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PubMed2026

Associations of TILs and genomic alterations in HER2+ early breast cancer.

This study investigated the associations between tumor-infiltrating lymphocytes (TILs), genomic features, and prognosis in HER2+ early breast cancer (EBC) patients receiving adjuvant trastuzumab. We retrospectively analyzed 864 HER2+ EBC patients from Shanghai Ruijin Hospital (2009-2017). The optimal threshold of TILs for predicting disease-free survival (DFS) and overall survival (OS) was explored. Whole-exome sequencing (WES) on 261 tumors assessed the mutational profiles, tumor mutational burden (TMB), and copy number alteration (CNA). Associations between these genomic features, TIL levels, and prognosis were further evaluated. TILs showed a right-skewed distribution (median: 15%, IQR: 1-30%), and higher TIL levels were significantly associated with hormone receptor negativity and high histologic grade (P < 0.001). A 15% TIL threshold optimally predicted prognosis, with low-TIL (≤15%, 63.0%) patients showing inferior DFS (HR: 1.63, P = 0.009) and OS (HR: 2.12, P = 0.037). WES identified frequent mutations in TP53 (62.8%), PIK3CA (34.5%), and BRCA2 (9.6%). A higher TIL density was observed in TP53-wild-type, low-TMB or low-CNA tumors (P < 0.05). PIK3CA mutations conferred a significant DFS advantage. Integrating TIL level with PIK3CA or BRCA2 mutational status yielded distinct DFS trajectories (log-rank P = 0.023 and 0.040, respectively); patients with both high TIL levels and either PIK3CA or BRCA2 mutations had the most favorable outcomes. Stromal TILs at a 15% cutoff provide robust prognostic information in trastuzumab-treated HER2+ EBC. Integrating TIL levels with PIK3CA or BRCA2 mutational status enables refined risk stratification, offering a practical framework for personalized treatment decisions.

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

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

Impact of homologous recombination repair gene mutations on survival in metastatic prostate cancer: A real-world analysis from an observational database.

The prognostic significance of homologous recombination repair gene (HRRg) mutations across the different metastatic prostate cancer stages remains unclear. This retrospective real-world study analyzed 162 metastatic castration-sensitive (mCSPC) and 126 castration-resistant (mCRPC) patients from the ProGène database, stratified by HRRg mutational status. Mutation prevalence was similar in both groups (16.0% in mCSPC vs. 13.5% in mCRPC). HRR-positive mCSPC patients had significantly shorter median overall survival (OS) (24.0months; 95% confidence interval [CI]: 16.0-41.0) compared to HRR-negative patients (45.0months; 95% CI: 34.0-69.0; P=0.04). Notably, BRCA2-mutated patients exhibited a reduced median OS of 24.0months (95% CI: 9.0-40.0; P=0.036) and a faster progression-free survival compared to HRR-negative patients (median PFS=8.0months; 95% CI: 0.0-14.0 vs. 17.0months; 95% CI: 12.0-20.0; P=0.006). These findings suggest that HRRg mutations - especially BRCA2 - are associated with worse prognosis in mCSPC, supporting the value of early genomic screening to guide personalized treatment strategies.

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↗

PubMed2025

Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma.

BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n=1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Journal Article↗

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↗

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

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↗

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↗

PubMed2025

Established Cancer Predisposition Genes in Single and Multiple Cancer Diagnoses.

IMPORTANCE: Much of the understanding of cancer risk associated with rare pathogenic variants (RPVs) is derived from family-based studies or clinically ascertained samples, which may be limited by ascertainment and selection bias. OBJECTIVE: To quantify associations between RPVs in previously implicated cancer predisposition genes and single and multiple cancer diagnoses in a large population-based study. DESIGN, SETTING, AND PARTICIPANTS: In this genetic association study, whole-exome sequencing data were used from the UK Biobank, a UK population-based cohort that enrolled participants aged 40 to 69 years between 2006 and 2010. Participants who were involved in the whole-exome sequencing release of 200 000 genomes in 2020 were included in this study. This analysis included White participants only, as findings in other racial and ethnic groups had small sample sizes. Participants were diagnosed before or after biobank enrollment until March 2024. EXPOSURES: The sequencing data of a set of 96 previously implicated cancer predisposition genes were analyzed and compared using 2 methods. To determine the statistical significance of an association, a robust optimal sequence kernel association test was used, while odds ratios (ORs) and 95% CIs were obtained through Firth logistic regression. MAIN OUTCOMES AND MEASURES: The primary study outcome was the diagnosis of 1 of 11 cancers (bladder, breast, central nervous system, colorectal, lung, melanoma, ovary, pancreatic, prostate, renal, thyroid) defined by relevant diagnosis codes in inpatient hospital diagnosis, cancer registry, and/or death registry data. RESULTS: Data from 183 627 participants (101 414 [55.2%] female) were analyzed, including 25 824 participants with at least 1 cancer diagnosis, of whom 23 704 (91.8%) had a single cancer diagnosis and 2130 (8.2%) had 2 or more cancer diagnoses. A total of 157 793 controls had no cancer diagnosis. The median (IQR) age was 62 (56-65) years in participants with at least 1 cancer diagnosis, compared to 57 (50-63) years in those without a cancer diagnosis. Genetic variation in 16 genes was significantly associated with at least 1 cancer of interest (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDKN2A, CHEK2, HOXB13, MITF, MLH1, MSH2, MSH6, NF1, PALB2, RAD51C, and RAD51D). The presence of an RPV in 1 of these 16 genes was associated with increased odds of at least 1 cancer (OR, 1.87; 95% CI, 1.76-1.98) and multiple primary cancers (OR, 2.56; 95% CI, 2.18-2.99). Carrier frequency was 6.28% and 8.36%, respectively. CONCLUSIONS AND RELEVANCE: This genetic association study demonstrates several established associations between cancer predisposition genes and cancer diagnoses in an unselected population-based study. These results also demonstrate that RPVs in cancer predisposition genes are associated with multiple primary cancer diagnoses, suggesting that multigene panel testing may be warranted in these individuals.

