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PubMed2025

Targeting RAD52 overcomes PARP inhibitor resistance in preclinical Brca2-deficient ovarian cancer model.

BRCA-mutated ovarian cancer commonly develops resistance to poly (ADP-ribose) polymerase (PARP) inhibitors. Here, we investigated the DNA repair protein RAD52 as a potential target to overcome resistance. In analysis of The Cancer Genome Atlas datasets and immunohistochemistry of tissue microarrays, elevated RAD52 expression correlated with poor overall survival in patients with high-grade serous ovarian cancers. We tested two PARP inhibitor-resistant Brca2-deficient mouse ovarian cancer models, ID8-OR and HGS2-OR. HGS2-OR cells had higher RAD52 expression than parental lines. Rad52 knockout or knockdown restored PARP inhibitor sensitivity in both models. In syngeneic mice, ID8-OR cells in which Rad52 was knocked out yielded lower tumor burden and longer overall survival than control cells. Rad52 depletion impaired single-strand annealing and homologous recombination and led to accumulation of DNA double-strand breaks after PARP inhibitor treatment. RNA sequencing demonstrated that PARP inhibitor treatment induced Polq expression in Brca2- and Rad52-deficient cells, suggesting a switch to microhomology-mediated end joining. Finally, the RAD52 inhibitor D-I03 synergized with a PARP inhibitor to reduce cell viability and tumor burden and prolong survival. Collectively, our findings establish RAD52 as a promising therapeutic target to overcome PARP inhibitor resistance in BRCA2-mutated ovarian cancer and offer mechanistic insights to inform future clinical strategies.

Journal Article↗

PubMed2026

A Novel BRCA1 Pathogenic Variant in Tunisian Patient With High Grade Ovarian Cancer: Favorable Therapeutic Response to Olaparib.

BACKGROUND: Ovarian cancer is one of the leading causes of death from gynecological cancer worldwide. Genetic mutations in genes involved in key cellular functions such as BRCA1/2 play a central role in tumorigenesis and have major implications for targeted therapeutic strategies, especially the use of poly (ADP-ribose) polymerase (PARP) inhibitors. CASE: Herein, we described a case of a 50-year-old woman diagnosed with severe anemia secondary to heavy menometrorrhagia. Initial gynecological evaluation, including transvaginal ultrasound, was unremarkable, and endometrial biopsy was not indicated. Imaging revealed no ovarian abnormalities; however, exploratory laparotomy identified a peritoneal nodule, leading to further investigation. Targeted NGS was performed on somatic and germline DNA samples and showed a frame shift deletion of 10 bp (c.1256_1265del: p.R419Ter) in the BRCA1 gene. This variant, identified only in tumor tissues, is novel and classified as pathogenic in ClinVar and ACMG databases. Additional somatic alterations were detected in TP53 and MSH6, while germline testing revealed only a variant of uncertain significance in BARD1. After first-line chemotherapy, the patient benefited from olaparib and achieved a progression-free survival of 23 months with good tolerance and no evidence of disease recurrence. CONCLUSION: This finding highlights the importance of integrating tumor-based genomic profiling with germline testing to identify actionable mutations and guide precision oncology. The identification of a novel somatic BRCA1 mutation expands the mutational spectrum of HGSOC and underscores the need to include underrepresented populations, such as those from North Africa, in genomic studies.

Humans↗

PubMed2026

Comprehensive Genomic Profiling Reveals the Mutational Spectrum and Clinical Significance of BRCA1/2 and Other Cancer-Susceptibility Genes in Breast Cancer Patients from Southern Tunisia.

BACKGROUND/OBJECTIVES: This study aims to investigate the mutational spectrum of BRCA1 and BRCA2 genes in a cohort of breast cancer (BC) patients from southern Tunisia, and to evaluate their clinical and prognostic significance. Additionally, this study explores the contribution of other cancer predisposition genes and the prevalence of variants of uncertain significance (VUS). RESULTS: Among the 165 patients included, pathogenic or likely pathogenic variants (P/LPVs) in BRCA1/BRCA2 were identified in 19 cases (11.51%), including 8 in BRCA1 and 11 in BRCA2. The presence of BRCA P/LPVs associated with young patients (p = 0.006) and those with TNBC (p = 0.036). Beyond BRCA1/2, PV/LPVs were detected in other cancer-related genes, including TP53 (n = 3), CHEK2, RAD50 (n = 2 cases each), and MUTYH, BARD1, and BRIP1 (one case each). Furthermore, 56 VUS were identified; among them, 7 were prioritized based on in silico predictive analyses, suggesting a potential deleterious effect. However, these VUS should not be used for clinical decision-making without additional evidence from functional and familial segregation studies. CONCLUSIONS: Our findings provide novel insights into the genetic landscape of breast cancer in southern Tunisia, highlighting the clinical relevance of BRCA1/2 mutations and the contribution of other susceptibility genes. These results support the personalized management of breast cancer patients and the implementation of expanded multigene panel testing in routine clinical practice to improve genetic counseling.

