Defining prostaglandin-driven dysregulation in <i>PIK3CA</i> -mutant colorectal cancers: A real-world multi-omic analysis.

Abstract

3667 Background: PIK3CA mutations occur in a meaningful subset of colorectal cancers (CRC) and have been associated with improved clinical outcomes in patients receiving aspirin and celecoxib. PIK3CA activation has been linked to upregulation of PTGS2 and downstream prostaglandin E2 signaling, promoting tumor-associated inflammation, angiogenesis, and immune suppression. Aspirin-mediated inhibition of prostaglandin synthesis may therefore counteract this biology in PIK3CA -mutant CRC, although the underlying molecular mechanisms remain incompletely characterized. Methods: A total of 823 CRC tumor samples underwent DNA-based next-generation sequencing, with matched whole-transcriptome sequencing (20,802 genes) available for 263 tumors. PIK3CA mutation prevalence, hotspot distribution, and co-mutation patterns were evaluated. A predefined prostaglandin–inflammation gene signature ( PTGS2, PTGES, PLA2G4A, IL6, STAT3, PTGER4, VEGFA, IDO1 ) was assessed (log₂ fold change &gt;2). Coordinated signature activation was quantified. Results: PIK3CA mutations were detected in 12.8% (105/823) of CRCs and were more frequent in right than left-sided tumors (15.2% vs 11.1%). Among PIK3CA -mutant tumors, 25.7% were KRAS/NRAS/BRAF wild type (WT), while KRAS co-mutation predominated (65.7%); NRAS and BRAF co-mutations were rare (1.9% and 5.7%), as summarized in the Table. ERBB2 alterations were rare in PIK3CA -mutant tumors (4.8%) and in KRAS/NRAS/BRAF -mutant tumors (3.2%,), while they were enriched in the KRAS/NRAS/BRAF WT subgroup (8.9%). Among PIK3CA -mutant tumors, key prostaglandin biosynthesis genes PTGS2, PTGES , and PLA2G4A were overexpressed in 8.8% (3/34), while downstream inflammatory and immune-modulatory genes including IL6, STAT3, IDO1 , and CD274 were overexpressed in 11.8% (4/34). Prostaglandin–inflammation signature activation was more frequent in KRAS WT than KRAS -co-mutant PIK3CA tumors (57.1% [4/7] vs 51.9% [14/27]). Among microsatellite-stable (MSS) tumors, 47.6% (10/21) showed signature activation. Tumors with combined PIK3CA mutation and prostaglandin pathway activation showed enrichment of inflammatory, angiogenic, and epithelial–mesenchymal transition–related programs. Conclusions: PIK3CA -mutant CRC represents a biologically distinct subset characterized by coordinated activation of prostaglandin-driven inflammatory and immune-modulatory pathways. These features provide a mechanistic rationale for the reported aspirin benefit in PIK3CA -mutant CRC and support integrated genomic–transcriptomic profiling to guide biomarker-driven therapeutic strategies. Prevalence of PIK3CA alterations and co-mutations in CRC. Biomarkers Prevalence (%; n=105) PIK3CA mutation (overall) 12.8 (105/823) E545K 21.9 E542K 19 H1047R 16.2 H1047L 6.7 Q546K 5.7 PIK3CA + KRAS 65.7 PIK3CA + NRAS 1.9 PIK3CA + BRAF 5.7 PIK3CA + KRAS/NRAS/BRAF WT 25.7