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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↗

PubMed2026

Prevalence of BRCA1/2 variants in an Ovarian Cancer Cohort: outcomes from a Nationwide Testing Program.

Poly(ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the management of BRCA1- and BRCA2-associated ovarian cancer (OC). In 2020, Ireland implemented a nationwide, oncology-led pathway for mainstreamed BRCA1/2 testing in patients with OC. This study evaluated the pathway and characterised the BRCA1/2 landscape in an Irish cohort of patients with OC. Samples collected between January 2020 and December 2023 were tested in two national molecular diagnostic laboratories. Single-molecule molecular inversion probe sequencing was used to detect single nucleotide variants, while multiplex ligation-dependent probe amplification assessed large genomic rearrangements. Variants were classified according to the American College of Medical Genetics and Genomics and Association for Clinical Genomic Science 2020 guidelines and CanVIG-UK specifications. In total, 535 patients were included, with a median age of 65.5 years (range, 27-89 years). Of these, 455/535 (85.0%) underwent germline BRCA1/2 (gBRCA) testing using peripheral blood, and 360/535 (67.2%) underwent tumour BRCA1/2 (tBRCA) testing, resulting in 292/535 (54.6%) patients having paired testing. Among gBRCA-tested patients, 10.3% (47/455) had a clinically actionable variant (CAV), while 2.1% (10/455) had a variant of uncertain significance. Of the 262 patients who underwent paired testing and had negative gBRCA results, 9.5% (25/262) had a somatic BRCA CAV. Recurrent germline BRCA CAVs were identified in regional clusters, including BRCA1 c.5266dup, BRCA1 c.1175_1214del, and BRCA2 c.4398_4402del. This nationwide real-world study demonstrates that mainstreamed germline and somatic BRCA1/2 testing is feasible in Ireland and reports the prevalence of BRCA CAVs in a cohort of patients with OC. Although the observed prevalence of germline BRCA CAVs was lower than anticipated, it is consistent with UK real-world data. The identification of recurrent, regionally clustered germline variants further enhances the characterisation of the Irish genomic landscape.

Journal Article↗

PubMed2022

Lurbinectedin, a selective inhibitor of oncogenic transcription, in patients with pretreated germline BRCA1/2 metastatic breast cancer: results from a phase II basket study.

BACKGROUND: Lurbinectedin, a selective inhibitor of oncogenic transcription, has shown preclinical antitumor activity against homologous recombination repair-deficient models and preliminary clinical activity in BRCA1/2 breast cancer. PATIENTS AND METHODS: This phase II basket multitumor trial (NCT02454972) evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 21 patients with pretreated germline BRCA1/2 breast cancer. Patients with any hormone receptor and human epidermal growth factor receptor 2 status were enrolled. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Confirmed partial response (PR) was observed in six patients [ORR = 28.6%; 95% confidence interval (CI) 11.3% to 52.2%] who had received a median of two prior advanced chemotherapy lines. Lurbinectedin was active in both BRCA mutations: four PRs in 11 patients (36.4%) with BRCA2 and two PRs in 10 patients (20.0%) with BRCA1. Median DoR was 8.6 months, median PFS was 4.1 months and median OS was 16.1 months. Stable disease (SD) was observed in 10 patients (47.6%), including 3 with unconfirmed response in a subsequent tumor assessment [ORR unconfirmed = 42.9% (95% CI 21.8% to 66.0%)]. Clinical benefit rate (PR + SD ≥ 4 months) was 76.2% (95% CI 52.8% to 91.8%). No objective response was observed among patients who had received prior poly (ADP-ribose) polymerase inhibitors. The most common treatment-related adverse events (AEs) were nausea (61.9%), fatigue (38.1%) and vomiting (23.8%). These AEs were mostly grade 1/2. The most common grade 3/4 toxicity was neutropenia (42.9%: grade 4, 23.8%: with no febrile neutropenia). CONCLUSIONS: This phase II study met its primary endpoint and showed activity of lurbinectedin in germline BRCA1/2 breast cancer. Lurbinectedin showed a predictable and manageable safety profile. Considering the exploratory aim of this trial as well as previous results in other phase II studies, further development of lurbinectedin in this indication is warranted.

