Disease-Associated Risk Variants in ANRIL are Associated with Tumor-Infiltrating Lymphocytes Presence in Primary Melanomas in the Population-Based GEM Study.

Background Genome-wide association studies have reported that genetic variation at ANRIL (CDKN2B-AS1) is associated with risk of several chronic diseases including coronary artery disease, coronary artery calcification, myocardial infarction, and type 2 diabetes mellitus. ANRIL is located at the CDKN2A/B 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 single-nucleotide polymorphisms (SNPs) at or near ANRIL, we used linear and logistic regression modeling to estimate, respectively, the per allele mean changes in log of Breslow thickness and odds ratios (ORs) for presence of ulceration and tumor-infiltrating lymphocytes (TILs). We also assessed effect modification by tumor NRAS/BRAF mutational status. Results Rs518394, rs10965215, and rs564398 passed false discovery and were each associated (P {less than or equal to} 0.005) with TILs, although only rs564398 was independently associated (P = 0.0005) with TILs. Stratified by NRAS/BRAF mutational status, rs564398*A was significantly positively associated with TILs among NRAS/BRAF mutant, but not wildtype, cases. We did not find SNP associations with Breslow thickness or ulceration. Conclusions ANRIL rs564398 was associated with TIL presence in primary melanomas, and this association may be limited to NRAS/BRAF mutant cases. Impact Pathways related to ANRIL variants warrant exploration in relationship to TILs in melanoma, especially given the impact of TILs on immunotherapy and survival.