Association between SIRT1 rs3758391 genetic variant and susceptibility to pancreatic and gastric cancer

Ilias Papantzimas; Rana Ozer; Dimitrios Linardoutsos; Emmanouil Kritsotakis; Konstantinos Georgiou; Maria Gazouli

Authors Ilias Papantzimas, Rana Ozer, Dimitrios Linardoutsos, Emmanouil Kritsotakis, Konstantinos Georgiou, Maria Gazouli.

Abstract

Background The SIRT1 gene encodes a NAD⁺-dependent deacetylase that regulates apoptosis, metabolism and genomic stability through interaction with p53 and other transcription factors. Functional single nucleotide polymorphisms within SIRT1 may alter gene expression and affect cancer susceptibility. The rs3758391 and rs369274325 polymorphisms have been implicated in various malignancies; however, their role in pancreatic and gastric cancer remains unclear.

Methods This case-control study included 94 patients with pancreatic ductal adenocarcinoma (PDAC), 38 patients with gastric cancer (GC), and 74 healthy controls, all of Greek origin. Genomic DNA was extracted from peripheral blood samples. Genotyping was performed by RFLP-PCR for rs3758391 and tetra-primer ARMS-PCR for rs369274325. Genotype and allele frequencies were compared using χ2 test and odds ratios (ORs) with 95% confidence intervals (CIs).

Results A significant association was identified between SIRT1 rs3758391 and PDAC and GC susceptibility. The TT genotype was overrepresented among PDAC patients, while the TC genotype conferred a protective effect against both PDAC (P=0.0039; OR 0.35, 95%CI 0.17-0.62) and GC (P=0.0059; OR 0.26, 95%CI 0.10-0.66). The C allele was more frequent in healthy controls compared to PDAC patients (P<0.001; OR 0.39, 95%CI 0.25-0.62). No significant association was observed for rs369274325 in either cancer type or with clinicopathological parameters.

Conclusions This is the first study to evaluate SIRT1 genetic variants in PDAC and GC. The rs3758391 polymorphism appears to influence susceptibility to both malignancies, potentially via altered p53-mediated regulation of SIRT1. These findings suggest SIRT1 as a candidate biomarker for gastrointestinal cancer risk, meriting further validation in larger, ethnically diverse cohorts.

Keywords SIRT1, rs3758391, rs369274325, pancreatic ductal adenocarcinoma, gastric cancer

Ann Gastroenterol 2026; 39 (2): 221-227