A Cross-Sectional Study of CHEK2 Pathogenic Variants: Cancer Risk Spectrum and Clinical Insights

Aims: CHEK2 is a tumor suppressor gene involved in DNA damage response and a moderate-risk gene for breast cancer. However, its role in other malignancies remains unclear, and the clinical impact of biallelic CHEK2 mutations is not well understood. This study aims to expand the cancer risk spectrum of CHEK2, including rare tumors, and to provide insights into the phenotypes associated with biallelic mutations and Multiple Inherited Neoplasia Alleles Syndrome (MINAS). Materials and Methods: We analyzed 40 individuals from 34 families carrying CHEK2 mutations, identified via multigene panel testing for hereditary cancer syndromes. Next-generation sequencing was performed for the probands, and segregation analysis in affected relatives was conducted using Sanger sequencing. Clinical data, including cancer type, age at diagnosis, and family history, were obtained from medical records and clinical evaluations. Results: We identified 16 distinct CHEK2 mutations, with c.1427C>T (p.Thr476Met) being the most frequent. Breast cancer was the most common diagnosis (75%), followed by thyroid cancer and rare tumors, including pancreatic neuroendocrine and cerebellopontine angle tumors. Multiple primary cancers occurred in 15% of patients, and 10% had MINAS, harboring additional variants in genes like PTEN and BRCA2. Biallelic CHEK2 mutations were linked to severe phenotypes, including bilateral breast cancer and adolescent-onset polyposis. Conclusions: Our findings broaden the CHEK2-associated cancer spectrum, extending beyond breast cancer to include rare malignancies and complex presentations. The identification of biallelic mutations and MINAS underscores the need for comprehensive genetic testing and tailored surveillance. These insights are crucial for refining risk assessment, enhancing prevention, and improving clinical management for individuals harboring CHEK2 mutations.