BRCA1/2 variant profiling and HPV/HMTV DNA detection in a cohort of Egyptian women with breast cancer

Abstract Breast cancer (BC) is a multifactorial disease influenced by both genetic and environmental factors. Pathogenic variants in BRCA1 and BRCA2 significantly increase hereditary BC risk, while oncogenic viruses such as human Papillomavirus (HPV) and human mammary tumor virus ( HMTV ) may modulate disease development. Population-specific studies integrating genetic, clinicopathological, and viral data remain limited. Genomic DNA was extracted from 48 BC patients (19 fresh tissues, 29 FFPE samples). BRCA1/2 libraries were prepared using the Devyser BRCA NGS kit and sequenced on the Illumina MiSeq platform. Variants were called using Freebayes and annotated with ANNOVAR. The DNA of HMTV and HPV were detected by PCR. Associations between BRCA variants, clinicopathological features, and viral status were investigated using statistical and rule-based analyses. Exonic variants constituted 72% of all detected variants in BRCA1 and 97% in BRCA2 , whereas intronic variants accounted for 23% and 1%, respectively. Variants were most frequently identified within BRCA1 exons 9–10 and BRCA2 exon 11. This distribution may reflect the large size and structural complexity of these regions, as well as cohort-specific genetic characteristics. Among the 48 patients, 46 (95.8%) were diagnosed with invasive breast carcinoma, predominantly grade II tumors, and more than 30% reported a family history of breast cancer. Pathogenic BRCA1/2 variants were detected in 39.6% of cases, with BRCA1 alterations occurring more frequently than BRCA2 alterations. Several BRCA1/2 variants showed significant associations with HPV or HMTV DNA detection, while the BRCA2 p.Pro1639Ser variant appeared to be associated with a reduced likelihood of viral DNA positivity. Furthermore, specific pathogenic BRCA variants co-occurred with HPV or HMTV DNA, suggesting potential interactions between host genetic susceptibility and viral presence. Carriers of BRCA variants tended to present with larger tumors, higher histological grade, left-sided disease, microcalcifications, and a greater prevalence of hormone receptor–positive breast cancer. This study presents the first comprehensive investigation of BRCA1/2 variants in conjunction with HPV and HMTV DNA detection in a cohort of Egyptian women with breast cancer. The findings reveal a distinct BRCA1/2 variant profile, identify novel variants, and provide preliminary evidence of potential associations between host genetic variation and viral DNA detection. These results broaden the current understanding of the genetic and viral landscape of breast cancer in the Egyptian population and highlight possible interactions that merit further investigation. Given the exploratory nature of the observed associations, validation in larger, independent cohorts, supported by functional and clinical correlation studies, is required. Such efforts may contribute to improving risk assessment, patient stratification, and the development of tailored preventive and management strategies for this population.