Mutation Analysis of TMB-High Colorectal Cancer: Insights Into Molecular Pathways and Clinical Implications

Area of Science:

• Oncology
• Genetics
• Cancer Research

Background:

• Colorectal cancer (CRC) pathogenesis is linked to common mutations in APC, TP53, and KRAS.
• Alternative carcinogenic mechanisms involving BRAF mutations are proposed for specific CRC subtypes.
• Understanding genetic drivers in high tumor mutation burden (TMB) CRC is crucial for identifying novel therapeutic targets.

Purpose of the Study:

• To characterize mutations in TMB-high CRC lacking common driver oncogenes.
• To investigate the relationship between mutation profiles, clinical features, and carcinogenesis mechanisms.
• To identify early genetic events in TMB-high CRC development.

Main Methods:

• Targeted sequencing of CRC tumors with linked clinical data.
• Analysis of mutation frequencies, tumor location, and microsatellite instability (MSI) scores.
• Variant allele frequency analysis to infer early mutational events.

Main Results:

• TMB-high CRC predominantly occurred on the right colon.
• These tumors exhibited lower KRAS and higher BRAF mutation frequencies, alongside elevated MSI scores.
• Mutations in DNA damage response (e.g., ATM, POLE) and MSI genes (e.g., MSH2, MSH6) were identified as potential early events.

Conclusions:

• TMB-high CRC presents a distinct molecular phenotype.
• Mutations in DNA damage response and mismatch repair genes may initiate the serrated pathway in CRC.
• These findings offer insights into CRC carcinogenesis and potential therapeutic strategies.