Klein, N.; Shweiki, D.

Significant sex-related differences exist in gastric cancer, yet the molecular basis remains unclear. Tumor mutational burden (TMB) correlates with successful immune checkpoint inhibitor therapy, but TMB varies across different cancers, and evidence regarding sex-specific differences remains inconsistent. We analyzed sex-specific single-nucleotide mutations in gastric cancer using The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) dataset and found that females had significantly higher autosomal TMB. We identified 1,052 sexually dimorphic genes, with enrichment analyses highlighting distinct biological pathways in each sex. These genes overlap key cancer pathways, emphasizing their role in tumorigenesis. Differing co-mutation pattern, with females exhibiting more stable patterns, enabled a machine-learning model to predict tumor sex from mutation profiles. Our findings suggest that male and female gastric cancers could represent distinct diseases, underscoring the need for sex-specific diagnostic markers and personalized therapies.