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PubMed2026

Comparative analysis of distinct genomic landscapes in young-onset gBRCA1/2 breast cancer.

Carriers of germline BRCA1/2 pathogenic variants (gBRCA1/2 PVs) have elevated young-onset breast cancer risk. To define the pretreatment genomic landscapes of young-onset gBRCA-associated breast cancer, we evaluated 136 treatment-naive tumors diagnosed before age 50 in the prospective POSH study and 66 noncarriers from The Cancer Genome Atlas. Using whole-exome sequencing, we analyzed somatic variation, allele-specific loss of heterozygosity (asLOH), homologous recombination deficiency (HRD), and single-base substitution (SBS) signatures. gBRCA1 and gBRCA2 breast cancers had high rates of asLOH but differed significantly in average HRD scores and median SBS composition of signatures SBS1 (aging-associated), SBS18 (ROS-associated), and SBS3 (HRD-associated). Compared with gBRCA2 tumors, gBRCA1 tumors with asLOH were significantly enriched for alterations in hallmark ROS, DNA repair, and epithelial-mesenchymal transition pathways. In ER-positive, HER2-negative tumors from gBRCA1/2 carriers compared with noncarriers, we found significant enrichment of RB1, TP53, FAT1, and MYC single-nucleotide variants, indels, and copy number variants associated with CDK4/6 inhibitor (CDK4/6i) resistance. Together, these findings demonstrate significant differences between gBRCA1- and gBRCA2-associated breast cancers, and preexisting CDK4/6i resistance mechanisms, supporting prospective trials comparing individualized therapy for gBRCA1 versus gBRCA2 carriers and comparing poly(ADP-ribose) polymerase inhibitors versus CDK4/6i for ER-positive gBRCA1/2-associated breast cancer.

Humans↗

PubMed2026

Genomic Landscape of 6597 Hong Kong HBOC Patients: Implications for Beyond-BRCA Multi-Gene Panel Testing and Cancer Surveillance.

Breast cancer remains highly prevalent, where the lifetime risk before age 75 is one in 13. However, known genetic factors were only identified in 14.7% of cases in our Hong Kong Hereditary Breast Cancer Family Registry. Our current local policy for genetic testing does not cover the detection of beyond BRCA1/2. Here we highlight the clinical value of extending testing to beyond BRCA susceptibility genes for improved prevention, diagnosis, and management. We recruited 6597 hereditary breast and ovarian cancer (HBOC) patients from our registry based on family history and clinical criteria. Germline mutations were identified by multi-gene sequencing analysis using next-generation sequencing (NGS). Clinical-pathological characteristics of BRCA and beyond BRCA carriers were compared and the real-world management and surveillance services adopted in Hong Kong were highlighted. In this multi-gene hereditary cancer cohort, germline mutations were identified in 10.9% of cases for BRCA1/2 and 3.5% for beyond BRCA susceptibility genes. These beyond BRCA mutations constitute a considerable proportion of actionable hereditary risk. Notably, PALB2 emerged as the most prevalent non-BRCA gene, followed by TP53, ATM, and BARD1. New cancers or recurrences were detected during their surveillance; the overall pick up rates were 8.3% (PALB2), 29.4% (TP53), 33.3% (PTEN) and 5.6% (BARD1). This study provides the first comprehensive characterization of the beyond BRCA germline landscape in a Hong Kong hereditary cancer cohort and highlights the current need for implementing multi-gene sequencing analysis and surveillance services for HBOC patients, establishing the predominant non-BRCA drivers and providing a robust empirical basis for expanding public genetic screening frameworks.

Humans↗

PubMed2025

Distinct roles of the two BRCA2 DNA-binding domains in DNA damage repair and replication fork preservation.

