Association between breast cancer, pancreatic cancer, and melanoma in a CDKN2A variant common in the Hispanic population.

Pathogenic and likely pathogenic variants (P/LP) in the CDKN2A gene are associated with melanoma-pancreatic cancer susceptibility syndrome. The lifetime risk for melanoma is estimated to be 28-76%, while the lifetime risk of pancreatic cancer is > 15%. A common CDKN2A variant in the Hispanic population, c.146 T > C, has conflicting interpretations of pathogenicity, with some laboratories calling this variant LP and others calling it uncertain significance (VUS), which leads to inconsistent clinical recommendations for cancer screening. The objective of this study was to determine if there is an association between the CDKN2A c.146 T > C variant and melanoma, pancreatic cancer, and/or breast cancer. We conducted a retrospective cohort study of the Southern California Kaiser Genetics Hereditary Cancer Database from January 2013 to January 2024. We determined the presence of melanoma, pancreatic cancer, and breast cancer among 202 individuals with the CDKN2A c.146 T > C variant ("c.146 T > C group") and compared them to 190 individuals with Hispanic ancestry and a negative germline panel ("negative control group") as well as 53 individuals with a CDKN2A P/LP variant other than c.146 T > C ("positive control group"). Multiple logistic regression was utilized to produce adjusted odds ratios (aOR), 95% confidence intervals (CI), and p-values. The adjusted odds of melanoma (aOR 6.1, 95% CI 1.3 to 27.9), pancreatic cancer (aOR 13.9, 95% CI 1.7 to 113.4), and breast cancer (aOR 3.2, 95% CI 1.8 to 5.6) were significantly higher in the c.146 T > C group compared to the negative control group. When the c.146 T > C group was compared to the positive control group, the adjusted odds of melanoma (aOR 0.9, 95% CI 0.1 to 8.0), pancreatic cancer (aOR 12.2, 95% CI 0.3 to 511.4), and breast cancer (aOR 1.9, 95% CI 0.4 to 8.4) were not significantly different. Although CDKN2A c.146 T > C is a relatively common variant in the Hispanic population, our data shows it may confer cancer risks similar to other CDKN2A P/LP variants. Increased risk of breast cancer has previously been reported with CDKN2A leading to questions about whether the increased breast cancer risk seen in this study is variant specific. Given the prevalence of this variant in an underserved population, our results suggest that the risks of cancer associated with this Hispanic variant warrant counseling and clinical follow-up.