A Customized Pigmentation SNP Array Identifies a Novel SNP Associated with Melanoma Predisposition in the SLC45A2 Gene

Abstract

As the incidence of Malignant Melanoma (MM) reflects an interaction between skin colour and UV exposure, variations in genes implicated in pigmentation and tanning response to UV may be associated with susceptibility to MM. In this study, 363 SNPs in 65 gene regions belonging to the pigmentation pathway have been successfully genotyped using a SNP array. Five hundred and ninety MM cases and 507 controls were analyzed in a discovery phase I. Ten candidate SNPs based on a p-value threshold of 0.01 were identified. Two of them, rs35414 (SLC45A2) and rs2069398 (SILV/CKD2), were statistically significant after conservative Bonferroni correction. The best six SNPs were further tested in an independent Spanish series (624 MM cases and 789 controls). A novel SNP located on the SLC45A2 gene (rs35414) was found to be significantly associated with melanoma in both phase I and phase II (P<0.0001). None of the other five SNPs were replicated in this second phase of the study. However, three SNPs in TYR, SILV/CDK2 and ADAMTS20 genes (rs17793678, rs2069398 and rs1510521 respectively) had an overall p-value<0.05 when considering the whole DNA collection (1214 MM cases and 1296 controls). Both the SLC45A2 and the SILV/CDK2 variants behave as protective alleles, while the TYR and ADAMTS20 variants seem to function as risk alleles. Cumulative effects were detected when these four variants were considered together. Furthermore, individuals carrying two or more mutations in MC1R, a well-known low penetrance melanoma-predisposing gene, had a decreased MM risk if concurrently bearing the SLC45A2 protective variant. To our knowledge, this is the largest study on Spanish sporadic MM cases to date.

The genetic basis of sunlight sensitivity and melanoma-risk pigmentation phenotypes: The role of sex-specific genetic effects, 3' untranslated regions and melanoma susceptibility genes

“…Logistic regression was performed to re-assess associations between genotypes and melanoma risk done previously (28), but separating individuals by sex in order to estimate sex-specific ORs, 95% CIs and P-values. As mentioned above, the minor allele was also modelled under an additive model.…”

“…A standardised questionnaire was used to collect information on sex, age, pigmentation characteristics (eye colour, hair colour, skin colour, number of naevi and presence of solar lentigines), history of childhood sunburns, Fitzpatrick's skin type classification, and personal and family history of cancer, to classify individuals as previously described (28).…”

“…Gene and SNP selection was performed as previously described (28 SNP genotyping was done using the Golden Gate Assay according to manufacturer's protocol (Illumina, San Diego, CA, USA), as previously described (28).…”

“…In a previous study published by our group, the association of some genes with phenotypic characteristics was reported (28). However, analyses were performed without taking into account sex data.…”

“…Polymorphisms showing potential differences in allelic effect by sex are located on genes that have functions related to melanocyte development, melanosome formation, maturation and transportation, as well as to skin cancer (26)(27)(28)31,54,56,158,(168)(169)(170).…”