Homologous recombination (HR) removes DNA double-strand breaks (DSBs) and preserves stressed DNA replication forks. Successful HR execution requires the tumor suppressor BRCA2, which harbors distinct DNA-binding domains (DBDs): one that possesses three oligonucleotide/oligosaccharide-binding (OB) folds (OB-DBD) and another residing in the C-terminal recombinase binding domain (CTRB-DBD). Here, we employ multi-faceted approaches to delineate the contributions of these domains toward HR and replication fork maintenance. We show that OB-DBD and CTRB-DBD confer single-strand DNA (ssDNA)- and dsDNA-binding capabilities, respectively, and that BRCA2 variants mutated in either domain are impaired in their ability to load the recombinase RAD51 onto ssDNA pre-occupied by RPA. While the CTRB-DBD mutant is modestly affected by DNA break repair, it exhibits a strong defect in the protection of stressed replication forks. In contrast, the OB-DBD is indispensable for both BRCA2 functions. Our study thus defines the unique contributions of the two BRCA2 DBDs in genome maintenance.

BRCA2 Protein↗

PubMed2026

International trends in concurrent hysterectomy at risk-reducing surgery in BRCA1/2 pathogenic variant carriers: a mixed-methods study.

BACKGROUND: BRCA1/2 pathogenic variant carriers are advised to undergo a risk-reducing salpingo-oophorectomy between the ages of 35 and 45 due to their increased risk of tubo-ovarian cancer. A concurrent hysterectomy may be performed at the time of risk-reducing salpingo-oophorectomy. Currently, the international execution of hysterectomy during risk-reducing surgery and the factors guiding related decision-making are unknown. OBJECTIVE: We aimed to evaluate the international execution of concurrent hysterectomy during risk-reducing surgery for tubo-ovarian cancer and factors guiding providers' decision-making about this. STUDY DESIGN: We conducted a mixed-methods study. First, we executed a quantitative analysis with data from the Women choosIng Surgical Prevention (WISP) and TUBectomy with delayed oophorectomy as Alternative for risk-reducing salpingo-oophorectomy in high-risk Women to assess the Safety of Prevention (TUBA-WISP II) study, both prospective preferential trials assessing surgical strategies for tubo-ovarian cancer prevention. Data were collected via electronic case report forms. Concurrent hysterectomy during risk-reducing salpingo-oophorectomy was compared between Europe, North- and South America, and Australia using Kruskal-Wallis tests. We used univariable logistic regression models to estimate the association of personal and prevention-related characteristics with the execution of hysterectomy at risk-reducing salpingo-oophorectomy in women from North- and South America. Subsequently, we conducted focus group interviews with gynecologic providers from 12 countries who provide preventive care for individuals at increased risk of tubo-ovarian cancer to identify indications, barriers, and facilitators for the execution of hysterectomy with risk-reducing salpingo-oophorectomy. RESULTS: In the quantitative analysis, we included 2181 participants, of whom 1647 (75.5%) were from Europe, 498 (22.8%) from North- and South America, and 36 (1.7%) from Australia. Execution of hysterectomy at risk-reducing salpingo-oophorectomy differed substantially between continents, with an execution of 48.8% in North- and South America, 14.2% in Australia, and 2.8% in Europe (P<.001). Execution of concurrent hysterectomy at risk-reducing salpingectomy in women from North- and South America occurred more often in women with a BRCA1 pathogenic variant compared to a BRCA2 pathogenic variant (adjusted odds ratio 0.4 [95% confidence interval, 0.2-0.7]). In the qualitative analysis, we interviewed 23 healthcare providers and identified 31 barriers and 32 facilitators regarding hysterectomy execution during risk-reducing salpingo-oophorectomy. A total of 8 different indications were mentioned, but opinions varied on the validity and weight given to each indication. Providers indicated that important barriers or facilitators for concurrent hysterectomy included a lack of clear guidelines, cultural variation between countries, (lack of) consensus within departments, and different interpretation of the endometrial cancer risk. CONCLUSION: Internationally, there is a large variation in execution of hysterectomy during risk-reducing surgery with frequent utilization in North- and South America, and rare utilization in Europe. This could be explained by the interpretation of indications for hysterectomy by providers, which might be explained by cultural variation, the absence of clear guidelines, and limited scientific evidence.

