Impact of chemotherapy exposure on tumor mutation burden in advanced colorectal cancer.

The determinants of tumor mutation burden (TMB) in microsatellite-stable (MSS) colorectal cancer (CRC) remain unclear. This study examined the impact of clinical, environmental, and genomic factors on TMB in advanced CRC using comprehensive genomic profiling (CGP). Eighty-eight patients with advanced or recurrent CRC who underwent CGP were analyzed and compared with 701 MSS CRC cases from a public dataset. Associations between TMB and clinicopathological, environmental, and genomic factors were evaluated. The number of prior chemotherapy regimens was significantly associated with higher TMB. No associations were observed between TMB and alcohol use, smoking history, or specific chemotherapeutic classes. Although variants in POLE or POLD1 were detected, all were non-pathogenic and were not linked to elevated TMB. The top 3 three most frequent genes were consistent with those in the public dataset, although variant frequencies were higher in this cohort. In MSS TMB high CRC, elevated TMB may reflect cumulative treatment-related effects rather than intrinsic hypermutagenic mechanisms, highlighting the need to interpret TMB in the context of therapeutic history.