ETD

• genetics
• pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains the most aggressive form of pancreatic cancer, with a five-year survival rate of approximately 12%. Surgical resection is the only curative option, yet fewer than 20% of patients are eligible at diagnosis due to advanced disease or distal metastasis. Neoadjuvant chemotherapy is often adopted to improve resectability and disease control; however, treatment responses remain highly variable among patients, emphasizing on the urgent need for predictive biomarkers to guide personalized therapy.

This research aimed to identify genetic variants associated with chemotherapy response in PDAC using a genome-wide association study (GWAS). A cohort of 94 PDAC patients treated at San Raffaele Hospital, Milan, was analyzed; after quality control, 74 individuals and 9.4 million imputed variants were retained for association analysis. Logistic regression models, adjusted for age, sex, tumor stage and population stratification, were applied to assess associations with disease control rate (DCR) and progression outcomes. In addition, Cox proportional hazards regression was performed to evaluate the impact of genetic variants on overall survival (OS) and progression free survival (PFS).

Findings identified four loci of interest. On chromosome 7, three single nucleotide variants (SNVs) within a linkage disequilibrium block encompassing the GALNT17 gene were associated with improved OS, with rs12333555 (T allele) showing the strongest effect (HR = 0.06, 95% CI = 0.02–0.17, p = 7.75×10-8). Again, on chromosome 7, the intronic variant rs13236614 in the AOAH gene (T allele) was associated with both DCR (OR = 0.01, 95% CI = 0.0009–0.09, p =2.24 × 10-8) and increased PFS. On chromosome 8, two variants in complete LD within the intronic region of CTSB gene demonstrated significant associations with Progression (OR = 0.03, 95% CI = 0.004–0.16, p = 1.08 × 10−4) and another on chromosome 6, one intronic variants (rs11753886) within the PLN gene demonstrated significant associations with Progression (OR = 0.04, 95% CI = 0.008–0.2, p = 9.56 × 10−5) .None of these associations remained significant after Bonferroni correction, likely reflecting the small sample size, however the magnitude of effect suggests biologically relevant signals.

These findings suggest that host genetic factors may influence chemotherapy response and disease progression in PDAC by affecting regulatory regions and intronic regions that modulate gene expression. If validated in larger cohorts, the identified variants could serve as predictive biomarkers, supporting the development of personalized therapeutic strategies and ultimately improving treatment outcomes in this highly lethal cancer.