Humans↗

PubMed2026

Copy number variants in BRCA1 and BRCA2 genes in Polish patients with breast and ovarian cancer.

PURPOSE: BRCA1 and BRCA2 are key susceptibility genes in hereditary breast and ovarian cancer (HBOC), with mutational status guiding PARP inhibitor therapy. While single-nucleotide variants (SNVs) predominate, the prevalence of copy number variants (CNVs) varies significantly across different populations. This study aims to determine the incidence of BRCA1/2 CNVs in the Polish population, where data remain scarce due to non-mandatory CNV testing. METHODS: We retrospectively analysed the results of genetic tests assessing the presence of BRCA1/2 CNVs performed in 2720 individuals tested at the Lower Silesian Oncology Centre (2021-2024), including 2702 breast/ovarian cancer patients and 18 unaffected relatives. The mean age was 54.7 ± 15.15 years. Genetic testing involved DNA extraction, NGS, and MLPA for CNV confirmation. Variants were classified according to ACMG-AMP guidelines and verified through independent testing. RESULTS: In this study, no BRCA2 CNVs were identified, consistent with previous Central European findings. Pathogenic BRCA1 CNVs were detected in 0.85% of the analyzed cohort and in 0.52% of the cancer patient subgroup, affecting 23 individuals from 13 families. Eight distinct BRCA1 CNVs were detected, the most common being exon 21 deletion. Affected families exhibited a high incidence of HBOC-related cancers, with early-onset breast cancer and a notable proportion of triple-negative breast cancer cases. CONCLUSIONS: This study highlights the clinical significance of BRCA1 CNVs in Polish patients with HBOC-spectrum cancers and their families. Although rare, these variants were associated with aggressive cancer phenotypes and early onset. Given their diagnostic and therapeutic implications, BRCA1 CNVs should be routinely analysed in high-risk families to ensure accurate detection and personalised treatment planning.

Humans↗

PubMed2017

Reanalysis of BRCA1/2 negative high risk ovarian cancer patients reveals novel germline risk loci and insights into missing heritability.

While up to 25% of ovarian cancer (OVCA) cases are thought to be due to inherited factors, the majority of genetic risk remains unexplained. To address this gap, we sought to identify previously undescribed OVCA risk variants through the whole exome sequencing (WES) and candidate gene analysis of 48 women with ovarian cancer and selected for high risk of genetic inheritance, yet negative for any known pathogenic variants in either BRCA1 or BRCA2. In silico SNP analysis was employed to identify suspect variants followed by validation using Sanger DNA sequencing. We identified five pathogenic variants in our sample, four of which are in two genes featured on current multi-gene panels; (RAD51D, ATM). In addition, we found a pathogenic FANCM variant (R1931*) which has been recently implicated in familial breast cancer risk. Numerous rare and predicted to be damaging variants of unknown significance were detected in genes on current commercial testing panels, most prominently in ATM (n = 6) and PALB2 (n = 5). The BRCA2 variant p.K3326*, resulting in a 93 amino acid truncation, was overrepresented in our sample (odds ratio = 4.95, p = 0.01) and coexisted in the germline of these women with other deleterious variants, suggesting a possible role as a modifier of genetic penetrance. Furthermore, we detected loss of function variants in non-panel genes involved in OVCA relevant pathways; DNA repair and cell cycle control, including CHEK1, TP53I3, REC8, HMMR, RAD52, RAD1, POLK, POLQ, and MCM4. In summary, our study implicates novel risk loci as well as highlights the clinical utility for retesting BRCA1/2 negative OVCA patients by genomic sequencing and analysis of genes in relevant pathways.

Adult↗

PubMed2026

Brazilian Society of Surgical Oncology Analysis in Cost-Effectiveness of Population-Based BRCA Testing for Ovarian Cancer in the Public Health System.

