Population-based analysis of CHEK2 pathogenic variants and their functional role in breast cancer development

CHEK2 is an essential tumor suppressor gene involved in DNA damage response and cell cycle regulation, and its germline variants are known to increase breast cancer suscept i bility. However, evidence regarding the clinical and molecular relevance of CHEK2 variants in Central Asian populations remains limited. This study aimed to assess the distribution and clinicopathological significance of the CHEK2 IVS2+1G>A and Ile157Thr polymorphisms in Uzbek women with breast cancer, with emphasis on molecular subtypes, immunohistochemical markers, and menopausal status. The study included 200 breast ca n cer patients and 100 conditionally healthy controls. CHEK2 polymorphisms were identified using PCR-based genotyping. Associations with clinicopathological features and immunohistochemical markers (ER, PR, HER2/ neu , Ki -67) were evaluated using odds ratios, relative risk estimates, χ² test, and Fisher’s exact test. The IVS2+1G>A variant was significantly associated with hormone receptor–positive tumors, predominantly luminal subtypes, and was more frequently observed in postmenopausal patients. In contrast, the Ile157Thr polymorphism showed a wider age distribution and was linked to a heterogeneous molecular profile, including highly proliferative and triple-negative breast cancer subtypes. Distinct patterns of hormone receptor expression and Ki-67 levels suggested variant-specific biological behavior. These findings demonstrate that CHEK2 polymorphisms differentially influence breast cancer risk and phenotype in a menopause-dependent manner. The results highlight the importance of population-specific genetic profiling and support the potential utility of CHEK2 variants in personalized risk stratification for breast cancer in Uzbek wo m en.

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