Extended Germline Profiling of Cancer Predisposition and Homologous Recombination Repair Genes in 275 Russian
Peter Alekseevich Shatalov1, Anna Aleksandrovna Bukaeva1, Egor Mikhailovich Veselovsky1
1National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Koroleva st. 4, 249036 Obninsk, Russia.
Abstract:
Background/Objectives: Triple-negative breast cancer (TNBC) is enriched for germline pathogenic variants in BRCA1/2 and other DNA repair genes, but the additional value of extended germline profiling beyond BRCA1/2 remains insufficiently characterized in Russian patients. We aimed to characterize germline pathogenic/likely pathogenic variants (GPV/LPVs) and variants of uncertain significance (VUSes) in cancer predisposition and homologous recombination repair (HRR)-related genes in Russian TNBC patients and to assess the additional yield of extended germline profiling beyond BRCA1/2. Methods: We retrospectively analyzed germline DNA from 275 patients with histologically confirmed TNBC. Exome sequencing was performed for 204 patients and focused HRR-panel testing for 71 patients on the MGISEQ-G400 platform. Results: Overall, 114 patients (41.5%) harbored at least one germline GPV/LPV. BRCA1/2 GPV/LPVs were detected in 53 patients (19.3%), with BRCA1 predominating over BRCA2 (48 vs. 5 carriers) and the recurrent BRCA1 c.5329dup variant accounting for 23 cases. In the exome subset, 79 of 204 patients (38.7%) carried a GPV/LPV in Groups 1-3, including 48 (23.5%) with BC-related GPV/LPVs; non-BRCA Group 1 genes contributed seven additional carriers beyond BRCA1/2-only analysis. The expanded HRR set identified 52 GPV/LPV carriers (25.5%) versus 45 (22.1%) in the reference HRR panel, while the common HRR gene set identified 68 carriers (24.7%) in the full cohort. In addition, 183 unique VUSes were found in Groups 1-3 in the exome subset, affecting 128 patients (62.7%). Conclusions: Russian TNBC patients show a substantial germline GPV/LPV burden dominated by BRCA1/2 alterations and the recurrent BRCA1 c.5329dup founder variant. Extended germline profiling identified additional non-BRCA and HRR-related findings beyond BRCA1/2, but the incremental yield was moderate and accompanied by a considerable VUS burden. Broader germline testing may therefore support hereditary risk assessment and exploratory HRR-focused stratification, but non-BRCA HRR findings should not be considered sufficient for therapy selection without additional tumor-level or clinical evidence.
