BACKGROUND: Progastricsin/Pepsinogen C (PGC) is an aspartyl endoprotease predominantly expressed by gastric fundic and chief cells, with additional expression reported in select extragastric tissues. While increased PGC expression has been described in several malignancies, progressive downregulation of PGC has been observed along the spectrum of gastric inflammation to carcinoma. However, data on PGC expression in stomach adenocarcinoma (STAD) from South Asian populations remain limited. Given the distinct genetic, dietary, and environmental context of this region, we investigated the expression profile and epigenetic regulation of PGC in STAD patients from Pakistan. METHODS: This observational study integrated experimental analysis of human gastric tissue samples with in silico interrogation of publicly available datasets. Snap-frozen gastric tissues from histopathologically confirmed STAD patients were analyzed for PGC expression using quantitative polymerase chain reaction and immunohistochemistry. Normal gastric tissues, stratified by Helicobacter pylori infection status, were used as controls. Public transcriptomic and DNA methylation datasets were analyzed to validate expression patterns, assess promoter methylation status, and explore associations with survival outcomes. RESULTS: The mean age of STAD patients was 53 years (range: 34-72), with a male predominance. PGC expression was consistently downregulated in STAD tissues compared with non-tumour gastric controls. All local cohort samples were negative for Helicobacter pylori, limiting assessment of infection-specific effects; however, in silico analyses suggested that PGC downregulation may occur independently of infection status. Independent dataset analyses confirmed reduced PGC expression in STAD. Increased promoter methylation of the PGC gene was observed in tumour samples and was inversely associated with gene expression, suggesting epigenetic silencing. Overall PGC expression was not significantly associated with survival in unstratified analyses; however, exploratory subgroup analyses suggested potential ethnicity- and gender-related patterns that did not reach statistical significance. CONCLUSIONS: PGC is consistently downregulated in stomach adenocarcinoma in a South Asian population, with promoter hypermethylation likely contributing to its suppression. Although not independently associated with overall survival, exploratory subgroup observations highlight the need for population- and context-aware analyses. These findings support further evaluation of PGC within integrated biomarker strategies.
Qureshi et al. (Mon,) studied this question.