Although ovarian cancer is the most lethal among gynecological cancers, access to massive BRCA testing is still limited. Its cost-effectiveness is still a topic of discussion in several countries. In Brazil, olaparib was recently incorporated into the public health system, access to BRCA testing is still limited. In this article, we aim to review the cost-effectiveness of offering BRCA testing to the at-risk population. A working group composed of 14 specialists in surgical oncology and cancer genetics was established to discuss the cost-effectiveness of population-based BRCA testing for ovarian cancer. The project was divided into five main areas, each with subtopics assigned among the 14 participants. They were: the existing clinical testing guidelines, the current healthcare infrastructure in the Brazilian public health system, cost-effectiveness analysis, challenges in implementing prophylactic surgeries, and family counseling and risk communication. A comprehensive literature review was conducted, followed by a series of meetings among the article's contributors to reach consensus on unresolved issues. These discussions aimed to build recommendations based on the best available scientific evidence. Using as a basis the current structure already existing within the Brazilian public health service (SUS [Sistema Único de Saude]), and based on the testing of the at-risk population chosen by our experts, we estimated savings. The net savings for a population of 100 000 women would range from BRL 7030.30 (US$1255.41) to BRL 1853.92 (US$331.05). And these costs could have an even greater impact when public service PARP inhibitors are incorporated. The working group of the Brazilian Society of Surgical Oncology understands that large-scale BRCA testing is cost-effective, especially when risk-reducing surgery is implemented. Other measures are important, such as training teams of non-specialists to recognize the population at risk, in addition to creating an entire line of care for patients with ovarian cancer in the SUS.

Humans↗

PubMed2024

Induced degradation of lineage-specific oncoproteins drives the therapeutic vulnerability of small cell lung cancer to PARP inhibitors.

Although BRCA1/2 mutations are not commonly found in small cell lung cancer (SCLC), a substantial fraction of SCLC shows clinically relevant response to PARP inhibitors (PARPis). However, the underlying mechanism(s) of PARPi sensitivity in SCLC is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in SCLC cells. We found that the vulnerability of SCLC to PARPi could be explained by the degradation of lineage-specific oncoproteins (e.g., ASCL1). PARPi-induced activation of the E3 ligase HUWE1 mediated the ubiquitin-proteasome system (UPS)-dependent ASCL1 degradation. Although PARPi induced a general DNA damage response in SCLC cells, this signal generated a cell-specific response in ASCL1 degradation, leading to the identification of HUWE1 expression as a predictive biomarker for PARPi. Combining PARPi with agents targeting these pathways markedly improved therapeutic response in SCLC. The degradation of lineage-specific oncoproteins therefore represents a previously unidentified mechanism for PARPi efficacy in SCLC.

Humans↗

PubMed2026

Risks of non-breast, non-ovarian cancers for BRCA1 and BRCA2 pathogenic variant carriers: a prospective cohort study.

BACKGROUND: The non-breast non-ovarian cancers associated with BRCA1 and BRCA2 pathogenic variants (PVs) are controversial. We aimed to examine this using a prospective cohort design. METHODS: This study included 1260 BRCA1 and 1058 BRCA2 PV carriers (91% were females) from two consortia: the Breast Cancer Family Registry (BCFR) and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer Follow-Up Study (kConFab-FUS). The carriers were free of cancer other than breast or ovarian cancer at baseline and had a median baseline age of 45.5 years. For 16 types of non-breast, non-ovarian cancers, standardized incidence ratios (SIRs) relative to population incidence, the probabilities of relative risk effect size > 2 (i.e., moderate risk) and cumulative risks to age 80 years were estimated. RESULTS: During a median follow-up time of 11.4 years, 161 non-breast, non-ovarian cancers were observed. For BRCA1 PV carriers, little evidence of increased risk was observed. The prostate, pancreatic, and all non-pancreatic cancer SIRs were 1.7 (95% CI 0.7-4.2), 1.1 (95% CI 0.3-4.6) and 0.85 (95% CI 0.68-1.06), respectively; the probabilities of relative risk > 2 were 0 and 67% for prostate and pancreatic cancers, respectively. For BRCA2 PV carriers, increased risks of pancreatic (SIR = 6.6, 95% CI 3.8-11.6), prostate (SIR = 3.6, 95% CI 1.9-6.8) and stomach (SIR = 3.1, 95% CI 1.01-9.8) cancer were observed, with a cumulative risk to age 80 years of 8.3, 82.0, and 1.6%, respectively. For all the other non-breast, non-ovarian cancers combined, the SIR was 0.85 (95% CI 0.66-1.10). CONCLUSIONS: Apart from pancreatic, prostate, and possibly stomach cancers for BRCA2 PV carriers, and possibly pancreatic cancer for BRCA1 PV carriers, there is no evidence that BRCA1 and BRCA2 PV carriers have substantially increased risks of other non-breast, non-ovarian cancers. Our prospective risk estimates are informative for cancer risk assessment for people with BRCA1 and BRCA2 PVs.

