Pleiotropic and sex-specific effects of cancer GWAS SNPs on melanoma risk in the population architecture using genomics and epidemiology (PAGE) study.

Kocarnik JM, Park SL, Han J, Dumitrescu L, Cheng I, Wilkens LR, Schumacher FR, Kolonel L, Carlson CS, Crawford DC, Goodloe RJ, Dilks HH, Baker P, Richardson D, Matise TC, Ambite JL, Song F, Qureshi AA, Zhang M, Duggan D, Hutter C, Hindorff L, Bush WS, Kooperberg C, Le Marchand L, Peters U
PLoS One. 2015 10 (3): e0120491

PMID: 25789475 · PMCID: PMC4366224 · DOI:10.1371/journal.pone.0120491

BACKGROUND - Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk.

METHODS - We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies.

RESULTS - We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8x10-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0x10-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e-4).

CONCLUSIONS - We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes.

MeSH Terms (22)

Aged Aged, 80 and over Alleles Case-Control Studies Female Genetic Pleiotropy Genome-Wide Association Study Genotype Humans Lung Neoplasms Male Melanoma Membrane Proteins Metagenomics Middle Aged Neoplasm Proteins Polymorphism, Single Nucleotide Prostatic Neoplasms Risk Sex Factors Skin Neoplasms Telomerase

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