Clinical and pathological study of mutL homolog 1-deficient gastric cancer and the search for background gene expression changes

Microsatellite instability caused by impaired mismatch repair (MMR) is referred to as MSI-high, and gastric cancers with this feature are classified as MSI-high gastric cancer. The loss-of-function of mutL homolog 1 (MLH1) is a major cause of MSI-high gastric cancer. This study aimed to investigate the role of MLH1 in the gastric cancer pathogenesis and to characterize MLH1-deficient cases compared with MLH1-preserved cases, focusing on tumor-related factors and patient background. We also aimed to identify the genes potentially associated with phenotypic differences. Patients who underwent gastrectomy for gastric cancer between June 2019 and December 2023 and had histopathological diagnoses indicating MLH1 expression were included in this study. Clinicopathological correlations were examined in 85 patients, including 14 MLH1-deficient and 71 MLH1-preserved cases. Finally, the gene characteristics of MLH1 deficiency were analyzed for correlations with MLH1 expression using cBioPortal. The MLH1-deficient group showed significant tumor depth progression, reduced alcohol consumption, fewer Helicobacter pylori infections, and low lymphocyte percentages in preoperative blood tests. Aldehyde dehydrogenase 1A1, nuclear factor kappa B1, and programmed death-ligand 1 were identified as candidate genes associated with this phenotype. We observed differences in the gastric adenocarcinoma properties according to MLH1 expression and identified important candidate genes to elucidate the pathological mechanisms.