LOH, LST, and TAI Profiles in Solid Tumors Harboring Pathogenic or Likely Pathogenic BRCA1/2 Variants: An Exploratory...

Homologous recombination deficiency (HRD) is a critical indicator of genomic instability; however, the composite HRD score may not reflect the distribution of distinct genomic scar components underlying this phenotype. In this exploratory study, we compared the absolute and relative contributions of loss of heterozygosity (LOH), large-scale state transitions (LST), and telomeric allelic imbalance (TAI) among solid tumors harboring pathogenic or likely pathogenic (P/LP) variants in BRCA1 or BRCA2. This retrospective study included 76 patients with solid tumors who underwent HRD testing between January 2023 and January 2026. P/LP variants in homologous recombination repair (HRR) genes, alongside LOH, LST, and TAI scores, were evaluated. The composite HRD score was calculated as LOH + LST + TAI, with values ≥ 56 defined as HRD-positive. Additionally, the relative contribution of each scar component to the total HRD score was determined. Given the small sizes of the BRCA1-only and BRCA2-only subgroups and the heterogeneity of the overall cohort, all gene-group comparisons were considered exploratory and hypothesis-generating. Overall, 21.1% of the cohort was HRD-positive. Patients harboring BRCA1/2 P/LP variants displayed a significantly higher median HRD score compared to non-carriers (47.0 vs. 30.0; p = 0.016). When comparing patients with tumors harboring BRCA1-only (n = 9) and BRCA2-only (n = 10) P/LP variants, LOH was higher in the BRCA2 group (19.0 vs. 5.0; p = 0.036); however, this difference did not retain statistical significance following false discovery rate (FDR) adjustment (q = 0.108). In an exploratory sensitivity analysis restricted to breast and ovarian tumors (BRCA1-only, n = 5; BRCA2-only, n = 9), the LOH/HRD ratio was higher in the BRCA2 group (0.301 vs. 0.000; p = 0.026; q = 0.039), whereas the LST/HRD ratio was higher in the BRCA1 group (0.488 vs. 0.310; p = 0.019; q = 0.039). These estimates were based on very small subgroups and should therefore be interpreted cautiously. This exploratory analysis identified differences in the relative distributions of LOH and LST between tumors harboring BRCA1-only and BRCA2-only P/LP variants, particularly in the breast/ovarian subset. However, the small and heterogeneous subgroups, together with the absence of systematic assessment of biallelic BRCA1/2 inactivation, preclude gene-specific or mechanistic conclusions. These observations should be regarded as hypothesis-generating and require validation in larger, tumor-specific, independent cohorts.