Search Results (1,732)

Background: Pathogenic BRCA1 and BRCA2 mutations confer a homologous recombination deficiency that underlies PARP inhibitor sensitivity. While BRCA1 mutation carriers more frequently develop triple-negative breast cancer (TNBC) and BRCA2 carriers hormone receptor-positive (HR+) disease, whether the specific protein domain harboring a pathogenic somatic mutation differs systematically between breast cancer subtypes remains uncertain. Apparent domain enrichment in earlier unfiltered analyses may be confounded by missense variants of uncertain significance (VUSs), which lack clinical actionability. Methods: We assembled three independent breast cancer cohorts via cBioPortal: TCGA-BRCA (brca_tcga_pub2015), METABRIC (brca_metabric), and MSK-CHORD (msk_chord_2024). All somatic BRCA1/2 mutations were mapped to UniProt-annotated functional domains and to Rebbeck-defined breast/ovarian cancer cluster regions (BCCR/OCCR). Per ENIGMA/ACMG guidance, pathogenic mutations (nonsense, frameshift, and canonical splice site) were analyzed inferentially, while missense and in-frame variants—predominantly VUSs—were only reported descriptively. Fisher’s exact tests with Benjamini–Hochberg FDR correction were applied across domain × subtype contingencies. Cohort heterogeneity was assessed via Cochran’s Q and I² statistics; pooled effect estimates were computed using inverse-variance fixed-effects meta-analysis. Results: A total of 394 somatic BRCA1/2 mutations were identified across the three cohorts (BRCA1 n = 166; BRCA2 n = 228), of which 147 (37.3%) met pathogenic criteria. Among 131 pathogenic mutations in HR+/HER2− or TNBC subtypes, 84 (64.1%) occurred in HR+/HER2− disease and 47 (35.9%) in TNBC. Domain-level distributions did not differ significantly between subtypes for any BRCA1 domain (BRCT: TNBC 20.0% vs. HR+ 18.8%, OR = 1.08, 95% CI 0.31–3.78, and FDR-adjusted p = 1.00) or BRCA2 domain (DBD: TNBC 17.6% vs. HR+ 30.8%, OR = 0.48, and FDR-adjusted p = 1.00). Cluster-region analyses (nine Rebbeck BCCR/OCCRs) similarly showed no significant enrichment. Post hoc power analysis indicated that the study could only reliably detect large effects (OR ≥ ~3.0 for the principal BRCT contrast), and formal equivalence testing (TOST) demonstrated equivalence within a prespecified ±20% margin for BRCA1 BRCT (TOST p = 0.031). Heterogeneity across cohorts was minimal (Cochran’s Q = 0.62, I² = 0.0%). Descriptive analyses of VUSs suggested the apparent enrichment of BRCA1 BRCT-localized missense variants in TNBC (31.8% vs. 17.9% in HR+), but this signal did not extend to pathogenic mutations. Conclusions: Within the statistical power available, our three-cohort analysis shows no evidence of large subtype-specific enrichment of pathogenic BRCA1/2 somatic mutations across protein domains or cluster regions; small to moderate effects cannot be excluded. Notably, the majority (64%) of pathogenic mutations occurred in HR+/HER2− disease, underscoring that BRCA1/2 testing should not be deprioritized in non-TNBC subtypes. The apparent BRCT enrichment observed in earlier unfiltered analyses appears to be driven by VUSs rather than pathogenic variants, highlighting the methodological necessity of pathogenicity filtering for clinically actionable inference. These findings provide cohort-scale supportive evidence for emerging clinical guidelines that recommend broader BRCA1/2 testing across breast cancer subtypes. Full article

Genomic sequencing can reveal potentially life-threatening clinically actionable secondary findings in healthy individuals. Little is known about the spectrum and frequency of secondary findings in healthy people in Russia. Here, we analyzed whole-genome sequences of 42,826 healthy volunteers from urban populations across Russia, focusing on known pathogenic and likely pathogenic variants of 81 genes associated with treatable or preventable monogenic diseases listed in the American College of Medical Genetics and Genomics’ Secondary Findings recommendations (ACMG SF v3.2). Based on the ClinVar 20250421 version, secondary findings were detected in 1186 (2.76%) participants. Cancer phenotypes were the most common category of secondary findings present in 565 (1.32%) participants, followed by cardiovascular phenotypes (454 individuals, 1.05%). Genes harboring the most frequent variants were BRCA1 (151 variants), BRCA2 (100), RYR1 (93), and LDLR (71). In addition, we found 238 potential loss-of-function variants in dominant ACMG SF v3.2 list genes in 280 (0.65%) participants, which, if confirmed by orthogonal methods, could increase the frequency of secondary findings to 3.41%. A study of such depth and scale was performed for the first time in the Russian population. Full article

