Abstract
BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer, but not all IPMNs progress to cancer. The objective of this study was to identify the germline genetic variants associated with IPMN clinical progression by conducting the first genome-wide association study (GWAS) and computing a polygenic hazard score (PHS) in 338 patients with IPMN. METHODS: The study population was divided into two subsets, and a Cox analysis adjusted for sex, age, cyst size at diagnosis, and the top 10 principal components was performed. A PHS was calculated using the genotypes of common variants associated with IPMN progression identified. RESULTS: Eight loci with significant associations (p < 5 × 10(-8)) were identified, and the most significant was 7q21.11-rs117620617 (hazard ratio, 16.35; 95% confidence interval, 6.93-38.60; p = 1.80 × 10(-10)). All variants were associated with inflammatory processes, suggesting that alleles that predispose to an inflammatory prone phenotype may promote progression. The PHS indicated a statistically significant association (hazard ratio, 18.05; 95% confidence interval, 7.96-45.80; p = 6.18 × 10(-11)) with IPMN progression among individuals who had the highest number of effect alleles (fourth quartile) compared with those who had the lowest number (first quartile). CONCLUSIONS: The current results study advance the understanding of individual predisposition to IPMN progression and underscore the potential use of genetics in the stratification of patients who have IPMN.