical multiple-mole melanoma (FAM MM) who are registered at the Leiden dermatology clinic share the same p16- inactivating deletion (p16-Leiden). Incomplete penetrance and variable clin ical expression suggest risk modification by other genetic and/or environme ntal factors. Variants of the melanocortin-1 receptor (MC1R) gene have been shown to be associated with red hair, fair skin, and melanoma in humans. C arriers of the p16-Leiden deletion in Dutch families with FAMMM show an inc reased risk of melanoma when they also carry MC1R variant alleles. The R151 C variant is overrepresented in patients with melanoma who are from familie s with the p16-Leiden mutation. Although some of the effect of the R151C va riant on melanoma risk may be attributable to its effect on skin type, our analyses indicate that the R151C variant contributes an increased melanoma risk even after statistical correction for its effect on skin type. These f indings suggest that the R151C variant may be involved in melanoma tumorige nesis in a dual manner, both as a determinant of fair skin and as a compone nt in an independent additional pathway.