Pathogenic Germline Variants in Very Early Onset Colorectal Cancer Patients in Kazakhstan
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Authors
Nurlan Baltayev
Almaty Oncology Center, Almaty, 050000, Kazakhstan
Saltanat Abdikerim
Institute of Genetics and Physiology, Almaty, 050060, Kazakhstan
Georgiy Afonin
Asfendiyarov Kazakh National Medical University, Almaty, 050012, Kazakhstan
Dilyara Kaidarova
Asfendiyarov Kazakh National Medical University, Almaty, 050012, Kazakhstan
Gulnur Zhunussova
Institute of Genetics and Physiology, Almaty, 050060, Kazakhstan
Abstract
Background: The incidence of colorectal cancer (CRC) in young individuals has been increasing over the past 20 years. In Kazakhstan, CRC incidence in young patients has risen by approximately 2.3% annually. Among early-onset (EO) CRC cases, about 30% of patients carry germline mutations associated with hereditary cancer predisposition syndromes, while 20% have familial CRC. In Kazakhstan, only a few NGS-based studies have been published, focusing on the frequency and spectrum of pathogenic variants (PVs) in young patients.
Objective: To investigate the spectrum and prevalence of PVs in EO-CRC patients.
Materials and Methods: In this study, we performed gene-panel NGS analysis on germline DNA of 94 established/candidate cancer predisposing genes in 66 individuals with sporadic and familial EO-CRC (<45 years).
Results: PVs were identified in 25.7% of patients, affecting the following genes: CHEK2, APC, BRCA1, MSH2, PMS1, TP53, EPCAM, NSD1, PMS2, and NBN. The PVs were represented by missense (29.4%), frameshift (29.4%), nonsense (23.5%), and splice-site (17.6%) variants. Three novel PVs were detected in PMS1, NBN, and EPCAM. The median age at diagnosis was 36.8 years. A positive family history of CRC or other cancers was reported in 33.3% of cases. In our cohort, PVs were distributed among three gene groups: MMR genes (29.4%, 5/17), genes associated with polyposis syndromes (11.8%, 2/17), and genes not typically associated with CRC (58.8%, 10/17). Two CHEK2 variants—missense c.470T>C and frameshift c.1100delC—were recurrent. Notably, PVs in young patients were predominantly identified in those without a family history of cancer.
Conclusions: Sporadic cancer cases at a young age are highly suggestive of an underlying genetic predisposition. Although novel cancer genes are associated with CRC in only a small percentage of cases, pathogenic variants in these genes should nevertheless be included in NGS- based CRC panels.
Key words: colorectal cancer, young patients, pathogenic variants, NGS.