e15590 Background: Colorectal cancer (CRC) is a malignant tumor of the digestive system, known for its high incidence and mortality rates worldwide. Although colorectal cancer brain metastases (CRCBM) are uncommon, they are extremely deadly and greatly affect patient survival and prognosis.This research seeks to explore the genomic changes and clonal evolution in CRCBM, focusing on driver mutations, CNVs, and their potential effects on treatment strategies. Methods: We performed a comprehensive analysis on a cohort of 26 CRC patients and a cohort of 55 patients with CRCBM, including non-synchronous matched primary samples from 13 individuals. This analysis encompassed the characteristics of various mutations, including genomic alterations, distribution and frequency patterns.We also examined driver genes and CNVs across the three cohorts. For the 13 matched cases with both primary and metastatic samples, we identified putative driver genetic events resulting from clonal evolution that could facilitate metastasis and examined the clonal evolution process. Additionally, we compared HLA typing, neoantigens, and pathways affected by genetic alterations in patients with brain metastases to enhance our understanding of the mechanisms that may determine the specific site of metastasis. Results: Compared to primary CRC, CRCBM demonstrated increased microsatellite instability (MSI), an elevated tumor mutational burden (TMB), and a greater number of predicted neoantigens. Nevertheless, an analysis of neoepitope-major histocompatibility complexbinding affinity indicated that the potential efficacy of immunotherapy in patients with CRCBM may be limited. Within the CRCBM cohort, we identified novel driver mutations, including those in AMER1, TCF7L2, and MAP2K7. Clonal evolution analysis revealed early mutations in genes such as LRP1B, CSMD3, and ZFHX3 in primary CRC tumors. In contrast, the brain metastases exhibited a distinct molecular trajectory characterized by early mutations in KMT2D, ZEB1, and TCF7L2, suggesting a unique molecular evolution pathway for CRCBM. Conclusions: This study offers significant insights into the clonal evolution of primary colorectal cancers and their brain metastases. The findings underscore the complexity of tumor evolution, with early mutations initiating tumorigenesis and subsequent subclonal mutations contributing to metastasis and treatment resistance. These results emphasize the importance of clonal diversity in the progression of CRC and suggest that targeting specific clones may present novel therapeutic strategies for CRCBM. Further investigation into clonal evolution and its functional implications in CRCBM could enhance our understanding of metastasis and improve treatment outcomes.
Niu et al. (Thu,) studied this question.