Genomic diversity and BCL9L mutational status in circulating tumor cells predict overall survival in metastatic colorectal cancer

Abstract Background Metastatic colorectal cancer (mCRC) remains a major cause of cancer-related mortality, but few noninvasive biomarkers exist to track disease progression or inform treatment strategies. Circulating tumor cells (CTCs) offer a minimally invasive source of tumor material, yet the prognostic significance of their genomic diversity remains unclear. Methods We conducted whole-exome sequencing of CTC pools from 29 mCRC patients to characterize their mutational landscape and assess associations with overall survival. Results Our analysis revealed substantial variation in mutational burden among patients, with all CTC pools harboring non-silent mutations in key CRC driver genes. Higher genomic diversity in CTC pools was significantly associated with reduced overall survival. Additionally, non-silent mutations in BCL9L emerged as a strong predictor of patient survival. Conclusion Genomic diversity and BCL9L mutational status in CTC pools emerged as strong predictors of survival in mCRC, underscoring the potential of CTC genomic profiling as a minimally invasive and clinically relevant prognostic tool in mCRC.