Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 150, Issue 7, Pages 1123-1133Publisher
WILEY
DOI: 10.1002/ijc.33883
Keywords
CPA1; CPB1; endoplasmic reticulum stress; pancreatic cancer; variant
Categories
Funding
- National Institute of Health, National Cancer Institute [CA62924, U01210170, R01CA176828, R00 CA190889, P30CA006973]
- Susan Wojcicki and Dennis Troper
- Lustgarten Foundation
- Uehara Memorial Foundation
- Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Interception Translational Cancer Research Grant [SU2C-AACR-DT25-17]
- Stand Up To Cancer is a program of the Entertainment Industry Foundation
- SU2C
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Rare variants in CPB1 and CPA1 that induce endoplasmic reticulum (ER) stress are associated with increased odds of developing pancreatic cancer. Meta-analysis showed strong associations for both CPA1 and CPB1 ER-stress inducing variants with pancreatic cancer risk.
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 < .023) and CPB1 (OR: 9.51 [3.46-26.15], P < .001). Rare variants in CPB1 and CPA1 that induce ER stress are associated with increased odds of developing pancreatic cancer.
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