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

Abstract

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 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.

RESULTS:

Rs518394, 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.

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.

• Authors: Danielle R Davari, Irene Orlow, Peter A Kanetsky, Li Luo, Sharon N Edmiston, Kathleen Conway, Eloise A Parrish, Honglin Hao, Klaus J Busam, Ajay Sharma, Anne Kricker, Anne E Cust, Hoda Anton-Culver, Stephen B Gruber, Richard P Gallagher, Roberto Zanetti, Stefano Rosso, Lidia Sacchetto, Terence Dwyer, David W Ollila, Colin B Begg, Marianne Berwick, Nancy E Thomas, GEM Study Group
• Journal: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology (Cancer Epidemiol Biomarkers Prev) Vol. 30 Issue 12 Pg. 2309-2316 (12 2021) ISSN: 1538-7755 [Electronic] United States
• PMID: 34607836 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Chemical References

• CDKN2B protein, human
• Cyclin-Dependent Kinase Inhibitor p15
• Membrane Proteins
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• GTP Phosphohydrolases
• NRAS protein, human

Topics

• Aged
• Cyclin-Dependent Kinase Inhibitor p15
• Female
• GTP Phosphohydrolases
• Genome-Wide Association Study
• Humans
• Lymphocytes, Tumor-Infiltrating (pathology)
• Male
• Melanoma (genetics, pathology)
• Membrane Proteins
• Middle Aged
• Mutation
• Proto-Oncogene Proteins B-raf
• Skin Neoplasms (genetics, pathology)
• Melanoma, Cutaneous Malignant