Humans↗

PubMed2026

Psychologically informed reminder messages for promoting BRCA1/2 carrier screening: evidence from a large-scale population-based study.

Psychologically Informed Reminder Messages (PIRMs) may promote health-behavior change, but their impact on preventive genetic screening is unclear. Due to low adherence to a screening program, Clalit Health Services initiated an intervention to encourage BRCA1/2 carrier screening in July 2022. This observational study assesses the effectiveness of the intervention in encouraging screening and its spillover effect on related healthcare utilization, focusing on Ashkenazi Jewish females aged 25-50 with no relevant cancer history. Patients were randomly assigned to receive one of five PIRMs. Four PIRMs utilized different psychological strategies, while the fifth served as a control. The effectiveness of the intervention on screening adherence was assessed using a regression discontinuity analysis. A Cox regression assessed the effectiveness of the four PIRMs compared to the control. Spillover effects on healthcare utilization were evaluated using logistic regressions. The intervention showed a positive correlation with increased adherence to screening (β = 0.37, 95% CI: 0.01-0.72). The "Barrier Remover" PIRM emphasized ease (hazards ratio = 1.09, 95% CI: 1.02-1.16), while the "Health Control" PIRM focused on autonomy (hazards ratio = 1.07, 95% CI: 1.01-1.14), both indicating greater effectiveness than the control. The findings suggest a positive short-term spillover effect of the "Health Control" PIRM on healthcare utilization compared to the control (odds ratio = 1.16, 95% CI: 1.04-1.29). PIRMs effectively increased BRCA1/2 carrier screening adherence, demonstrating a scalable, low-cost intervention to improve preventive healthcare uptake. The effect varied by the psychological strategies, highlighting the potential of tailored behavioral interventions to enhance public health.

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

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↗

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↗

PubMed2017

Predictors of BRCA1/2 genetic testing among Black women with breast cancer: a population-based study.

Evidence shows that Black women diagnosed with breast cancer are substantially less likely to undergo BRCA testing and other multipanel genetic testing compared to White women, despite having a higher incidence of early-age onset breast cancer and triple-negative breast cancer (TNBC). Our study identifies predictors of BRCA testing among Black women treated for breast cancer and examines differences between BRCA testers and nontesters. We conducted an analysis of 945 Black women ages 18-64 diagnosed with localized or regional-stage invasive breast cancer in Pennsylvania and Florida between 2007 and 2009. Logistic regression was used to identify predictors of BRCA 1/2 testing. Few (27%) (n = 252) of the participants reported having BRCA testing. In the multivariate analysis, we found that perceived benefits of BRCA testing (predisposing factor) ([OR], 1.16; 95% CI: 1.11-1.21; P < 0.001), income (enabling factor) ([OR], 2.10; 95% CI: 1.16-3.80; p = 0.014), and BRCA mutation risk category (need factor) ([OR], 3.78; 95% CI: 2.31-6.19; P < 0.001) predicted BRCA testing. These results suggest that interventions to reduce disparities in BRCA testing should focus on identifying patients with high risk of mutation, increasing patient understanding of the benefits of BRCA testing, and removing financial and other administrative barriers to genetic testing.

Adolescent↗

PubMed2026

Liquid biopsy: a new window on the BRCA genes.

