Genomic characterization of patients with colorectal cancer

Hereditary colorectal cancer (CRC) predisposition syndromes account for 5-10% of all diagnosed CRC cases. Lynch syndrome (LS), Familial Adenomatous Polyposis (FAP), and MUTYH-associated polyposis (MAP) are well-characterized hereditary syndromes known to contribute to colorectal cancer predisposition. However, other inherited genetic factors beyond these established conditions remain underexplored. Recent advancements in next-generation sequencing (NGS) have facilitated the identification of germline pathogenic variants (gPV) in cancer predisposition genes, enhancing diagnostic and management strategies for hereditary CRC syndromes. Using this technology, this study aimed to investigate the genetic causes of CRC in 23 Turkish patients belonging to 23 different families.

Patients with a personal or familial history of colorectal cancer (CRC) or polyposis were selected from a cohort of 54 individuals examined between 2019 and 2022. Genetic testing was performed using the TruSight^® Cancer and Qiaseq panels on the Illumina NextSeq next-generation sequencing (NGS) platform.

A total of 23 variants were identified, including 10 pathogenic or likely pathogenic variants, 5 of which were novel. These germline pathogenic/likely pathogenic variants were detected in the key genes MLH1, MSH6, PMS2, and APC, which are associated with LS and FAP. Variants were also found in other genes, including FANCC, CHEK2, ATM, and MUC16. Additionally, 13 variants of uncertain significance (VUS) were identified, 5 of which were novel. These VUS were detected in the genes MUTYH (linked to MAP), ATR, XRCC3, PALB2, ATM, SYNE1, RAD51D, NF1, ABRAXAS1, ERBB2, FGFR, and CHEK2, necessitating further investigation to determine their potential role in CRC predisposition.

These findings highlight the utility of NGS in identifying germline variants linked to hereditary CRC syndromes and emphasize the need for functional studies to assess the pathogenicity of VUS.