Endoplasmic stress-inducing variants in CPB1 and CPA1 and risk of pancreatic cancer: A case-control study and meta-analysis

• Published in: International journal of cancer 2022-04, Vol.150 (7), p.1123-1133
• Main Authors: Kawamoto, Makoto, Kohi, Shiro, Abe, Toshiya, Dbouk, Mohamad, Macgregor-Das, Anne, Koi, Chiho, Song, Ki-Byung, Borges, Michael, Sugimine, Ryo, Laheru, Daniel, Hruban, Ralph H, Roberts, Nicholas, Klein, Alison P, Goggins, Michael
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Cancer; Carboxypeptidase B - genetics; Carboxypeptidase B - physiology; Carboxypeptidases A - genetics; Carboxypeptidases A - physiology; Carcinoma, Pancreatic Ductal - etiology; Carcinoma, Pancreatic Ductal - genetics; Case-Control Studies; Computer programs; CPA1 gene; Endoplasmic reticulum; Endoplasmic Reticulum Stress - physiology; Genetic Predisposition to Disease; Genetic Variation; Genomes; Humans; Medical research; Meta-analysis; Pancreatic cancer; Pancreatic Neoplasms - etiology; Pancreatic Neoplasms - genetics; Pancreatitis; Risk; Secretion; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.33883

Gene variants that encode pancreatic enzymes with impaired secretion can induce pancreatic acinar endoplasmic reticulum (ER) stress, cellular injury and pancreatitis. The role of such variants in pancreatic cancer risk has received little attention. We compared the prevalence of ER stress-inducing variants in CPA1 and CPB1 in patients with pancreatic ductal adenocarcinoma (PDAC cases), enrolled in the National Familial Pancreas Tumor Registry, to their prevalence in noncancer controls in the Genome Aggregation Database (gnomAD). Variants of unknown significance were expressed and variants with reduced secretion assessed for ER stress induction. In vitro assessments were compared with software predictions of variant function. Protein variant software was used to assess variants found in only one gnomAD control ("n-of-one" variants). A meta-analysis of prior PDAC case/control studies was also performed. Of the 1385 patients with PDAC, 0.65% were found to harbor an ER stress-inducing variant in CPA1 or CPB1, compared to 0.17% of the 64 026 controls (odds ratio [OR]: 3.80 [1.92-7.51], P = .0001). ER stress-inducing variants in the CPA1 gene were identified in 4 of 1385 PDAC cases vs 77 of 64 026 gnomAD controls (OR: 2.4 [0.88-6.58], P = .087), and variants in CPB1 were detected in 5 of 1385 cases vs 33 of 64 026 controls (OR: 7.02 [2.74-18.01], P = .0001). Meta-analysis demonstrated strong associations for pancreatic cancer and ER-stress inducing variants for both CPA1 (OR: 3.65 [1.58-8.39], P