Cancer cells, like yeast, use fermentation despite the presence of oxygen, a phenomenon called aerobic glycolysis. The advantage is that it maintains many C-C bonds of glucose, allowing highly proliferating cells to produce the biomolecules that are necessary for cytokinesis. However, aerobic glycolysis is less energy-efficient than respiration, and it must operate at high frequency and produces large amounts of lactate, which modifies and stimulates DNA repair enzymes via lysine lactylation. This makes cancer cells resistant to radiotherapy, which requires a combination with chemotherapy using drugs that inhibit DNA repair. However, this converts healthy cells to cancer cells, indicating that research is still required regarding the relationship between glycolysis and cancer. Using yeast as a model, we discovered that the glycolytic enzymes TPI and GAPDH (Tpi1p and Tdh1-3p in yeast) interact with the DNA damage-dependent Checkpoint Rad9p (53BP1/BRCA1/MDC1 in humans). We propose that Tpi1p and Tdh1-3p override Rad9p, allowing cells with damaged DNA to proliferate. We isolated tpi and gapdh mutant strains that are deficient in DNA repair. While the tpi mutant strain has lower enzymatic activity, the gapdh mutant strains have normal enzymatic activity, confirming previous reports that GAPDH moonlights in the DNA damage response. Full article

Skeletal muscle differentiation relies on transient DNA strand breaks (DSBs), yet excessive DNA damage remains harmful to myogenic progression. The RNA-binding protein Zfp36l1 is expressed in skeletal muscle and contributes to muscle regeneration; nevertheless, its role in preserving genome stability during myogenic differentiation has not been defined. Here, we investigated the role and mechanism of Zfp36l1 in regulating DNA damage using C2C12 myoblast cells, combining loss- and gain-of-function assays, RNA-seq, and rescue experiments. The results revealed that Zfp36l1 expression is strongly induced during early myogenic differentiation, coinciding with the onset of physiological DSBs. Functional assays revealed that silencing Zfp36l1 aggravates DSB accumulation, reinforces G0/G1 cell cycle arrest, and promotes apoptosis, whereas Zfp36l1 overexpression attenuates these abnormalities. Transcriptomic profiling shows that Zfp36l1 depletion impairs homologous recombination (HR)-mediated DNA repair by downregulating core repair factors, including Rad51 and Brca1. Gene set enrichment analysis further confirms significant suppression of the HR-dependent DSB repair pathway. Mechanistically, Zfp36l1 regulates HR repair by suppressing p21 expression, thereby relieving inhibition of E2F1-mediated Rad51 transcription. Co-silencing p21 restores Rad51 expression and reduces DNA damage in Zfp36l1-knockdown cells. Collectively, these findings identify Zfp36l1 as an essential safeguard of genome stability during myogenic differentiation by balancing DNA damage levels through the p21-E2F1-Rad51 signaling axis, and provide new insights into the regulatory basis of muscle development and genomic instability-associated muscle diseases. Full article

