Integrated clinico-molecular analysis of gastric cancer in European and Latin American populations: LEGACY project

Abstract

Gastric cancer; Gastric cancer biomarkers; Precision medicine

Cáncer gástrico; Biomarcadores de cáncer gástrico; Medicina de precisión

Càncer gàstric; Biomarcadors de càncer gàstric; Medicina de precisió

Background Gastric cancer (GC) is recognized for intrinsic heterogeneity, although it is similarly approached in Europe and Latin America (LATAM). The LEGACY project aimed to deepen GC molecular understanding through multi-omics analysis in Europe and LATAM GC samples. Patients and methods Tumor samples were centrally reviewed for histology, human epidermal growth factor receptor 2 (HER2) expression, and mismatch repair-deficient (dMMR)/microsatellite instability (MSI) status. In addition, we assessed Epstein–Barr virus (EBV) status, programmed death-ligand 1 (PD-L1) combined positive score (CPS), and carried out tissue genomic profiling including tumor mutation burden (TMB) quantification plus targeted transcriptomics for immune microenvironment and cancer cell signaling scores. Results In total, 328 GC patients were enrolled. HER2-positive GC and high PD-L1 CPS were more frequent in Europe than in LATAM (9% versus 3% and 15% versus 3%, respectively), whereas EBV was mainly found in LATAM (7%, versus 3% in Europe), and dMMR/MSI tumors were equally distributed (16%). High TMB was enriched in dMMR/MSI and EBV tumors. Mutations in homologous recombination repair (HRR) genes were frequent in both cohorts (24.8% and 14.7% in Europe and LATAM, respectively), and mostly found in dMMR/MSI (63.6%) and intestinal HER2-negative (18.7%) tumors. The prognosis was poor in diffuse HER2-negative GC patients, whose tumors presented an immunosuppressive microenvironment and other distinct pathway activation signatures. Conclusions Our findings relate specific molecular alterations of GC tumors from Europe and LATAM to actionable biomarkers for precision cancer therapies. The proposed GC stratification can be implemented in routine care and guide drug development strategies.

This work was supported by the European Union’s Horizon 2020 [grant number 825832] research and innovation program [grant number GA825832]. The European Union was not involved in the collection, analysis, and interpretation of data, in writing future manuscripts, or in deciding to submit manuscripts for publication. This work was also further supported by ANID-FONDAP-152220002 & 15130011 [grant number 1523A0008], PROGRAMA ICM-ANID [grant number ICN2021_045], ANID FONDECYT [grant number 1220586], FONDECYT [grant number 1230504] and ANID-FONDAP [grant number 152220002], in Chile; and by CONAHCyT [grant number N°297681]; CELAC and European Consortium for Personalized Medicine Approach to Gastric Cancer (LEGACY) in Mexico.