Abstract
Genome-wide association studies (GWAS) and candidate pathway studies have identified low-penetrant genetic variants associated with cutaneous melanoma. We investigated the association of melanoma-risk variants with primary melanoma tumor prognostic characteristics and melanoma-specific survival. The Genes, Environment, and Melanoma Study enrolled 3285 European origin participants with incident invasive primary melanoma. For each of 47 melanoma-risk single nucleotide polymorphisms (SNPs), we used linear and logistic regression modeling to estimate, respectively, the per allele mean changes in log of Breslow thickness and odds ratios for presence of ulceration, mitoses, and tumor-infiltrating lymphocytes (TILs). We also used Cox proportional hazards regression modeling to estimate the per allele hazard ratios for melanoma-specific survival. Passing the false discovery threshold (p = 0.0026) were associations of IRF4 rs12203592 and CCND1 rs1485993 with log of Breslow thickness, and association of TERT rs2242652 with presence of mitoses. IRF4 rs12203592 also had nominal associations (p < 0.05) with presence of mitoses and melanoma-specific survival, as well as a borderline association (p = 0.07) with ulceration. CCND1 rs1485993 also had a borderline association with presence of mitoses (p = 0.06). MX2 rs45430 had nominal associations with log of Breslow thickness, presence of mitoses, and melanoma-specific survival. Our study indicates that further research investigating the associations of these genetic variants with underlying biologic pathways related to tumor progression is warranted.
Highlights
Genome-wide association studies (GWAS) and candidate pathway studies have identified low-penetrant genetic variants associated with cutaneous melanoma [1,2]
We investigated the association of 47 single nucleotide polymorphisms (SNPs) in putative melanoma-risk loci identified through GWAS or candidate studies with multiple primary melanoma occurrence and found that several of these susceptibility loci are generalizable to the risk of subsequent melanomas [3]
To explore whether genetic variants associated with melanoma risk could influence tumor aggressivity, we examined the associations of melanoma-risk SNPs with primary melanoma tumor prognostic characteristics
Summary
Genome-wide association studies (GWAS) and candidate pathway studies have identified low-penetrant genetic variants associated with cutaneous melanoma [1,2]. We investigated the association of 47 single nucleotide polymorphisms (SNPs) in putative melanoma-risk loci identified through GWAS or candidate studies with multiple primary melanoma occurrence and found that several of these susceptibility loci are generalizable to the risk of subsequent melanomas [3] Many of these variants are in gene regions associated with pigmentation, such as SLC45A2, TYRP1, TYR, and ASIP [4,5,6,7,8,9,10,11]; nevi, such as NID1, MTAP, and PLA2G6 [4,6,12,13,14,15,16,17,18]; or both, such as IRF4 and HERC2/OCA2 [4,7,13,14,19,20,21,22,23]. To investigate whether genetic variants associated with melanoma risk could influence outcomes, we examined the associations of these SNPs with melanoma-specific survival
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