Background: Pathogenic germline BRCA1 and BRCA2 variants cause most hereditary breast and ovarian cancers. Widespread genetic testing has revealed thousands of variants with unknown effects on disease risk, known as variants of uncertain significance (VUS). BRCA VUS, the majority of which are missense, complicate genetic test interpretation and clinical decision-making. This study aimed to evaluate BRCA1 VUS pathogenicity with enhanced accuracy through computational, functional and structural methods. Methods: We characterized the structural distribution of BRCA1 variants. In silico tools scored known consequence variants within a specific region of BRCA1. The Molecular Feature Selection Tool (MolecularFeaST; Renwick Lab at Queen’s University; Kingston, ON, Canada) performed feature selection of the most discriminative tools. MATLAB (MATLAB R2024a; Mathworks; Natick, MA, USA) Classification Learner Application trained supervised machine learning models using combinations of the most accurate tools; the best model assigned pathogenicity prediction scores to VUS. Select VUS were functionally assessed through phosphopeptide binding pull-down assays and structurally analyzed on PyMOL (v2.4.1; Schrödinger Inc.; New York, NY, USA). Results: The RING and BRCT domains were identified as hotspots for missense pathogenic variants and VUS; BRCT was selected as the focus of the computational classifier. Nine in silico tools (CADD hg19, MetaRNN, ClinPred, VEST4, BayesDel AD, EVE, Eigen PC, gMVP and PolyPhen2) defined the BRCT-specific missense variant classifier. Twenty-two VUS (R1699P, F1704S, W1837L, W1712G, F1734S, V1804A, I1674V, V1804L, V1804I, I1807V, T1675S, I1764L, N1774I, E1698K, Q1848K, P1749S, A1669T, N1774H, L1839V, T1658I, L1705I, V1654L) demonstrated varying phosphopeptide binding ability and protein levels relative to the wildtype. Computational structural modeling contextualized VUS phosphopeptide interactions and structural implications. Conclusions: We provide in silico and functional evidence for the classification of BRCA1 BRCT VUS and highlight the utility of domain-specific computational approaches for characterizing missense variants in multi-domain genes. Full article

Background: Homologous recombination deficiency (HRD) is emerging as a clinically relevant biomarker across diverse tumor types, in addition to ovarian cancer. In this study, we evaluated the genomic instability score (GIS) across multiple tumor types using the TruSight Oncology 500 HRD assay, which incorporates the Myriad Genetics GIS algorithm, a widely used reference standard for HRD assessment. Methods: A total of 162 tumor samples (17 ovarian cancers and 145 non-ovarian tumors) underwent next-generation sequencing using the TruSight Oncology 500 HRD assay. Results: A total of 14 tumors were classified as GIS-High, defined as a GIS score ≥42, representing 8.6% of all cases. Among ovarian cancers, 7 out of 17 cases (41.2%) met the GIS-High threshold. Among non-ovarian tumors, seven GIS-High tumors were identified, accounting for 4.8% of cases (7/145). GIS-High cases occurred in breast (n = 4), lung (n = 2), and hepatobiliary tract (n = 1) cancers. GIS scores showed significant associations with BRCA1/2 and TP53 mutational status. In contrast, alterations in HRD-related genes other than BRCA1/2 did not show significant associations with GIS score. Conclusions: GIS-High tumors were identified in a small subset of non-ovarian cancers. These findings support further investigation of GIS as an exploratory biomarker of HRD-like genomic scarring beyond ovarian cancer, but its predictive and therapeutic relevance in non-ovarian tumors requires additional validation. Full article

Introduction: Breast cancer is the most common malignancy in women of reproductive age, and treatment advances have heightened the importance of fertility preservation (FP) for young patients. Despite heterogeneity across subtypes—hormone receptor-positive (HR+), HER2-positive, triple-negative (TNBC), and BRCA1/2-associated—existing guidelines lack subtype-specific FP guidance. Methods: This systematic review compared FP strategies across subtypes, identified subtype-specific challenges, and proposed pathways toward precision oncofertility care. PubMed, Scopus, and Web of Science were searched following PRISMA guidelines for English-language studies from 2004 to 2024. Results: After screening 1837 records, 19 studies met eligibility criteria (2 RCTs, 17 cohort studies); 11 of 17 non-randomized studies were at low overall risk of bias, and 6 at moderate risk due to confounding. Discussion: COS using letrozole- or tamoxifen-modified protocols was feasible, yielding 8–14 mature oocytes per cycle with reduced estradiol exposure suitable for HR+ disease. Evidence was strongest for HR+ patients; TNBC and HER2+ data were more limited, with some studies noting reduced ovarian reserve. GnRH agonists during chemotherapy reduced ovarian failure rates and improved post-treatment recovery, most consistently in hormone receptor-negative disease. BRCA1/2 carriers showed broadly comparable FP outcomes to non-carriers, though BRCA1-positive patients had modestly reduced oocyte yields in some studies with inconsistent results. Conclusions: Among studies with medium-term follow-up (3–5.5 years), no significant increase in recurrence or mortality attributable to FP was identified; long-term data beyond 5 years remain sparse. Substantial heterogeneity precluded meta-analysis; all synthesis is narrative. Standardized outco reporting and larger prospective subtype-stratified studies are required to establish precision oncofertility recommendations. Full article

