Multigene Germline Panel Testing in Gastric Cancer Patients in a Portuguese Population.

[BACKGROUND] Gastric cancer is a heterogeneous disease with both environmental and genetic determinants. While Multigene Germline Panel Testing (MGPT) increasingly reveals hereditary predisposition, the prevalence and clinical significance of germline variants in Portuguese gastric cancer patients tested through institutional MGPT programs remain insufficiently characterised. The main objective of this study was to determine the prevalence and spectrum of germline pathogenic variants and likely pathogenic variants in gastric cancer patients from Portugal, and to explore their clinicopathological correlations.

[METHODS] We conducted a pilot retrospective observational study including 51 patients with histologically confirmed gastric cancer who underwent MGPT between 2020 and 2025. Genetic testing was performed using validated 15 or 30 gene panels. Clinical, pathological, and survival data were retrieved from medical records.

[RESULTS] Germline pathogenic or likely pathogenic variants were detected in 6 patients (11.8%), involving MLH1, MSH6, PMS2, CHEK2, and BLM. Variants of uncertain significance (VUS) were identified in 11.8%. No CDH1 alterations were observed. Compared with MGPT-negative cases, MGPT-positive patients were significantly younger at diagnosis (median 48 vs. 76 years, p = 0.00) and more frequently presented with mixed-type gastric cancer (33.3% vs. 4.4%, p = 0.05). No significant associations were found with tumour stage or treatment.

[CONCLUSIONS] In this Portuguese cohort, nearly 12% of consecutive real-world MGPT-tested gastric cancer patients had germline pathogenic or likely pathogenic variants, predominantly in mismatch repair genes but also in CHEK2 and BLM. These findings further illustrate the heterogeneity of hereditary gastric cancer beyond classical CDH1 mutations and support the integration of MGPT into clinical care to identify at-risk individuals not captured by current criteria. Larger multicentre studies are warranted to validate these results and clarify the role of emerging susceptibility genes.

[TRIAL REGISTRATION] Study Registration Number: NCT07387237.