Association of MC1R Variants and Host Phenotypes With Melanoma Risk in CDKN2A Mutation Carriers: A GenoMEL Study

Abstract

BackgroundCarrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited.MethodsWe included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided.ResultsCarrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10−6 ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; Ptrend = 1.86 × 10−8). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10−6 ≤ P ≤ .02).ConclusionResults show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.

GPCRs and cancer

“…For instance, several GPCRs are overexpressed in different tumors [6] and GPCR variants can lead to increased cancer risk. In this regard, it should be mentio-ned that in genetic association studies melanocortin-1 receptor (MC1R) polymorphisms were associated with an enhanced threat of skin cancer [7] . In addition, an aberrant activation of GPCRs by high levels of ligands like LPA, S1P and chemokines was involved in cell transformation, proliferation, angiogenesis, metastasis and drug resistance [6] .…”

Cutaneous malignant melanoma incidences analyzed worldwide by skin type over advancing age of males and females: Evidence estrogen and androgenic hair are risk factors

“…Because UVB is not a factor in this analysis and bodily androgenic hair of European descendants around the world is similar, these differences align with the observed melanocortin-1-receptor gene variants associated with CDKN2A mutation carriers found in Australia (and possibly more in New Zealand) that are almost twice as many as those found in Europe. [33] Australia and New Zealand have Europeans who primarily emigrated from England, especially Wales, and Ireland with populations having the highest percentages of red-haired people in the world. More evidence supporting the notion that red hair is important is seen in Figure 5B, where the Chinese, Japanese, and Koreans (along with the Thai, results not shown) having black hair and low percentage of androgenic body hair and they also have the lowest CMM incidences of all the world's populations with skin type III-IV.…”

A short acidic motif in ARF guards against mitochondrial dysfunction and melanoma susceptibility

“…Small fractions of endogenous ARF have been demonstrated in mitochondrial preparations from MEFs and human tumour cells 55 ; however, the functional significance of endogenous mitochondrial ARF has not been determined, partly because cellular signals or mechanisms that could trigger translocation of ARF to mitochondria have remained elusive. Our investigation of ARF in the melanocytic lineage was prompted by previous work 14,19,52 . Information on somatic CDKN2A mutations in melanoma was obtained from COSMIC (http://www.sanger.ac.uk/cosmic; accessed September 2011) 64 .…”