Background/Objectives: Poly (ADP-ribose) polymerase (PARP1) has emerged as a promising therapeutic target in human breast cancer particularly in BRCA1/2 mutation carriers where a synthetic lethal interaction leads to massive tumor cell death upon specific inhibitors’ administration. Current clinically approved PARP inhibitors (Talazoparib and Olaparib) show outstanding therapeutic capabilities but suffer from severe side effects. Most importantly, some of them can cause life-threatening cardiotoxicity through hERG off-target effects. Here, we performed an extensive study to identify lead compounds with improved binding modes and favorable predicted pharmacokinetics using an integrated computational strategy. Methods: An artificial intelligence-driven drug design (AIDDISON™ v2023) workflow was employed to search ultra-large chemical space libraries for active compounds, which were then optimized via computer-aided methods to form a PARP-Tailored Database (PTD). This database was then analyzed through a virtual screening workflow, molecular docking studies, molecular dynamics (MD) simulations, MM/GBSA binding free energy calculations, DFT analysis and ADME/Tox predictions using the Schrödinger suite (v2023-2), MobaXterm v25.2, Gaussian 16.0, ProTox-3 and Pred-hERG v5.0 respectively. Results: Three compounds (1a–1c) were identified as promising candidates. Among them 1a appeared to be the most active compound with a favorable docking score (−9.488 kcal/mol) that is not only higher than 1b and 1c but also higher than that of Talazoparib (−6.778 kcal/mol). MD simulations of 1a–1c in the active site revealed an average RMSD of ~2.5–3.6 Å which is better compared to the parent Talazoparib (5.6 Å). Interestingly, on the 250 ns extended MD study, 1a exhibited a slightly reduced RMSD between 2.4 and 3.2 Å, whereas Talazoparib retained higher fluctuations of ~5 Å to 6 Å. MM/GBSA binding energy analysis indicated 1a to have better predicted binding affinity (−67.820 kcal/mol), which is also better than Talazoparib (−63.734 kcal/mol). DFT calculations showed good electronic properties and in silico ADMET studies also indicated 1a to have good drug-likeness and lower predicted hepatotoxicity and cardiotoxicity risk. Conclusions: These findings identify compound 1a as a promising lead, while compounds 1b and 1c remain viable candidates for further optimization. However, experimental validation is critical to confirm the predicted biological activity and safety profiles. Full article

Background: Given the challenges in early detection and diagnosis, understanding the molecular underpinnings of endometrioid ovarian cancer (EOC) is crucial for improving patient outcomes. This multi-level study provides a new perspective on EOC, focusing on the expression of ARID1a (BAF250a) and RIF1. Methods: This study evaluates patient cohorts with EOC through semi-quantitative immunohistochemical staining of BAF250a (protein encoded by ARID1a) and RIF1 proteins alongside mutations that influence the gene expression of ARID1a and RIF1. Besides survival analyses, platinum- and taxane-based treatment responsiveness with regard to ARID1a and RIF1 expression has been analyzed using an online available database. Results: Histological and immunohistochemical analysis of clinical samples revealed a significant reciprocal alteration in protein expression, characterized by a marked reduction in the tumor suppressor BAF250a (p < 0.0001) and a concomitant elevation of RIF1 (p < 0.0001) in EOC compared to controls. Tumors harboring mutations in BRCA1 exhibited significantly (p = 2.82 × 10⁻⁴) lower ARID1a expression levels compared with corresponding wild-type tumors, whereas LAMB3-mutant tumors showed a significant (p = 5.16 × 10⁻³) upregulation of RIF1 mRNA expression. Conclusions: In conclusion, our study offers a new perspective, emphasizing that EOC is a distinct clinical and molecular entity. We demonstrated the expression patterns of ARID1a/BAF250a and RIF1 in EOC, establishing their potential relevance in the context of tumor biology and malignant transformation. Full article