Humans↗

PubMed2026

Integrative proteomics reveals MSH6 to modulate PARP inhibitor sensitivity in BRCA1/2-proficient ovarian cancer.

Ovarian cancer remains a leading cause of gynecologic cancer-related deaths worldwide. Deficiencies in BRCA1/2 are well-established biomarkers that predict sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPis). However, emerging evidence indicates that a subset of BRCA-proficient tumors also responds to PARPi therapy, suggesting the presence of additional molecular mechanisms. We hypothesized that the composition of the PARP1 protein complex and PARylation-mediated signaling contribute to PARPi response in BRCA-proficient HGSOC. We assessed PARPi response across a panel of BRCA-proficient ovarian cancer cell lines and identified distinct sensitive and resistant groups. Chemical proteomics with rucaparib revealed different PARP1 complexes including higher enrichment of MSH6 in sensitive cells. Co-immunoprecipitation analyses further confirmed differential assembly of PARP1-MSH6-PARP2 complexes between sensitive and resistant models. To explore PARylation signaling, we performed ADP-ribosylation proteomics using clickable NAD⁺ analogs, revealing distinct PARylation profiles between sensitive and resistant cell lines. CHAF1A, a known MSH6 interactor and PARP1 substrate, showed more pronounced reduction in ADP-ribosylation in PARPi-sensitive cells. Targeting MSH6 using CRISPR or siRNA decreased PARPi sensitivity. In addition, mTOR signaling was reduced in sensitive, but increased in resistant cells, following rucaparib treatment. Notably, MSH6 knockdown led to increased CHAF1A expression regardless of rucaparib treatment. Importantly, knockdown of CHAF1A significantly impaired cell viability, especially in A2780 cells, and suppressed mTOR signaling, suggesting that CHAF1A acts downstream of MSH6 to regulate the mTOR axis. Furthermore, co-treatment with mTORC1 inhibitors enhanced the cellular effects of rucaparib in resistant cells, suggesting a therapeutic potential of targeting downstream mTOR effectors to overcome intrinsic resistance. In conclusion, this study identifies the PARP1-MSH6 interaction to modulate PARPi sensitivity via CHAF1A-mTOR signaling in BRCA-proficient ovarian cancer. By integrating chemical proteomics and ADP-ribosylation proteomics, we delineate the interplay between PARP1 complex composition and signaling dynamics, highlighting MSH6 as a critical modulator of PARPi response and potential biomarker to enhance therapeutic efficacy in BRCA-proficient HGSOC.

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↗

PubMed2025

BRCA genetic testing utilization and expenditures among privately insured adults in the United States, 2013 to 2022.