The Breast Cancer Susceptibility Gene (BRCA)-associated tumors represent a constantly evolving and intriguing scenario in oncology, in which the availability of novel systemic treatment, mainly including the poly (ADP-ribose) polymerase (PARP) inhibitors, has enabled an improved survival benefit in clinical subgroups. The expanding regulatory approvals of PARP inhibitors have inevitably reshaped the clinical indications for BRCA testing, moving the BRCA1/2 profiling from the traditional and preventive workflows to therapeutic paths. Despite advances in technology and treatment, substantial limitations remain in current genetic and genomic tools for the detection of deleterious BRCA1/2 variants. Germline and tumor tissue testing provide only a snapshot of a patient's disease, failing to capture the dynamic and longitudinal aspects of tumor clonal evolution. In this scenario, liquid biopsy (LB) profiling of BRCA1/2 genes, primarily as circulating tumor DNA, represents a highly active area of research potentially affecting many aspects of cancer screening, diagnosis, and monitoring in individuals who are carriers of BRCA1/2 deleterious variants. Beyond the attractive potential to surrogate the tumor tissue testing, to overcome the cancer spatial and temporal heterogeneity, and to monitor the tumor mutational profile over time, accurately detecting all clinically relevant BRCA genetic variants and epigenetic modifications using LB remains technically challenging.

BRCA1/2↗

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↗

PubMed2021

Towards a CRISPeR understanding of homologous recombination with high-throughput functional genomics.

CRISPR-dependent genome editing enables the study of genes and mutations on a large scale. Here we review CRISPR-based functional genomics technologies that generate gene knockouts and single nucleotide variants (SNVs) and discuss how their use has provided new important insights into the function of homologous recombination (HR) genes. In particular, we highlight discoveries from CRISPR screens that have contributed to define the response to PARP inhibition in cells deficient for the HR genes BRCA1 and BRCA2, uncover genes whose loss causes synthetic lethality in combination with BRCA1/2 deficiency, and characterize the function of BRCA1/2 SNVs of uncertain clinical significance. Further use of these approaches, combined with next-generation CRISPR-based technologies, will aid to dissect the genetic network of the HR pathway, define the impact of HR mutations on cancer etiology and treatment, and develop novel targeted therapies for HR-deficient tumors.

Gene Regulatory Networks↗

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

Estimands for Clinical Effectiveness of Risk-Reducing Early Salpingectomy in Women With High Risk of Ovarian Cancer.

IMPORTANCE: Risk-reducing early-salpingectomy (RRES) and delayed oophorectomy (DO) is a novel 2-stage alternative prevention strategy to risk-reducing salpingo-oophorectomy (RRSO) that avoids detrimental consequences of premature menopause. However, direct data on the clinical effectiveness for ovarian cancer (OC) risk reduction are lacking. OBJECTIVE: To explore how to define clinical effectiveness from prospective cohort studies using the estimand framework and sample size requirements. DESIGN, SETTING, AND PARTICIPANTS: In this comparative effectiveness research study, estimand and analysis options were considered to evaluate the clinical effectiveness of RRES with DO by extending the UK PROTECTOR cohort study, a multicenter, prospective, observational, national cohort study (N = 1250 recruited from January 1, 2019, to December 31, 2024) evaluating RRES and DO for OC surgical prevention. Participants were premenopausal women 30 years or older at increased OC risk due to BRCA1/BRCA2 pathogenic variants. Participants could choose RRES, RRSO, or no surgery at entry. Sample size requirements used initial data (eg, age and BRCA1/2 distribution) from PROTECTOR (analysis undertaken from January 1, 2024, to December 31, 2025). MAIN OUTCOMES AND MEASURES: Incidence of OC after (not at) RRES and before or at DO in women with normal histologic analysis findings at surgery. The proportion of cancers prevented was estimated as the completement of the observed (O) to expected (E; assuming no preventive effect of surgery) number of cancers detected (1 - O/E). RESULTS: Initial data were obtained from 889 women in PROTECTOR (overall mean [SD] age, 39 [5] years), with 255 (28.7%) choosing RRSO (mean [SD] age, 42 [4] years), 405 (45.5%) choosing RRES (mean [SD] age, 38 [4] years), and 229 (25.7%) choosing no surgery (mean [SD], 38 [5] years). The preferred estimand outcome was OC incidence after surgery (RRES or RRSO) with a "while on intervention" strategy to account for intercurrent events. The primary target measure was the proportion of cancers prevented for RRES vs no surgery with superiority testing. The secondary target measure was noninferiority of RRES vs RRSO. An estimated 1150 RRES participants with 8 to 10 years of follow-up would provide approximately 92% power to show that 20% or more of cancers are prevented using a 1-sample binomial test of the O:E risk (external reference) at the 5% level under a range of assumptions and at least the same power for a noninferiority margin for the proportion of cancers prevented by RRES of those prevented by RRSO. Estimands based on incidence ratios had an infeasible sample size. CONCLUSIONS AND RELEVANCE: In this comparative effectiveness study of UK BRCA carriers, the estimand differed from other ongoing clinical effectiveness studies of RRES and DO. Advantages include direct use of expected risk at baseline (unknown at design stage), easier interpretation across cohorts than absolute risk differences, and providing a feasible recruitment target for PROTECTOR to evaluate clinical effectiveness.

Humans↗

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

Translational case series comparing next-generation sequencing profiles of primary breast cancer and brain metastases.

BACKGROUND: Breast cancer (BC) is a heterogeneous disease, and its molecular and immunohistochemical (IHC) profiles may change over time, particularly under therapeutic pressure. IHC discordance between primary tumors and BC brain metastases (BCBM) has been reported, yet its biological and clinical significance remains incompletely defined. Genomic profiling using next-generation sequencing (NGS) may provide additional insight into tumor evolution and clonal selection, although data from paired BC and BCBM are limited. METHODS: This translational case series included six patients randomly selected from an institutional cohort of BC patients who underwent neurosurgical resection of BCBM. IHC reassessment (ER, PR, and HER2) and NGS profiling using targeted panels were performed. RESULTS: Three of the six cases presented with IHC discordance, mainly loss of HR expression and gain of HER2 in BCBM. Genomic profiling identified 23 mutations in primary tumors compared with four in BCBM. BRCA1/2 variants predominated in primary tumors (21/23, 91%), most predicted to result in loss-of-function alterations. One mutation (PIK3CA/N345K) was shared between primary and metastatic tissues within the same patient. Overall survival ranged from 28 to 146 months. CONCLUSION: This paired analysis demonstrates immunophenotypic and genomic divergence between BC and BCBM, supporting the concept of dynamic tumor evolution. Receptor conversion and emergence or loss of actionable genomic alterations highlight the potential value of repeat molecular assessment in advanced stages. Although limited by a small sample size, retrospective design, and absence of matched germline testing, these findings reinforce the importance of integrating biomarker reevaluation into the management of selected patients.

Humans↗

PubMed2026

Prevalence of homologous recombination repair genes alterations in metastatic castration-resistant prostate cancer, a multicentric study.

INTRODUCTION: Homologous Recombination Repair (HRR) genes alterations are a resistance mechanism to therapies by taxanes or Androgen Receptor Signalling inhibitors in Metastatic Castration Resistant Prostate Cancer (mCRPC). BRCA-mutated mCRPC patients are eligible to poly adenosine diphosphateribose polymerase inhibitors (PARPi). Therefore, assessing the population-specific prevalence of HRR-related genes alterations is of public healthcare importance. METHODS: This retrospective, non-interventional, multicentric study was conducted across 6 reference French centers in a "real-life" setting. 788 paraffin-embedded mCRPC patient-samples were included and submitted to testing for BRCA1/2 in six different centers; additionally, non-BRCA HRR-related genes were investigated in two different centers. RESULTS: Among the samples, n=602 (76.4%) were contributive for molecular testing. In multivariate analysis by logistic regression and sensitivity analysis, only sample age (P<0.01), sample surface area (P=0.02) and institution (P=0.018) remained statistically significant. BRCA alterations were detected in n=39/602 (6.5%) of contributive samples, with n=35 and n=4 alterations of BRCA2 and BRCA1 respectively. Non-BRCA HRR-related genes alterations were detected in n=12/157 (7.6%) of contributive samples, with alterations of mainly ATM (n=6, 3.8%), CDK12 (n=4, 2.5%) and CHEK2 (n=2, 1.3%). DISCUSSION: In this study, testing contributivity was similar or higher that of other studies in the literature, and observed mutations prevalences were similar to that of other screenings of western populations. Harmonising per-centres protocols and enhancing molecular testing contributivity with the screening of circulating DNA samples and expanding its range by including non-BRCA HRR-related genes in all reference centres will enable more patients to be accurately treated by targeted therapies. LEVEL OF EVIDENCE: 3 (grade C).

