Potential Role of APC Mutations in the Prognosis and Targeted Therapy of Gastric Adenocarcinoma

Background: Adenomatous polyposis coli (APC) gene, an oncogene, has been implicated in stomach adenocarcinoma (STAD), which is a common type of gastric cancer (GC). Although the relationship between APC gene mutations and gastric adenocarcinoma has been comprehensively studied, the potential role of these mutations in the prognosis and targeted therapy remains known.

Methods: We utilized The Cancer Genome Atlas (TCGA) database to obtain gene expression matrices, clinical information, and mutation data from patients with STAD. The mutation status of the APC gene was analyzed, and its correlation with tumor mutational burden (TMB), microsatellite instability (MSI), and clinical prognosis in STAD was investigated. Gene set enrichment analysis (GSEA) was conducted to explore the pathological role of APC gene mutations in STAD metabolic pathways. Drug sensitivity analysis was conducted to identify potential targeted antitumor drugs for patients with APC gene mutations in gastric adenocarcinoma.

Results: The results revealed that 88% (46/52) of STAD samples had nonsynonymous mutations. The mutation group exhibited a significantly higher TMB than the wild-type group (p < 0.001), and the percentage of high MSI (MSI-H) was significantly higher in the mutation group than in the wild-type group (p < 0.001). Patients with APC mutations had a worse prognosis than those with APC wild-type (p = 0.009). The APC gene mutation group displayed significant enrichment in amino acids, RNA, and several pathways (|NES| > 1 and nominal p value < 0.01). Compared to the wild-type group, the mutation group exhibited a higher infiltration proportion of natural killer (NK) cells resting and eosinophils, whereas a lower infiltration proportion of monocytes and resting mast cells (p value < 0.05). AZD5991 exhibited significant sensitivity in patients with STAD carrying APC mutations (p = 0.028).

Conclusion: APC gene mutations play a crucial role in the prognosis, molecular characteristics, and potential therapeutic strategies for gastric adenocarcinoma.