PURPOSE: Recent clinical guidelines have broadened the criteria for BRCA counseling and testing for women and men, including indications based on family history, personal history, and current diagnosis of breast, ovarian, pancreatic, and prostate cancer. METHODS: Using claims data from 2013 to 2022, we identified BRCA testing using procedure codes to evaluate annual utilization, median expenditures per enrollee, and the percentage of 0 out-of-pocket expenditures by sex among enrollees aged 18 to 64 years who were continuously enrolled within calendar years. We examined BRCA utilization by metropolitan status and indications. RESULTS: Annual BRCA testing utilization among women (and men) increased 10.2% (44.5%) per year during 2014 to 2015 and 1.7% (10.0%) per year during 2016 to 2019, decreased 34.4% (44.8%) in 2020, and rebounded 8.5% (22.3%) per year during 2021 to 2022, remaining below prepandemic levels in 2022. Median expenditures for comprehensive BRCA testing per enrollee decreased by 68% from 2013 to 2022, most of whom had 0 out-of-pocket expenditures. Most BRCA testing was done based on family health history of breast, ovarian, or prostate cancer and among women aged 18 to 50 years. CONCLUSION: Health care providers who are knowledgeable about evolving indications for germline BRCA testing can help ensure that eligible individuals have access to germline BRCA testing as preventive service.

Humans↗

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 BRCA1/2 status on young women's sexual function, relationships, and reproduction after predictive genetic testing.

The experiences and outcomes for women identified with a BRCA1/2 pathogenic variant during young adulthood are qualitatively described but not well quantified. This study investigated the impact of BRCA1/2 status on women's reproduction, intimate partner relationships, and sexual functioning. Australian women aged 18-40 years who had predictive BRCA1/2 testing, received either a positive or negative result, and had no personal cancer history, completed an online survey that used a case-control design. Outcome measures included childbearing, use of reproductive technologies, relationship status, and sexual functioning. 579 women participated (62.0% with a BRCA1/2 PV; 38.0% without a BRCA1/2 PV). More women with a BRCA1/2 PV had children compared to those who did not (49.0% c.f., 40.5%; p = 0.045). BRCA1/2 status did not predict whether women were partnered at survey completion (Odds Ratio 1.20; 95% CI 0.80, 1.78) or their sexual functioning over the previous month (β-coefficient -0.08; 95% CI -1.15, 0.98). Women with a BRCA1/2 PV were more likely to have children after genetic testing (OR 1.83: 95% CI 1.05, 3.21) and were more likely to have a greater number of children after genetic testing (β-coefficient 0.41; 95% CI 0.10, 0.73) compared to women without a BRCA1/2 PV, after adjustment for confounders. Receiving a positive predictive BRCA1/2 result is associated with an increased likelihood of childbearing and having a greater number of children compared to receiving a negative predictive BRCA1/2 result. These findings contribute to the evidence base to inform long-term follow-up for women after predictive BRCA1/2 testing.

Humans↗

PubMed2023

DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation.

The tumor suppressor BRCA2 participates in DNA double-strand break repair by RAD51-dependent homologous recombination and protects stressed DNA replication forks from nucleolytic attack. We demonstrate that the C-terminal Recombinase Binding (CTRB) region of BRCA2, encoded by gene exon 27, harbors a DNA binding activity. CTRB alone stimulates the DNA strand exchange activity of RAD51 and permits the utilization of RPA-coated ssDNA by RAD51 for strand exchange. Moreover, CTRB functionally synergizes with the Oligonucleotide Binding fold containing DNA binding domain and BRC4 repeat of BRCA2 in RPA-RAD51 exchange on ssDNA. Importantly, we show that the DNA binding and RAD51 interaction attributes of the CTRB are crucial for homologous recombination and protection of replication forks against MRE11-mediated attrition. Our findings shed light on the role of the CTRB region in genome repair, reveal remarkable functional plasticity of BRCA2, and help explain why deletion of Brca2 exon 27 impacts upon embryonic lethality.

DNA Replication↗

PubMed2025

Moss BRCA2 lacking the canonical DNA-binding domain promotes homologous recombination and binds to DNA.