Male↗

PubMed2025

Clinicopathologic and Molecular Analysis of Colorectal Carcinomas With Spectrum of Neuroendocrine Carcinoma Components.

The genetics of colorectal carcinoma (CRC) with neuroendocrine differentiation remain poorly understood; recent studies focusing on pure neuroendocrine carcinomas (NECs) demonstrated mutation profiles closely resembling colorectal adenocarcinomas (ACAs) with more frequent BRAF mutations and Rb/p16 pathway dysregulation. However, pathogenesis of mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) and ACAs with minor NEC component (AMiNECs) remains controversial. We aimed to define the behavior and molecular underpinnings of these tumors in comparison with conventional ACAs. In total, 20 NECs, 10 MiNENs, and 8 AMiNECs were compared with 100 controls with ACAs. Well-differentiated neuroendocrine tumors of any grade were excluded. CRCs with NEC components presented at a slightly earlier age (mean, 59 vs 65 years; P = .24) in a similar sex distribution (male:female, 1:1.11 vs 1.04:1; P = .97). The majority of cases arose either from a precursor adenoma (42%) or in the setting of inflammatory bowel disease (18%), whereas 5 of 10 cases (50%) originating from the rectum were human papillomavirus driven. Despite similarity in tumor size and depth of invasion among all groups, CRCs with NEC components showed more frequent lymph node and distant metastases (P < .001 each), leading to more advanced disease stage (stage III/IV; P < .001) and worse 5-year survival outcomes (35.4% for NECs, 30% for MiNENs, and 41.6% for AMiNECs vs 85.1% for ACAs; P < .001), compared with ACAs. Next-generation sequencing revealed more frequent BRAF (40% vs 3%; P < .001) and BRCA1 alterations (15% vs 1%; P = .001) in NECs compared with ACAs. Genomic alterations in RB1 were exclusively found in NECs (10%) and MiNENs (20%). In conclusion, the presence of any NEC component (from AMiNEC to pure NEC) in CRC carries a dismal prognosis. Yet, these tumors are more likely to harbor potentially targetable mutations such as BRAF p.V600E and alterations in BRCA1/2, which are of therapeutic value.

Humans↗

PubMed2025

Noncompetitive Inhibition of DNA Polymerase β by a Nonnative Nucleotide.

Base excision repair (BER) is a DNA repair pathway responsible for protecting the genome against modified nucleotides. DNA polymerase β (Pol β) participates in this process by removing the remnants of a damaged nucleotide and filling in the resulting gap. Pol β is overexpressed in some cancers and is synthetic lethal in cells deficient in BRCA1/2, providing additional impetus for identifying inhibitors of this enzyme. We report noncovalent Pol β inhibitors that are nonnative nucleotides. The inhibitors were identified via a combination of structural and biochemical analysis, as well as serendipity, from an initial library of covalent inhibitor candidates in which diversity was introduced sequentially at the C3'- and C5-positions of pyrimidine nucleotides. The molecules are among the most potent Pol β inhibitors (Ki ≤ 70 nM) of the enzyme's polymerase and lyase activities. Kinetic analyses reveal that the molecules inhibit Pol β noncompetitively. Fluorescence anisotropy and kinetic experiments reveal that the more potent inhibitor binds in the lyase domain and does not prevent DNA binding. Neither the more potent noncompetitive inhibitor nor a neutral protide exhibits cytotoxic synergism with the DNA damaging agent methyl methanesulfonate in HeLa cells. Cell permeability experiments suggest that micromolar levels of the more potent noncompetitive inhibitor and corresponding protide are taken up by HeLa cells following 24 h incubation (25 μM). However, based upon a comparison with other molecules, it is possible that they are membrane bound. The molecules identified could be useful tools in biochemical studies and provide a starting point for creating new Pol β inhibitors that function in cells.

DNA Polymerase beta↗