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BrCa), owing to its lack of targetable receptors and resistance to chemical and molecularly targeted therapeutic approaches. While chemotherapy and surgical resection remain the standard of care, these interventions have significant side effects and varying patient outcomes. Thermally ablative focused ultrasound (T-FUS)—a non-invasive and non-ionizing therapy that utilizes targeted acoustic energy to debulk tumors—has displayed immunomodulatory effects in BrCa. However, T-FUS as a monotherapy has had limited clinical efficacy in TNBC due to the presence of anti-inflammatory immunosuppressive myeloid cells (isMCs). We hypothesized that the elimination of isMCs or initiating tumoricidal activity from them would lead to augmented activity of T-FUS. Thus, we interrogated the ability of myeloablative chemotherapies and antibodies; myeloid recruiting chemokine receptor blockade; and TLR agonists to remodel the tumor myeloid populations. Consistent with our previous studies, we found that while myeloablative chemotherapies decreased circulating isMCs, they had little impact on intratumoral isMCs. In contrast, antibodies targeting Ly6C and Ly6G ablated intratumoral isMCs and systemic isMCs, yet their effect was transient and was accompanied by a surprising depletion of T cells. While targeting CCR2, the dominant chemokine receptor for intratumoral isMC diminished a large subset of immunosuppressive cells within the TME; it also depleted T cells and dendritic cells. Contrary to previous studies, TLR stimulation failed to repolarize myeloid cells into a pro-inflammatory, tumoricidal phenotype but did lead to their depletion from the tumor microenvironment (TME) and mobilization of conventional dendritic cells to the draining lymph nodes. We therefore hypothesized that combining isMC depletion and TLR-driven immune activation would enhance FUS efficacy; however, this combinatorial regimen did not enhance overall survival or control tumor volume after T-FUS treatment. Thus, the BrCa TME is highly resistant to approaches intended to remodel the myeloid cell component which fail to synergize with T-FUS-mediated tumor ablation. Full article

Accurate deconvolution of bulk transcriptomes is essential for characterizing the breast cancer tumor microenvironment (TME), yet existing reference matrices incompletely capture tumor-specific cellular diversity. Here, we developed breast cancer–specific multiresolution CIBERSORTx signature matrices from single-cell RNA sequencing data and systematically evaluated their analytical performance and interpretability. Major-, minor-, and subset-level matrices were constructed and assessed using pseudo-bulk mixtures and pure cell profiles, while biological and clinical coherence were evaluated in TCGA-BRCA and the I-SPY2 cohort. All matrices demonstrated high accuracy in reconstructing pseudo-bulk compositions, with performance declining at finer resolution. Spillover increased with granularity but was largely restricted within related lineages. Lineage-wise deconvolution modestly reduced spillover but consistently decreased accuracy, highlighting the importance of cross-lineage transcriptional contrast. In external datasets, most inferred cell populations showed biologically coherent associations with canonical markers and pathways, whereas some fine-resolution subsets exhibited non-canonical patterns, likely reflecting intra-lineage trade-offs or context-dependent transcriptional states. In the I-SPY2 cohort, plasmablasts and selected myeloid populations were positively associated with pathological complete response, whereas fibroblastic and perivascular-like populations showed negative associations. These findings establish a validated and interpretable resource for breast cancer TME deconvolution and clarify its performance characteristics and limitations. Full article

Background: Triple-negative breast cancer (TNBC) remains a clinical challenge due to its aggressive nature and the frequent emergence of therapeutic resistance. While the role of protein-coding genes in DNA repair is well-documented, the regulatory contributions of the non-coding genome, specifically long intergenic non-coding RNAs (lincRNAs), remain largely undefined. Objectives: In this study, we characterize the biological significance of LincRNA-BC7, a novel transcript identified within the breast cancer field effect. Methods: Through a combined in silico and in vitro approach, we investigated the transcriptional dynamics of the LincRNA-BC7/miR-663a/BRCA1 axis in response to the PARP inhibitor, Olaparib. Results: Our results demonstrate that Olaparib induces selective cytotoxicity in BRCA1-deficient MDA-MB-231 cells while sparing non-cancerous HEK293 cells, a response accompanied by a significant downregulation of LincRNA-BC7 and a reciprocal upregulation of BRCA1. Bioinformatics analysis through BLASTN, miRBase, and KEGG revealed that LincRNA-BC7 contains highly complementary binding sites for miR-663a, suggesting it functions as a competing endogenous RNA (ceRNA) or “molecular sponge.” Conclusions: By sequestering miR-663a, LincRNA-BC7 appears to modulate the expression of critical signaling nodes within the PI3K-AKT and TP53 pathways, thereby influencing cellular sensitivity to DNA-damaging agents. These findings suggest that LincRNA-BC7 is a key determinant of the aggressive TNBC phenotype and the response to PARP inhibition. Our study establishes the LincRNA-BC7/miR-663a axis as a novel biomarker for precision risk stratification and a promising therapeutic target to enhance treatment outcomes in BRCA1-associated breast cancers. Full article

