The importance of expression changes in Homologous Recombination genes in cases of unknown clinical significance variants, mutations and normal findings of BRCA 1 and BRCA 2 genes in breast cancer patients

Breast cancer is one of the most common types of cancer among women and constitutes a major health problem worldwide. It covers one quarter of all cancer cases in women. 16% of cancer deaths in women are caused by breast cancer. Approximately 1% of all cancers result from defects in repair of DNA strand breaks transmitted germline. The BRCA1 and BRCA2 genes are high-penetrance tumor suppressor genes that play a critical role in the repair of DNA double-strand breaks via homologous recombination (HR) and are responsible for approximately 10% of breast cancers. The clinical significance of many variants in these genes is not yet fully understood. In this study, we aimed to evaluate the clinical significance of variants in BRCA1 and BRCA2 by investigating their effects on the expression of other HR genes. Our study included 37 patients who underwent BRCA1 and BRCA2 whole gene sequence analysis, underwent surgery, and had invasive carcinoma as a result of pathology biopsy. According to the alterations detected in BRCA1 and BRCA2 genes, our patients were divided into three groups as follows: those with BRCA2 rs4987117 (T1915M) benign variant, those with variants with allele frequencies below 5% (VUS), and those with variants with allele frequencies above 5%. It was examined whether these three groups in BRCA1 and BRCA2 were effective on the expression of nine other genes (ATM, BARD1, BRIP1, CHEK2, MRE11A, NBN, PALB2, RAD51C, RAD51D) within the homologous recombination mechanism in which they function together. As a result of the statistical evaluation between the groups, it was observed that the expression of the ATM gene increased in the T1915M group compared to the VUS group. v Likewise, it was determined that the expression of the CHEK2 gene was increased in the T1915M group compared to the other patient group with an allele frequency above 5%. A close relationship of the T1915M change with CHEK2 has been reported in the literature. The results of our study support this relationship. However, while it has been reported that the T1915M genotype is associated with the lack of CHEK2 protein in the cell, increased CHEK2 expression was detected in our study. It is reported that the expression of the ATM gene decreases in case of BRCA mutations. In our study, it was found that its expression increased in patients with the T1915M genotype compared to the other VUS group. This variation, which is classified as benign, our finding may provide evidence for evaluating as a likely pathogenic variation. As a result, the presence of variations in BRCA1 or BRCA2 genes may affect the expression of other HR genes with which they function together. This effect may vary depending on the affected domains of the gene products.