Comparison of clinical features and pancreatic cancer risk between genetic mutations associated versus alcohol associated chronic pancreatitis.

[BACKGROUND/OBJECTIVES] Genetic mutations associated chronic pancreatitis (GCP), caused by pathogenic variants in SPINK1, PRSS1, or CFTR, represents a distinct subset of chronic pancreatitis, whereas alcoholic chronic pancreatitis (ACP) is the predominant adult etiology. We compared the clinical course and pancreatic cancer risk between GCP and ACP.

[METHODS] This retrospective cohort included GCP patients from a prospective registry with genetic testing (2009-2023) and ACP patients from a clinical database (1989-2023). Propensity score matching (1:3) balanced age, sex, BMI, smoking, diabetes, and Cambridge grade, yielding 139 GCP and 309 ACP patients. Outcomes were assessed using Kaplan-Meier and Cox regression, and cancer incidence was calculated per person-years with Poisson regression.

[RESULTS] In the matched GCP cohort, mutation distribution was SPINK1 67.6 % (94/139), PRSS1 15.8 % (22/139), and CFTR 11.5 % (16/139). Compared with ACP, GCP patients had more frequent pancreatic pain (89.2 % vs 77.3 %, p = 0.005) and a younger mean age at onset (26.5 vs 40.6 years, p < 0.001). New-onset diabetes was more common (35.3 % vs 21.7 %, p = 0.004) but developed later (22.5 vs 12.7 years, p < 0.001). Pancreatic atrophy occurred less often and later in GCP. Pancreatic cancer incidence was higher in GCP (4.24 vs 0.40 per 1000 person-years; IRR 10.61, p = 0.031), with all cancers arising within 5 years of diagnosis, predominantly in SPINK1 gene mutation carriers.

[CONCLUSIONS] GCP shows distinct trajectories and an elevated early pancreatic cancer risk, particularly in SPINK1 gene mutation carriers, supporting genotype-stratified surveillance.