Deficiencies in germline DNA repair are associated with early-onset gastrointestinal cancers and inform precision prevention strategies.

[BACKGROUND] Gastrointestinal (GI) cancers impose a significant global health burden and germline gene alterations play a significant role in the malignant transformation of epithelial cells. However, the prevalence and clinical relevance of pathogenic germline variations (PGVs) in Asian populations remain incompletely characterized.

[METHODS] This multicenter study analyzed six GI cancer types across 9470 Chinese patients through germline sequencing of 112 cancer susceptibility genes. PGVs were identified and characterized, and associated clinical, molecular, and somatic features were evaluated. Tumor mutation burden (TMB) and somatic mutation profiles were compared between PGV carriers and non-carriers to explore the biological implications of germline alterations.

[RESULTS] PGVs were identified in 5.4% (504/9,470) of patients, with pancreatic cancer (PC) exhibiting the highest prevalence (6.7%). Defects in the DNA damage response (DDR) pathway dominated, accounting for 84.2% of PGV carriers and demonstrating cancer-type specificity: homologous recombination repair (HRR) variants were enriched in cholangiocarcinoma (CCA; 72.7%) and PC (64.9%), whereas mismatch repair (MMR) defects were predominant in colorectal cancer (CRC; 23.0%). PGV carriers had a younger median age at diagnosis (59 vs. 61 years;  = 0.003) and a higher proportion of advanced-stage disease (82.2% vs. 79.7% for stages III–IV). Dual-PGV carriers manifested an even earlier age of onset (median 53 vs. 61 years;  < 0.001), with CRC dual-PGV carriers presenting the earliest onset (median 48 years; range 33–57). Non-MMR PGV carriers with CCA had a uniquely increased TMB ( = 0.005), redefining immunotherapy stratification. Somatic mutation profiles diverged between PGV carriers and non-carriers, with reduced TP53 mutations in patients with PC, GC, and CRC ( < 0.01) and enrichment of PIK3CA in CRC ( = 0.002).

[CONCLUSIONS] These findings emphasize that DDR defects are key drivers of GI cancer biology, highlighting dual PGVs as biomarkers for aggressive, early-onset disease and underscoring the need for genetic screening in young patients. The interplay between germline susceptibility and somatic evolution highlights potential avenues for precision interventions—such as PARP inhibitors for HRR-deficient tumors and immunotherapy for MMR-deficient subtypes—offering biologically meaningful hypotheses that, while not yet validated in clinical trials, provide valuable direction for future precision oncology research. The study advocates population-specific genetic screening and biomarker-driven approaches to optimize clinical management in underrepresented Asian populations.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12967-025-07595-9.