SPECTRUM OF BRCA MUTATIONS DETECTED BY NEXT-GENERATIONSEQUENCING IN PATIENTS WITH HEREDITARY PREDISPOSITION TO BREASTAND OVARIAN CANCER

Abstract

Hereditary predisposition to breast and ovarian cancer is most commonly caused by mutations in the BRCA1/BRCA2 genes, which account for a significant proportion of early-onset oncological diseases. The present study and data analysis demonstrate clinical and phenotypic heterogeneity in 19 Bulgarian patients carrying pathogenic and likely pathogenic BRCA1/BRCA2 variants, identified through next-generation sequencing (NGS) performed at the Laboratory of Medical Genetics, University Hospital “Heart and Brain”, Pleven. The most frequent variant detected was BRCA1:c.5266dup (44% of the cohort), characteristic of Eastern European populations, supporting the hypothesis of a regional founder mutation in Bulgaria. A documented case of discordance between germline BRCA1 mutation and HRD-negative tumor status highlights the necessity of parallel testing of germline and tumor DNA when planning PARP inhibitor therapy. The absence of family history in a significant proportion of patients (32%) supports the need to apply modern recommendations for expanded indications for genetic testing beyond family history-based criteria. The results confirm the importance of NGS technologies, cascade screening, and a multidisciplinary approach for the personalization of preventive and therapeutic strategies in hereditary tumor syndromes in Bulgaria.