Germline landscape of pancreatic cancer in Singapore and dual architecture of DNA repair and pancreatitis-associated gene variants: Implications for population-tailored testing.

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Background: Germline pathogenic/likely pathogenic (P/LP) variants occur in up to 10% of pancreatic cancer (PC) patients, predominantly in DNA damage repair (DDR) genes, and increasingly guide therapeutic decisions including PARP inhibitor eligibility. However, germline data derive almost exclusively from European-ancestry cohorts, leaving a critical gap in Asian populations where PC incidence is rising. We characterised the prevalence, spectrum and clinical correlates of germline P/LP variants in a multi-ethnic Singapore PC cohort. Methods: We retrospectively reviewed 398 consecutive PC patients referred to the Cancer Genetics Service, National Cancer Centre Singapore (2014-2025); 332 (83.4%) underwent multigene germline panel testing. Variant distribution was assessed across functional gene categories and ethnicities. Pancreatitis-genotype correlations were evaluated among pancreatitis-gene carriers. Case-control enrichment analyses compared allele frequencies against 9,702 ancestry-matched controls from the Singapore 10K Genome Project using Fisher’s exact test with Benjamini-Hochberg correction. Results: Germline P/LP variants were identified in 64/332 tested patients (19.3%) across 18 genes, revealing two predominant functional categories: DDR genes (50.0% of carriers; ATM 17.2%, BRCA2 10.9%, PALB2 7.8%, BRCA1 4.7%) and pancreatitis-associated genes (45.3%; CFTR 29.7%, SPINK1 12.5%, PRSS1 3.1%). CFTR was the single most frequently mutated gene. P/LP carriers were younger at diagnosis (mean 59.8 vs 62.5 years), with the highest detection rate in patients <50 years (40.0%). Among pancreatitis-gene carriers, documented pancreatitis occurred in 37.5% of CFTR and 28.6% of SPINK1 carriers despite ascertainment limited to clinically apparent episodes. Case-control analysis confirmed significant enrichment for ATM, BRCA2 , and MLH1 variants (q<0.05), with suggestive enrichment for CFTR . Eighty-one percent of DDR carriers harboured PARP inhibitor-eligible gene variants, representing ~10% of all tested patients. Conclusions: This first Southeast Asian PC germline study reveals a dual genetic architecture-DDR and pancreatitis-associated pathways-distinct from Western cohorts where BRCA2 predominates. The prominence of CFTR , SPINK1 and PRSS1, comprising nearly half of all findings, demands that germline panels for Asian patients include pancreatitis-associated genes to avoid missing ~45% of actionable variants. These findings support universal germline testing, a dual-surveillance paradigm integrating cancer-focused and inflammation-directed monitoring, and provide population-specific evidence to inform testing strategies and guideline development for Asian populations.