Germline pathogenic variant spectrum and prevalence among colorectal cancer patients undergoing multigene panel testing in Kazakhstan

Colorectal cancer (CRC) is a type of malignancy with a hereditary component. In Kazakhstan, the spectrum of germline pathogenic variants (PV) among individuals with CRC remains limited. In this study, multigene panel testing was performed on a Kazakhstani cohort of CRC patients and their relatives to better understand genetic risk factors. The study included 155 CRC patients and 92 healthy relatives. Whole coding regions (> 1700 exons) and flanking noncoding sequences of 94 cancer-associated genes were analyzed using the Illumina TruSight Cancer NGS panel on blood-derived DNA. Results showed that 30 patients (19.4%) carried 31 PVs. Overall, 34.2% of patients had a family history of cancer, including 9.7% who had a family history of CRC. The most frequent germline PVs were in CHEK2 (22.58%) and APC (12.91%), followed by MLH1 (6.46%), MSH2 (6.46%), MSH6 (6.46%), MUTYH (6.46%), and BRCA1 (6.46%). Missense (35.5%) and frameshift (32.3%) variants predominated. A high number of PVs was found in individuals aged 18-44 years. Among overall identified PVs, six were novel: APC c.3405T > G, APC c.419_422delAGAG, PMS1 c.1258delC, MLH1 c.1291_1292delAT, NBN c.877delA, and EPCAM c.184 + 1G > A. The observed prevalence of clinically actionable PVs in both patients and their relatives highlights the potential clinical value of multigene panel testing and cascade screening strategies in Kazakhstan.