Increased risk of developing cutaneous malignant melanoma is associated with variation in pigmentation genes and VDR, and may involve epistatic effects

Abstract

Cutaneous malignant melanoma (CMM) is a malicious human skin cancer that primarily affects individuals with light pigmentation and heavy sun exposure, but also has a known familial association. Multiple genes and polymorphisms have been reported as low-penetrance susceptibility loci for CMM. Here, we examined 33 candidate polymorphisms located in 11 pigmentation genes and the vitamin D receptor gene (VDR) in a population of 130 cutaneous melanoma patients and 707 healthy controls. The genotypes obtained were evaluated for main association effects and potential gene-gene interactions. MC1R, TYR, VDR and SLC45A2 genes were found to be associated with CMM in our population. The results obtained for major function MC1R mutations were the most significant [with odds ratio (OR)=1.787, confidence interval (CI)=1.320-2.419 and P=1.715(-4)], followed by TYR (rs1393350) (with OR=1.569, CI=1.162-2.118, P=0.003), VDR (GCCC haplotype in rs2238136-rs4516035-rs7139166-rs11568820 block) (with OR=5.653, CI=1.794-17.811, P=0.003) and SLC45A2 (rs16891982) (with OR=0.238, CI=0.057-0.987, P=0.048). The study also detected significant intermolecular epistatic effects between MC1R and TYR, SLC45A2 and VDR, HERC2 and VDR, OCA2 and TPCN2, as well as intramolecular interactions between variants within the genes MC1R and VDR. In the final multivariate logistic regression model for CMM development, only the gene-gene interactions discovered remained significant, showing that epistasis may be an important factor in the risk of melanoma.

Worldwide cutaneous malignant melanoma incidences analyzed by sex, age, and skin type over time (1955–2007): Is HPV infection of androgenic hair follicular melanocytes a risk factor for developing melanoma exclusively in people of European-ancestry?

“…The common explanation of lighter skin color does not explain this dramatic increase because, besides our findings, others found no significant difference exists in the CMM incidence between skin type I/II and III/IV Europeans (p = 0.79) 50 or Americans 23 . One plausible explanation is the hormonal changes that occur during puberty associated with growing androgenic body hair, the distribution of which 51 aligns well with the distribution of CMM 9,52 .…”

Identification of Susceptibility Loci for Cutaneous Squamous Cell Carcinoma

“…SNP rs16891982 at locus 5p13, a nonsynonymous SNP (Phe374Leu) in SLC45A2 , has been associated with SCC (Stacey et al, 2009), BCC (Stacey et al, 2009), and CMM (Barrett et al, 2011; Stacey et al, 2009; Guedj et al, 2008; Duffy et al, 2010b; Ibarrola-Villava et al, 2012; Kosiniak-Kamysz et al, 2014; Fernandez et al, 2008) as well as eye, hair and skin color (Duffy et al, 2010b; Branicki et al, 2009; Eriksson et al, 2010; Stokowski et al, 2007; Soejima and Koda, 2007; Liu et al, 2015). SLC45A2 encodes a membrane-associated transporter enzyme, and loss of SLC45A2 activity has been found to disrupt post-Golgi-level trafficking of tyrosinase to the melanosomes (Newton et al, 2007) where melanin is synthesized and stored.…”

Further evidence for population specific differences in the effect of DNA markers and gender on eye colour prediction in forensics

“…Thus, OR ~ 1.17 may suggest the problem with statistical power to detect association between eye colour and rs12203592 in this study. Interestingly, IRF4 shows ambiguous pattern of association with cutaneous cancers in various populations [ 37 – 41 ]. Pietroni et al has reported three IrisPlex SNPs to be the only informative for eye colour prediction, and this set comprised rs12913832 in HERC2 , rs1800407 in OCA2 and rs16891982 in SLC45A2 [ 13 ].…”