Disease-Associated Risk Variants in Are Associated with Tumor-Infiltrating Lymphocyte Presence in Primary Melanomas in the Population-Based GEM Study.

Background: Genome-wide association studies have reported that genetic variation at () is associated with risk of several chronic diseases including coronary artery disease, coronary artery calcification, myocardial infarction, and type 2 diabetes mellitus. is located at the locus, which encodes multiple melanoma tumor suppressors. We investigated the association of these variants with melanoma prognostic characteristics.

Methods: The Genes, Environment, and Melanoma Study enrolled 3,285 European origin participants with incident invasive primary melanoma. For each of ten disease-associated SNPs at or near , we used linear and logistic regression modeling to estimate, respectively, the per allele mean changes in log of Breslow thickness and ORs for presence of ulceration and tumor-infiltrating lymphocytes (TIL). We also assessed effect modification by tumor mutational status.

Results: Rs518394, rs10965215, and rs564398 passed false discovery and were each associated ( ≤ 0.005) with TILs, although only rs564398 was independently associated ( = 0.0005) with TILs. Stratified by mutational status, rs564398*A was significantly positively associated with TILs among mutant, but not wild-type, cases. We did not find SNP associations with Breslow thickness or ulceration.

Conclusions: rs564398 was associated with TIL presence in primary melanomas, and this association may be limited to -mutant cases.

Impact: Pathways related to variants warrant exploration in relationship to TILs in melanoma, especially given the impact of TILs on immunotherapy and survival.