Clinical and molecular implications of sex differences in surgically treated early-onset gastric cancer.

Background: Gastric cancer predominantly occurs in middle-aged and elderly individuals, whereas cases arising in individuals before the age of 45 years are defined as early-onset gastric cancer (EOGC). The biological and clinical characteristics of EOGC remain insufficiently understood. This study aimed to investigate the sex-specific clinicopathological and molecular features of EOGC. Methods: We retrospectively analysed a large cohort of 4,903 gastric cancer patients, including 410 EOGC patients, to compare survival outcomes and clinicopathological features between EOGC patients and late-onset gastric cancer (LOGC) patients and between male and female EOGC patients. Additionally, transcriptome and genome sequencing data from a public Korean EOGC cohort were analysed to identify sex-specific molecular alterations, which were further validated in a Chinese EOGC cohort by using immunohistochemistry. Results: Overall survival was significantly shorter in the LOGC group than in the EOGC group. In contrast, EOGC patients were characterized by a greater proportion of females, later T and N stages, more tumours located in the middle third of the stomach, a higher prevalence of diffuse and signet ring cell types, poorer differentiation, smaller tumour size, and lower HER2- and Ki67-positive rates. Among patients with EOGC, females accounted for the majority but had worse outcomes; these female EOGC patients were diagnosed earlier, presented with high proportions of lymph node metastasis and advanced stage, and a higher incidence of differentiated diffuse-type tumours than male EOGC patients. Molecular analyses further revealed female-specific HOXB8 expression upregulation, increased CDH1 mutation numbers, and distinct immune infiltration patterns, which were validated in a Chinese cohort. Conclusion: EOGC displays pronounced sex-specific clinicopathological and molecular features. These findings highlight the need for sex-based considerations in understanding EOGC biology and tailoring clinical management strategies.