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Objectives: Variant c.811+32C>A in intron 4 of the cholecystokinin-B receptor gene (CCKBR) was reported to correlate with higher pancreatic cancer risk and poorer survival. The variant was suggested to induce retention of intron 4, resulting in a new splice form with enhanced receptor activity. Our objective was to validate the c.811+32C>A variant as an emerging biomarker for pancreatic cancer risk and prognosis., Methods: We genotyped variant c.811+32C>A in 122 pancreatic adenocarcinoma case patients and 106 control subjects by sequencing and examined its association with cancer risk and patient survival. We tested the functional effect of variant c.811+32C>A on pre-messenger RNA splicing in human embryonic kidney 293T and Capan-1 cells transfected with CCKBR minigenes., Results: The allele frequency of the variant was similar between patients and control subjects (18.4% and 17.9%, respectively). Survival analysis showed no significant difference between median survival of patients with the C/C genotype (266 days) and patients with the A/C or A/A genotypes (257 days). CCKBR minigenes with or without variant c.811+32C>A exhibited no difference in expression of the intron-retaining splice variant., Conclusion: These data indicate that variant c.811+32C>A in CCKBR does not have a significant impact on pancreatic cancer risk or survival in a Hungarian cohort.

Objectives: Serine protease inhibitor Kazal type 1 (SPINK1) provides an important line of defense against premature trypsinogen activation within the pancreas. Our aim was to identify pathogenic SPINK1 promoter variants associated with chronic pancreatitis (CP)., Methods: One hundred CP patients (cases) and 100 controls with no pancreatic disease from the Hungarian National Pancreas Registry were enrolled. Direct sequencing of SPINK1 promoter region was performed. Functional characterization of variants was carried out using luciferase reporter gene assay., Results: Two common polymorphisms (c.-253T>C and c.-807C>T) were found in both cases and controls. Variant c.253T>C was enriched in cases relative to controls (odds ratio, 2.1; 95% confidence interval, 1.2-3.8; P = 0.015). Variant c.-215G>A was detected in 3 of 100 cases; always linked with the pathogenic variant c.194+2T>C. Novel promoter variants c.-14G>A, c.-108G>T, and c.-246A>G were identified in 1 case each. Functional analysis showed decreased promoter activity for variants c.-14G>A (80%), c.-108G>T (31%), and c.-246A>G (47%) whereas activity of variant c.-215G>A was increased (201%) and variant c.-253T>C was unchanged compared with wild type., Conclusions: The common promoter variant c.-253T>C was associated with CP in this cohort. Two of 3 newly identified SPINK1 promoter variants seem to exhibit significant functional defects and should be considered potential risk factors for CP.