SPINK1 Mutations and Risk of Pancreatic Cancer in Patients with Chronic Pancreatitis: Data from a Prospective Cohort Study

Objective: The relationship between SPINK1 and pancreatic cancer (PC) remains controversial. The current study aimed to determine the effect of SPINK1 mutations on PC development among patients with chronic pancreatitis (CP). Methods: This is a prospective observational study including a large cohort of 965 CP patients with 11-year follow-up. Patients’ demographic characteristics and clinical CP outcomes were documented in detail. Genetic testing was performed, and rare pathogenic variants of SPINK1 were included in the study. The effect of SPINK1 mutations on the clinical development of PC was explored using Cox proportional hazards regression. Subgroup analyses conducted included the consideration of gender, onset age of CP (early- and late-onset), etiologies of CP, smoking, and alcoholic drinking status. Results: PC was diagnosed in 2.5% (24/965) of patients, and the cumulative incidence rates were 0.2%, 0.8%, and 1.5% at 3, 5, and 10 years since the onset of CP, respectively. SPINK1 c.194+2T>C was the most common variant with a proportion of 39.1%. The risk of PC development varied marginally between patients with and without SPINK1 mutations (Cox HR 0.39(0.14-1.04), P=0.059). In the subgroup analyses, patients carrying SPINK1 mutations had a significantly lower risk of PC (Cox HR 0.18(0.04-0.80), P=0.025) in the non-smoking group. SPINK1 mutations showed no significant effect in the other subgroups considered. Conclusions: CP patients harboring SPINK1 mutations do not have an elevated risk of PC development. On the contrary, SPINK1 mutation appears to be a protective factor in non-smoking patients with CP. The exact relationship between SPINK1 mutations and PC warrants further investigation. Funding Statement: Financial support for this study came from the National Natural Science Foundation of China (Grant Nos. 82070661 [W.B.Z.], 81970560[Z.L.], 81873588[Z.S.L.]); Scientific Innovation Program of Shanghai Municipal Education Committee (No. 201901070007E00052); the fund for “Clinical Technology Innovation Project Task (Contract)” of Shanghai Shenkang Hospital Development Center (to ZL, No. SHDC2020CR2032B). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The study was approved by the Ethics Committee of Changhai Hospital.