Background: PIK3CA is the second most frequently mutated gene in cancers and is extensively studied for its role in promoting cancer cell resistance to chemotherapy or targeted therapy. However, PIK3CA functions have mostly been investigated at a lower-order genetic level, and therapeutic strategies targeting PIK3CA mutations have limited effects. Here, we explore crucial factors interacting with PIK3CA mutations to facilitate a significant marginal survival effect at the higher-order level and identify therapeutic strategies based on these marginal factors.
Methods: Mutations in stomach adenocarcinoma (STAD), breast adenocarcinoma (BRCA), and colon adenocarcinoma (COAD) samples from The Cancer Genome Atlas (TCGA) database were top-selected and combined for Cox proportional-hazards model analysis to calculate hazard ratios of mutation combinations according to overall survival data and define criteria to acquire mutation combinations with considerable marginal effects. We next analyzed the PIK3CA + HMCN1 + LRP1B mutation combination with marginal effects in STAD patients by Kaplan-Meier, transcriptomic differential, and KEGG integrated pathway enrichment analyses. Lastly, we adopted a connectivity map (CMap) to find potentially useful drugs specifically targeting LRP1B mutation in STAD patients.
Results: Factors interacting with PIK3CA mutations in a higher-order manner significantly influenced patient cohort survival curves (hazard ratio (HR) = 2.93, p-value = 2.63 × 10- 6). Moreover, PIK3CA mutations interacting with higher-order combination elements distinctly differentiated survival curves, with or without a marginal factor (HR = 0.26, p-value = 6.18 × 10- 8). Approximately 3238 PIK3CA-specific higher-order mutational combinations producing marginal survival effects were obtained. In STAD patients, PIK3CA + HMCN1 mutation yielded a substantial beneficial survival effect by interacting with LRP1B (HR = 3.78 × 10- 8, p-value = 0.0361) and AHNAK2 (HR = 3.86 × 10- 8, p-value = 0.0493) mutations. We next identified 208 differentially expressed genes (DEGs) induced by PIK3CA + HMCN1 compared with LRP1B mutation and mapped them to specific KEGG modules. Finally, small-molecule drugs such as geldanamycin (connectivity score = - 0.4011) and vemurafenib (connectivity score = - 0.4488) were selected as optimal therapeutic agents for targeting the STAD subtype with LRP1B mutation.
Conclusions: Overall, PIK3CA-induced marginal survival effects need to be analyzed. We established a framework to systematically identify crucial factors responsible for marginal survival effects, analyzed mechanisms underlying marginal effects, and identified related drugs.
Keywords: Cancer prognosis; Higher-order genetic interaction; Marginal effect; PIK3CA mutation; Stomach adenocarcinoma.