CDKN2A Germline Rare Coding Variants and Risk of Pancreatic Cancer in Minority Populations

Background: Pathogenic germline mutations in the CDKN2A tumor suppressor gene are rare and associated with highly penetrate familial melanoma and pancreatic cancer in non-Hispanic whites (NHW). To date, the prevalence and impact of CDKN2A rare coding variants (RCV) in racial minority groups remain poorly characterized. We examined the role of CDKN2A RCVs on the risk of pancreatic cancer among minority subjects. Methods: We sequenced CDKN2A in 220 African American (AA) pancreatic cancer cases, 900 noncancer AA controls, and 183 Nigerian controls. RCV frequencies were determined for each group and compared with that of 1,537 NHW patients with pancreatic cancer. Odds ratios (OR) and 95% confidence intervals (Cl) were calculated for both a case-case comparison of RCV frequencies in Ms versus NHWs, and case-control comparison between AA cases versus noncancer AA controls plus Nigerian controls, Smaller sets of Hispanic and Native American cases and controls also were sequenced. Results: One novel missense RCV and one novel frame-shift RCV were found among AA patients: 400G>A and 258_278del. RCV carrier status was associated with increased risk of pancreatic cancer among AA cases (11/220; OR, 3.3; 95% CI, 1.5-7.1; P = 0.004) compared with AA and Nigerian controls (17/1,083). Further, AA cases had higher frequency of RCVs: 5.0% (OR, 13.4; 95% CI, 4.9-36.7; P< 0.001) compared with NHW cases (0.4%). Conclusions: CDKN2A RCVs are more common in AA than in NHW patients with pancreatic cancer and associated with moderately increased pancreatic cancer risk among Ms. Impact: RCVs in CDKN2A are frequent in AAs and are associated with risk for pancreatic cancer. (C) 2018 AACR.