MC1R variants increase risk of melanomas harboring BRAF mutations.
Melanocortin-1 receptor (MC1R) variants have been associated with BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutations in non-CSD (chronic solar-damaged) melanomas in an Italian and an American population. We studied an independent Italian population of 330 subjects (165 melanoma patients and 165 controls) to verify and estimate the magnitude of this association and to explore possible effect modifiers. We sequenced MC1R in all subjects and exon 15 of BRAF in 92/165 melanoma patients. Patients with MC1R variants had a high risk of carrying BRAF mutations in melanomas (odds ratio (OR)=7.0, 95% confidence interval (CI)=2.1-23.8) that increased with the number of MC1R variants and variants associated with red hair color. Combining these subjects with the originally reported Italian population (513 subjects overall), MC1R variant carriers had a 5- to 15-fold increased risk of BRAF-mutant melanomas based on carrying one or two variants (P<0.0001, test for trend), and regardless of signs of chronic solar damage. In contrast, no association with BRAF-negative melanomas was found (OR=1.0, 95% CI=0.6-1.6). No characteristics of subjects or melanomas, including age, nevus count, pigmentation, and melanoma thickness or location on chronically or intermittently sun-exposed body sites, substantially modified this association, although results could be affected by the small numbers in some categories. This study confirms that the known MC1R-melanoma risk association is confined to subjects whose melanomas harbor BRAF mutations.
Fargnoli
Maria Concetta
MC
Department of Dermatology, University of L'Aquila, L'Aquila, Italy.
Fargnoli
Maria Concetia
MC
Pike
Kris
K
Pfeiffer
Ruth M
RM
Tsang
Shirley
S
Rozenblum
Ester
E
Munroe
David J
DJ
Golubeva
Yelena
Y
Calista
Donato
D
Seidenari
Stefania
S
Massi
Daniela
D
Carli
Paolo
P
Bauer
Juergen
J
Elder
David E
DE
Bastian
Boris C
BC
Peris
Ketty
K
Landi
Maria T
MT
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006200:Hair Color / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009378:Neoplasms, Multiple Primary / Q000473:pathology; D009506:Nevus / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics*; D013472:Sunlight
D044102:Receptor, Melanocortin, Type 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf