Assessment of POLE and POLD1 mutations as prognosis and immunotherapy biomarkers for stomach adenocarcinoma

Background: Cancer patients with POLE or POLD1 mutations may be excellent candidates for immune checkpoint inhibitors (ICIs) therapy and have favorable prognosis, but their potential in stomach adenocarcinoma (STAD) remains unknown. Therefore, the clinical significance of POLE and POLD1 mutations in STAD was evaluated. Methods: A summary of POLE/POLD1 mutations and clinical characteristics was performed on all 613 STAD samples, from which 360 samples were screened for analysis of the potential clinical relevance of POLE/POLD1 mutations to prognosis and immunotherapy. Results: The total frequency of both POLE and POLD1 mutations was 7.99% in STAD patients, correlating with an older age of onset and more frequently in the antrum anatomic subdivisions. Several genes that related to prognosis and immunotherapy also had high mutation frequencies in POLE/POLD1mutant STADs. Furthermore, the STAD subgroup with POLE/POLD1 mutations had longer progression free survival (PFS) and overall survival (OS) in the subpopulation under 80. More importantly, STAD patients with POLE/POLD1 mutations exhibited adaptive immune resistance tumor microenvironment (TME) and deficient mismatch repair (dMMR) status, and possessed significantly higher PD-L1 expression level, higher tumor mutational load (TMB), higher microsatellite instability (MSI) percentage, and lower aneuploidy score, all of which may have potential implications for better ICIs treatment outcomes. Conclusions: POLE and POLD1 mutations are promising useful biomarkers to improve the clinical efficiency of practicing precision medicine in STAD patients, including as positive prognostic markers and predictive biomarkers of immunotherapy outcomes for STAD patients.