BRCA2 is crucial for mediating homology-directed DNA repair (HDR) through its binding to single-stranded DNA (ssDNA) and the recombinases RAD51 and DMC1. Most BRCA2 orthologs have a canonical DNA-binding domain (DBD) with the exception of Drosophila melanogaster. It remains unclear whether such a noncanonical BRCA2 variant without DBD possesses a DNA-binding activity. Here, we identify a new noncanonical BRCA2 in the model plant Physcomitrium patens (PpBRCA2). We establish that PpBRCA2 is essential for genome integrity maintenance, somatic DNA double-strand break (DSB) repair, HDR-mediated gene targeting, and RAD51 foci recruitment at DNA break sites. PpBRCA2 is also critical for DSB repair during meiosis. Interestingly, PpBRCA2 interacts strongly with RAD51 but weakly with DMC1, suggesting a distinct meiotic function compared to other BRCA2 homologs. Despite lacking the canonical DBD, PpBRCA2 binds ssDNA through its disordered N-terminal region and efficiently promotes HDR. Our work highlights that the ssDNA binding capacity of BRCA2 homologs is conserved regardless of the presence of a canonical DBD and provides a deeper understanding of BRCA2's functional diversity across species.

BRCA2 Protein↗

PubMed2026

Real-World Outcomes of Olaparib in Japanese Patients With BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer: Exploratory Analysis of BRCA2 Loss and Microsatellite Instability Status.

OBJECTIVES: Metastatic castration-resistant prostate cancer has a poor prognosis. Although olaparib has demonstrated efficacy in patients with BRCA1/2 mutations, real-world data in Japanese patients remain limited. We aimed to evaluate the efficacy and safety of olaparib in patients with BRCA-mutated metastatic castration-resistant prostate cancer and explore the association of BRCA2 loss and microsatellite instability status with treatment outcomes. METHODS: We conducted a multicenter retrospective study of 34 patients with BRCA-mutated metastatic castration-resistant prostate cancer treated with olaparib between December 2020 and December 2024. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, prostate-specific antigen-50 response rate, and safety. Exploratory analyses were performed. RESULTS: Among the 34 patients, 33 had a BRCA2 mutation and one had a BRCA1 mutation. Prostate-specific antigen reduction was observed in 76.4% of patients; prostate-specific antigen-50 response rate was 58.8%. Median progression-free and overall survival were 15.8 and 35.1 months, respectively. Grade ≥ 3 adverse events (most commonly anemia) occurred in 17.6% of patients. Treatment discontinuation due to adverse events occurred in one patient. Exploratory analyses were performed in 23 BRCA2-mutated patients who underwent comprehensive genomic profiling. BRCA2 loss was observed in 39.1% of patients and showed a trend toward prolonged progression-free survival, whereas microsatellite instability-high status was observed in 13.0% and was associated with shorter progression-free survival. CONCLUSIONS: Olaparib demonstrated efficacy and safety in Japanese patients with BRCA-mutated metastatic castration-resistant prostate cancer. Exploratory analyses revealed that BRCA2 loss may be associated with prolonged progression-free survival, whereas microsatellite instability-high status may be associated with shorter progression-free survival. These findings require validation in larger cohorts.

Humans↗

PubMed2026

Updated ENIGMA recommendations for reporting germline variants in cancer susceptibility genes and their translation into twenty languages.

Genetic testing for cancer susceptibility underpins precision cancer prevention and care. Gaps in the healthcare providers' genetic literacy and an ambiguous lexicon for variant description may hinder proper delivery and clinical application of consistently trustworthy test results. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) international consortium supports controlled terminology and recommends a framework for reporting germline variants in cancer susceptibility genes, using breast cancer as an exemplar. Moving forward towards terminological coherence across disciplines and borders, the ENIGMA Clinical Working Group launched a multinational effort to release consortium-approved translations of the published recommendations. The herein reported Vocabulary Translation Project offered an opportunity to reappraise and align the reference text to the recent BRCA1 and BRCA2 specifications to the American College of Medical Genetics and Genomics/Association for Molecular Pathology rules by the ENIGMA Variant Curation Expert Panel and to highlight country-specific differences in breast cancer risk assessment and management. The updated recommendations and their 20 translations are now provided as easy to handle documents, covering 11 of the most widely spoken languages in the world. They will contribute to minimised erroneous inferences, more informed decision-making, improved health outcomes and equity in the use of genetic testing for cancer predisposition and in translational oncology.

Humans↗