Genetic landscape of colorectal cancer. A pilot study in the Russian Federation

The purpose of the study was a comprehensive analysis of molecular genetic changes in tumor and normal tissues of patients with colorectal cancer using whole-genome sequencing to identify de novo mutations, microsatellite instability patterns, and mutational signatures associated with tumor development.

Material and Methods. A single-time cross-sectional study was conducted in the Kaliningrad region. Colorectal cancer samples were analyzed using whole-genome next-generation sequencing (WGS). The human reference genome GRCh38.p14 was used for read mapping. Bioinformatic analysis of signatures was conducted separately for each patient. 71 pairs of samples were sequenced: complete genomes of tumor biopsies and DNA isolated from blood samples for 71 patients. The average age among the analyzed patients was 69 years, with a median of 71 years.

Results. Genetic alterations associated with tumor development and progression, as well as potential therapeutic targets were identified. Using the Oncovar database, 151 driver mutations were detected in 62 patients. Using the CIVIC database, 70 marker mutations were found in 45 patients. It was found that the most common driver mutations in the study cohort were mutations in the KRAS gene (KRAS:G35T, KRAS:G35A, KRAS:G38A), associated with tumor resistance to Panitumumab and Cetuximab. The frequency of the most common driver mutations in the study cohort was low, indicating high heterogeneity of colorectal cancer. Analysis of the tumor mutational burden (TMB) revealed a high average value of 5.5, suggesting a significant potential of immunotherapy in colorectal cancer treatment. In the studied population, the mutational signatures SBS1, SBS5, and SBS39 were the most common.

Conclusion. The identified diversity of genomic changes may be associated with DNA replication errors, exposure to external factors, and genetic predisposition. The pattern of mutational signatures was very similar among all patients in the studied samples, suggesting a single mutagenic factor is involved in the development of colorectal cancer in all patients.

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