PIK3CA-Mutated Colorectal Cancer Exhibits a Unique Gut Dysbiosis Profile: Insights from a Nationwide Pan-Cancer Screen in Japan

Background While gut microbiota composition is increasingly linked to various solid tumors, the specific association with oncogenic driver mutations across different cancer types is not fully understood. PIK3CA mutations are known drivers in colorectal cancer (CRC) associated with therapeutic resistance. Methods and Results We conducted an analysis of fecal gut microbiota using 16S ribosomal RNA sequencing and tumor genomic profiling from patients with solid tumors in which antibiotics were not prescribed for the analysis, as part of the MONSTAR-SCREEN study, a nationwide cancer genome and microbiome screening project in Japan. Our pan-cancer analysis of 1,414 solid tumors revealed that PIK3CA -mutated CRC was specifically associated with a significant decrease in gut microbiota diversity (effect size: tissue, -0.87 [p = 0.018]; blood, -0.53 [p = 0.024]), a finding not consistently observed in other solid tumors. Within the 84 CRC cases, 10 (11.9%) harbored PIK3CA mutations. Further analysis of these CRC cases demonstrated that PIK3CA mutation was associated with a lower abundance of Desulfovibrio (effect size: -0.36, p = 0.046) and Oscillospira (effect size: -0.31, p = 0.027) and predicted enrichment of the bile acid biosynthesis pathway (effect size: 0.37, p = 0.045). Conclusion This pan-cancer screen highlights PIK3CA -mutated CRC as a distinct entity characterized by significant gut dysbiosis. The combination of reduced diversity, specific bacterial depletion, and altered bile acid metabolism suggests that the gut microbiome is a key feature of PIK3CA -driven tumorigenesis in the colon. These findings nominate PIK3CA -mutated CRC as a promising candidate for microbiota-targeted interventions.