Melanocortin-1 Receptor Variant R151C Modifies Melanoma Risk in Dutch Families with Melanoma

• Published in: American journal of human genetics Vol. 69; no. 4; pp. 774 - 779
• Main Authors: van der Velden, Pieter A., Sandkuijl, Lodewijk A., Bergman, Wilma, Pavel, Stan, van Mourik, Leny, Frants, Rune R., Gruis, Nelleke A.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.10.2001; University of Chicago Press; The American Society of Human Genetics
• Subjects: Adult; Age of Onset; Alleles; Biological and medical sciences; Chromosome aberrations; DNA Mutational Analysis; Female; Gene Frequency - genetics; Genetic Predisposition to Disease - genetics; Genetic Variation - genetics; Heterozygote; Humans; Male; Medical genetics; Medical sciences; Melanoma - epidemiology; Melanoma - genetics; Middle Aged; Molecular Sequence Data; Mutation, Missense - genetics; Netherlands; Pedigree; Receptors, Corticotropin - genetics; Receptors, Melanocortin; Skin Pigmentation - genetics; Netherlands; Chromosomal aberration; Modification; Skin disease; Variability; Environmental factor; Risk; Regulator; Association; Gene; Cell cycle; Malignant melanoma; Deletion; Genetics; Biological receptor; Dysplastic nevus; Multiple; Family study; Malignant tumor; Gene expression; Variant; Register; Gene penetrance; Risk factor; Abnormal chromosome; Mutation; Dutch
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/323411

Germline mutations of the cell-cycle regulator p16 (also called “CDKN2A”) in kindreds with melanoma implicate this gene in susceptibility to malignant melanoma. Most families with familial atypical multiple-mole melanoma (FAMMM) who are registered at the Leiden dermatology clinic share the same p16-inactivating deletion (p16-Leiden). Incomplete penetrance and variable clinical expression suggest risk modification by other genetic and/or environmental factors. Variants of the melanocortin-1 receptor (MC1R) gene have been shown to be associated with red hair, fair skin, and melanoma in humans. Carriers of the p16-Leiden deletion in Dutch families with FAMMM show an increased risk of melanoma when they also carry MC1R variant alleles. The R151C variant is overrepresented in patients with melanoma who are from families with the p16-Leiden mutation. Although some of the effect of the R151C variant 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 findings suggest that the R151C variant may be involved in melanoma tumorigenesis in a dual manner, both as a determinant of fair skin and as a component in an independent additional pathway.