1. Disease-Associated Risk Variants in ANRIL Are Associated with Tumor-Infiltrating Lymphocyte Presence in Primary Melanomas in the Population-Based GEM Study
- Author
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Davari, Danielle R, Orlow, Irene, Kanetsky, Peter A, Luo, Li, Edmiston, Sharon N, Conway, Kathleen, Parrish, Eloise A, Hao, Honglin, Busam, Klaus J, Sharma, Ajay, Kricker, Anne, Cust, Anne E, Anton-Culver, Hoda, Gruber, Stephen B, Gallagher, Richard P, Zanetti, Roberto, Rosso, Stefano, Sacchetto, Lidia, Dwyer, Terence, Ollila, David W, Begg, Colin B, Berwick, Marianne, Thomas, Nancy E, and Group, on behalf of the GEM Study
- Subjects
Clinical Research ,Human Genome ,Cardiovascular ,Cancer ,Genetics ,Diabetes ,Heart Disease ,Heart Disease - Coronary Heart Disease ,Aged ,Cyclin-Dependent Kinase Inhibitor p15 ,Female ,GTP Phosphohydrolases ,Genome-Wide Association Study ,Humans ,Lymphocytes ,Tumor-Infiltrating ,Male ,Melanoma ,Membrane Proteins ,Middle Aged ,Mutation ,Proto-Oncogene Proteins B-raf ,Skin Neoplasms ,coronary artery disease ,coronary artery calci fi cation ,myocardial ,GEM Study Group ,Medical and Health Sciences ,Epidemiology - Abstract
BackgroundGenome-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.MethodsThe 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 ANRIL, 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 NRAS/BRAF mutational status.ResultsRs518394, rs10965215, and rs564398 passed false discovery and were each associated (P ≤ 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 wild-type, cases. We did not find SNP associations with Breslow thickness or ulceration.ConclusionsANRIL rs564398 was associated with TIL presence in primary melanomas, and this association may be limited to NRAS/BRAF-mutant cases.ImpactPathways related to ANRIL variants warrant exploration in relationship to TILs in melanoma, especially given the impact of TILs on immunotherapy and survival.
- Published
- 2021