Effect of chemotherapy on passenger mutations in metastatic colorectal cancer

Metastatic colorectal cancer (mCRC), particularly microsatellite stable (MSS) cases, often exhibits limited responsiveness to immunotherapy, leaving chemotherapy as the primary treatment option. While chemotherapy effectively targets tumor cells, its impact on the broader mutational landscape, including passenger mutations in large genes such as Titin (TTN), remains poorly understood. Passenger mutations, traditionally deemed biologically inert, may reflect tumor mutational burden (TMB) and influence treatment outcomes. In our study involving whole exome sequencing of paired primary and metastatic tumor samples from 22 mCRC patients, recurrent driver mutations in APC, KRAS, and TP53 were consistently observed. However, passenger mutations in large genes, particularly TTN, were notably enriched in chemonaïve specimens and associated with higher TMB. Chemotherapy-treated samples exhibited a significant reduction in these mutations, suggesting selective depletion of hypermutated subclones. Our findings demonstrate that chemotherapy may selectively reduce passenger mutations in mCRC, potentially influencing the persistence of hypermutated subclones. This highlights the potential role of passenger mutation patterns and TMB as biomarkers for treatment response and raises the hypothesis that they could help guide immunotherapy considerations for patients with MSS mCRC.