Next-Generation Sequencing-Based Detection of KRAS G12D Variants in Colorectal Cancer: A Retrospective Cohort Study

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Abstract
Purpose: Colorectal cancer (CRC) is a highly aggressive malignancy of the digestive system. Somatic variants in the Kirsten rat sarcoma virus oncogene homolog (KRAS) gene have a significant influence on CRC progression and serve as key predictors of resistance to anti-epidermal growth factor receptor (EGFR) therapy. This study aimed to determine the prevalence of KRAS variants, with a particular focus on G12D variants, which represent potential for targeted therapy. Methods: A cohort of 73 CRC patients was evaluated between January 2021 and August 2024. Next-generation sequencing (NGS) was performed using the Archer® VariantPlex® Solid Tumor Focus v2 (Integrated DNA Technologies, Inc., Boulder, CO, USA) assay on the Illumina NextSeq platform. The gene panel included 20 genes frequently mutated in solid tumors, assessing point variants, insertions/deletions, and microsatellite instability. Results: The cohort of the study comprised 38 female (52%) and 35 males (48%) patients aged 31–83 years (mean, 58.77 ± 12.72). No significant difference in mean age was observed between males and females (60.31 ± 12.32 vs. 57.34 ± 13.08; p > 0.05). KRAS variants were detected in 30 patients (41%). Among these, the variant frequencies for G12D, G12V, and G13D were 7%, 11%, and 11%, respectively. Additionally, one patient (1.4%) harbored an ERBB2 amplification. All KRAS variants were associated with resistance to anti-EGFR therapy. Notably, KRAS G12D variants have potential responsiveness to targeted therapy, while human epidermal growth factor receptor 2 (ERBB2) amplifications are responsive to anti-HER2 treatments and resistant to anti-EGFR therapies. Conclusions: These findings highlight the clinical significance of KRAS variant profiling for prognosis and personalized treatment planning in CRC. Moreover, assessing KRAS variants individually is crucial to better understanding treatment response and exploring the potential targeted therapy in CRC management.

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