BRCA1↗

PubMed2026

Homologous recombination-deficient high-grade serous ovarian cancers exhibit distinct morphological features.

OBJECTIVE: Access to homologous recombination testing remains limited in many centers. We aim to correlate the morphology and immunophenotype of high-grade serous ovarian carcinoma with homologous recombination statuses. METHODS: A retrospective analysis of a high-grade serous ovarian carcinoma tumors with known homologous recombination status. A pathological review of morphology was performed for each tumor, along with immunohistochemical profiling. Tumor morphology was classified as (1) solid, pseudo-endometrioid, or transitional (2) micropapillary or nested. RESULTS: Overall, 81 tumors were included. The median age was 62 (interquartile range; 52-71). Of those, 27 (33.3%) tumors were BRCA1mut, 19 (23.5%) were BRCA2mut, 15 (18.5%) tumors had no BRCA1 or BRCA2 mutations but exhibited a genomic instability score ≥42 and were classified as BRCA1/2-wild-type with homologous recombinant deficient. The remainder 20 (24.7%) cases were homologous recombinant proficient. The proportion of tumors with solid transitional-like morphology was higher in BRCA1 (12/21, 57%) and BRCA2 (12/18, 67%) compared to the tumors with homologous recombinant proficient (3/17, 18%), p =.019. When stratified by genomic instability score, tumors with low score (genomic instability score <26) exhibited 0% solid transitional-like morphology versus 43% solid transitional-like morphology in high-score (genomic instability score >26), p =.03. PAX8 diffuse expression was detected in 71% of BRCA1, 65% of BRCA2, 92% of BRCA-wild-type homologous recombinant deficient tumors, and 100% of homologous recombinant proficient tumors, p =.071. The proportion of diffuse expression was higher in homologous recombinant proficient (100%) versus BRCA2 (65%) (Bonferroni-adjusted pairwise comparisons). CONCLUSIONS: Homologous recombinant deficient tumors are associated with the solid transitional-like morphology, with the BRCA1/2-mutated homologous recombinant deficient cases showing the strongest correlation. Genomic instability score alone may not fully capture the spectrum of homologous recombinant deficient-related phenotypes. The variation in solid transitional-like morphology features among BRCA1- or BRCA2-mutated, BRCA1/2- wild-type with homologous recombinant deficient, and homologous recombinant proficient cases may reflect the diverse biological spectrum of different homologous recombination alterations.

Humans↗

PubMed2026

Impact of BRCA2 pathogenic variants on outcomes to first-line CDK4/6 inhibitors plus endocrine therapy in HR-positive/HER2-negative metastatic breast cancer.

BACKGROUND: Currently, three cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are approved in combination with endocrine therapy (ET) as first-line treatment of patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). The impact of homologous recombination repair (HRR) pathogenic variants (PV) on outcomes with first-line CDK4/6i plus ET in HR-positive/HER2-negative MBC remains uncertain. PATIENTS AND METHODS: We conducted a multicenter, real-world, case-control study including 233 patients with HR-positive/HER2-negative MBC treated with first-line CDK4/6i and ET. Among them, 116 presented HRR PVs and 117 were matched controls with negative germline testing. The primary objective was to compare progression-free survival (PFS) and overall survival among germline-BRCA2 PV carriers, other HRR PV carriers, and controls. To minimize baseline differences in prognostic factors between PV carriers and controls, inverse probability of treatment weighting was applied. Molecular analyses in pre-CDK4/6i samples among patients with BRCA2 PV were carried out, including RAD51-foci, PAM50 intrinsic subtype, and RB1 loss of heterozygosity (LOH). RESULTS: Among the included 233 patients, median age at diagnosis was 45 years (interquartile range 39-56) and 33% had de novo metastatic disease. Primary resistance to adjuvant ET was present in 10% and secondary resistance in 27%. After a median follow-up of 44 months, patients with germline-BRCA2 PVs (n = 67) had significantly shorter PFS [11 versus 27 months; adjusted hazard ratio (aHR) 2.73, 95% confidence interval (CI) 1.65-4.51, P < 0.001] compared with controls. Among patients with endocrine-sensitive disease, germline BRCA2 PV carriers had markedly shorter PFS (median PFS 12 versus 39 months; aHR 4.04; 95% CI 1.82-8.98, P < 0.001). Exploratory analyses revealed RB1 LOH before CDK4/6i-treatment in most evaluable BRCA2 tumors. CONCLUSIONS: BRCA2 PVs were independently associated with poorer outcomes to first-line CDK4/6i plus ET in HR-positive/HER2-negative MBC compared with controls, especially relevant among patients with endocrine-sensitive disease. These findings suggest that patients with a germline PV in BRCA2 may require alternative first-line strategies.

Humans↗