Background: Breast cancer (BRCA) is a common malignant tumor that seriously threatens women’s health. Studies have shown that histone modifications (HMs) play a vital role in the occurrence and development of BRCA. This study aims to explore the distribution patterns of HMs in the mammary epithelial cell line (HMEC) and breast cancer cell line (MCF-7), and their potential associations with gene expression, patient prognosis, and drug efficacy. Methods: First, the distribution of histone modification (HM) signals in HMEC and MCF-7 cell lines was analyzed. Multiple algorithms were then used to predict the effects of different HMs and their modified regions on gene expression in the two cell lines. Based on four key regions identified from this analysis, 268 HM-related immune-related genes (H_IRGs) were screened, followed by functional enrichment and pathway analysis. Subsequently, Cox and LASSO regression analyses were performed on the H_IRGs to construct a risk scoring model. Results: The random forest algorithm showed the best predictive performance (AUC = 0.92) and identified three key HMs (H3K4me2, H3K27me3, and H3K36me3) and four key regions that strongly influenced gene expression. A risk scoring model was constructed from 11 key IRGs (BCL2A1, PSME2, STC2, ESRRG, CRISP3, IL13RA1, LCN1, EED, CLEC10A, SLURP1, and FGF12). This model effectively predicted patients’ survival in both the training and validation cohorts. Conclusions: In summary, our research results provide a theoretical basis for the occurrence and development of BRCA, and the 11 key IRGs discovered are expected to become potential biomarkers for BRCA prognostic assessment and treatment response prediction. Full article

Background: Accurate and efficient analysis of mitotic figures in whole-slide images (WSIs) is essential for tumor grading and prognosis. Methods: In this work, we present a three-stage pipeline for WSI-scale mitosis analysis that balances accuracy with clinical throughput: (1) a YOLOv11-based detector to propose mitosis candidates; (2) an ultra-lightweight classifier to refine detections and suppress false positives; and (3) a downstream classifier to distinguish atypical from normal mitoses for deeper biological insight. Results: In benchmark datasets, the two-stage detector improves F1 over detection-only baselines, while the atypical/normal module achieves strong accuracy, demonstrating cross-domain generalization. We further perform a proof-of-concept survival analysis on early-stage (I–II) cases from the TCGA-BRCA cohort, suggesting that mitosis-derived features may provide modest incremental prognostic information beyond the clinical baseline and nuclei features. Conclusions: Overall, the method delivers accurate detection, robust atypical mitosis classification, and high efficiency, processing gigapixel WSIs in minutes on a single GPU, positioning it for large-scale translational studies and future clinical workflow validation. Full article

Germline loss-of-function mutations in BRCA1 and BRCA2 markedly increase susceptibility to breast, ovarian, and other cancers. Mechanistically, BRCA2 facilitates RAD51 recruitment to sites of DNA damage, whereas BRCA1 regulates homologous recombination repair (HRR) through double-strand break resection and broader DNA damage response signaling. These insights underpin targeted therapies such as poly (ADP-ribose) polymerase inhibitors (PARPis), which induce synthetic lethality in homologous recombination-deficient tumors. Clinically, PARPis have demonstrated significant benefit in BRCA1/2-mutated breast, ovarian, pancreatic, and prostate cancers. However, resistance remains a major obstacle, with secondary intragenic BRCA1/2 mutations restoring partial protein function representing a prominent mechanism. Despite therapeutic advances, critical gaps persist in understanding how specific BRCA1/2 domains and residual protein activities contribute to tumorigenesis and treatment response. In this review, we summarize the structural and functional domains of BRCA1/2, their pathogenic mutation profiles, and therapeutic strategies targeting BRCA1/2-deficient cancers. Despite therapeutic advances, critical gaps persist in understanding how specific BRCA1/2 domains and residual protein activities contribute to tumorigenesis and treatment response. This review emphasizes the need for functional studies of BRCA1/2 variants to refine risk prediction and develop mutation-tailored therapies. Full article