Cutaneous phenotype and MC1R variants as modifying factors for the development of melanoma in CDKN2A G101W mutation carriers from 4 countries

Abstract

The G101W founder mutation is the most common CDKN2A mutation in Italy, Spain, and France. As the background of modifying genes, environmental exposures, and sun behavior vary across countries, studying G101W carriers from distinct countries offers a unique opportunity to evaluate possible modifying factors in melanoma development. We evaluated 76 G101W cases and 59 carrier controls from France, Italy, Spain, and the United States. Hair color and dysplastic nevi distributions differed significantly in cases and controls across the 4 study groups. Cases also varied significantly for eye color, freckling, and nevi. The distribution of MC1R variants in cases differed significantly across study groups because 12% of Italian melanoma patients had 2 MC1R variants vs. >50% for the other case groups. Several MC1R covariates showed significant associations with melanoma risk in all groups combined and in the American, French, and Spanish samples; no significant findings were observed in the Italian sample. In multiple-case families, the number and type of MC1R variants varied significantly between multiple-primary-melanoma and single-primary-melanoma patients from the 4 groups; there was also a significant decrease in median age at melanoma diagnosis as the number or type of MC1R variants increased. The variation in the effects of the cutaneous phenotypic and MC1R factors across the study sample suggests that these factors differentially contribute to development of melanoma even on a common genetic background of a germline CDKN2A mutation. Differences in melanoma risk across geographic regions justify the need for individual studies in each country before counseling should be considered. ' 2007 Wiley-Liss, Inc.Key words: melanoma; CDKN2A; MC1R; G101W Germline mutations within the coding region of the CDKN2A gene (9p21) have been observed in affected members of melanoma-prone families. 1,2 G101W is one of the most common CDKN2A missense mutations identified to date. It is the most common mutation observed in Italy, Spain, and France. G101W also has a high occurrence in the United States. Similar to most of the other frequent recurrent CDKN2A mutations, G101W appears to have resulted from a single mutational event. Previous evaluation of 20 melanoma-prone families with G101W mutations from France, Italy, and the United States provided compelling evidence for a single genetic origin for G101W; the mutation was estimated to have originated about 97 generations ago (1 LODunit support interval 70-133 generations). 3 Although CDKN2A mutations confer substantial risk for melanoma, not all carriers of mutations develop melanoma. Other host/ clinical, environmental, and genetic factors also modulate risk. It is well known that the incidence of melanoma varies worldwide and even in the context of familial melanoma, penetrance of CDKN2A mutations differs between Europe and the United States. 4 These differences could be related to different genetic backgrounds or to variation in host/clinical characteristics and/or sun behavior. Pr...

MC1R variation and melanoma risk in relation to host/clinical and environmental factors in CDKN2A positive and negative melanoma patients

“…The results of this study confirm previous findings in our population, showing that Italian CDKN2A+ CM cases have substantially fewer MC1R variants than cases from other geographic areas and that Italian cases do not show an association between MC1R and CM risk (17,21). Our findings suggest that other genes, besides MC1R, may modify CM risk in CDKN2A + cases and that MC1R plays a role in CM development in CDKN2AÀ cases both via pigmentary and non-pigmentary pathways.…”

“…Separate observation of data from the Italian families we contributed did not show the association (21), confirming the results of a previous study on carriers of the common CDKN2A G101W founder mutation, which showed an impact of MC1R variants on CM risk in G101W carriers from Spain, France and the United States but not in G101W carriers from Italy (17).…”

“…Furthermore, it has been suggested that MC1R variants may be involved in CM development both via pigmentary and non-pigmentary pathways (8) and in increased CM risk in families with CDKN2A mutations (9,(16)(17)(18)(19)(20).…”

Early Stages of Melanoma on the Limbs of High-risk Patients: Clinical, Dermoscopic, Reflectance Confocal Microscopy and Histopathological Characterization for Improved Recognition

“…To date, no clinical, dermoscopic, or histopathological special feature has been related to tumours in FamMM (5)(6)(7). Polymorphisms in melanocortin I receptor (MCIR) gene, especially the red hair variants (RHV), are considered low susceptibility genes to MM development, increasing the MM risk up to 10 times in respect to wild type (8). We studied the interaction between these lowrisk variants among FamMM cases, and found that they can increase the genetic risk in CDKN2A (high-risk gene) mutation carriers by up to 14 times and contribute to a less suspicious clinical and dermoscopic appearance of tumours, less colour, and fewer structures (9).…”

Protective effect of copy number polymorphism of glutathione S-transferase T1 gene on melanoma risk in presence of CDKN2A mutations, MC1R variants and host-related phenotypes

“…Regarding GSTP1, heterozygous and homozygous for the less frequent allele were pooled since there were few (p.I105V variant) or none (p.A114V variant) homozygous subjects. Since the risk of melanoma was found to increase with the number of MC1R variants in various populations including ours [21], a MC1R variable was created by assigning subjects to one of the three following categories: MC1R consensus homozygous subjects vs. subjects with one MC1R variant vs. subjects with at least two MC1R variants. A RHC variable (pooling the red hair and fair skin associated variants i.e., p.R151C, p.R160W, p.D84E and p.D294H) and a NRHC variable (pooling all non-synonymous non-RHC variants) were also considered.…”