Humans↗

PubMed2026

Long-Term Outcomes in Patients With Recurrent Ovarian Cancer and Exceptional Response to PARP Inhibitors.

IMPORTANCE: A subset of patients with platinum-sensitive recurrent ovarian cancer (PS-ROC) treated with maintenance poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have exceptional response. Although licensing recommends continuing PARP inhibitors until progression or unacceptable toxic effects, the optimal duration of PARP inhibitors, and the risks of late progression, myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML) in patients with exceptional response are unknown. OBJECTIVE: To determine the long-term outcomes of patients with PS-ROC who have exceptional response to PARP inhibitors, and to explore genotype-phenotype associations. DESIGN, SETTING, AND PARTICIPANTS: This was an international, multicenter, retrospective cohort study of patients with exceptional response to PARP inhibitors, defined as patients with PS-ROC and progression-free survival (PFS) of 5 years or longer from PARP inhibitor commencement. The study was conducted across 41 sites in 14 countries from January 11, 2023, to November 10, 2025. EXPOSURES: Treatment with PARP inhibitors. MAIN OUTCOMES AND MEASURES: The primary end point was PFS, and secondary end points included overall survival, toxic effects, and dose reductions. RESULTS: A total of 320 patients with exceptional response (mean [SD] age, 56.4 [9.4] years) were included, with a median follow-up of 6.8 years (95% CI, 6.6-7.0 years). The median (IQR) PARP inhibitor duration was 75.0 (64.0-91.0) months. Of patients with exceptional response, 211 (65.9%) received continuous PARP inhibitors, but 109 (34.1%) discontinued: 34 (10.6%) due to physician recommendation, 2 (7.5%) had disease progression beyond 5 years, 22 (6.9%) had toxic effects, 17 (5.3%) for patient preference, and 12 (3.8%) for another reason. The 7.5-year and 10-year PFS rates were 88.8% (95% CI, 84.5%-93.3%) and 78.7% (95% CI, 70.5%-87.9%), respectively. Among the patients, 85 (26.6%) discontinued PARP inhibitors for reasons other than disease progression, with a 10-year PFS of 90.1% (95% CI, 80.6%-100%) vs 72.5% (95% CI, 60.3%-87.2%) for those who continued taking PARP inhibitors. Five patients (1.6%) were diagnosed with late-onset MDS/AML. Patients with exceptional response were enriched for variants in the BRCA1 RING domain and the BRCA2 DNA-binding domain. CONCLUSIONS AND RELEVANCE: In this cohort study, most patients with exceptional response to PARP inhibitors remained progression free, including those who discontinued PARP inhibitors without progression. The risk of late-onset MDS/AML was low. These results can guide counseling on the duration of maintenance PARP inhibitors in patients with exceptional response and suggest that functional cure may be possible in patients with PS-ROC and exceptional response to PARP inhibitors.

Humans↗

PubMed2025

Germline variants in CDKN2A wild-type melanoma prone families.

Germline pathogenic variants in CDKN2A are well established as an underlying cause of familial malignant melanoma. While pathogenic variants in other genes have also been linked to melanoma, most familial cases remain unexplained. We assessed pathogenic germline variants in 360 cancer-related genes in 56 Norwegian melanoma-prone families. The index cases were selected based on familial history of melanoma and/or multiple primary melanomas, along with previous negative tests for pathogenic CDKN2A variants. We found 6 out of 56 index individuals to carry germline pathogenic or likely pathogenic variants in BRCA2, MRE11, ATM, MSH2, CHEK2, and AR. One family member with melanoma (not index case) carried a pathogenic variant in MAP3K6. In addition, we found a high fraction of variants previously considered benign and/or as variants of uncertain significance in xeroderma pigmentosum-related genes. In particular, XPCL48F was found in 8 indexes; thus, the allele fraction (0.07) was significantly higher than in comparable healthy populations (0.02-0.03; P-values from 0.007 to 0.014). In conclusion, we found that several melanoma-prone families have pathogenic variants in genes not usually linked to melanoma.

Humans↗

PubMed2026

Bipolar Androgen Therapy as a Potential Mechanistic Bridge to Enhance PARP Inhibitor Efficacy in Prostate Cancer.

Prostate cancer remains a leading cause of cancer-related mortality, largely driven by progression to metastatic castration-resistant prostate cancer (mCRPC). Although poly(ADP-ribose) polymerase inhibitors (PARPis) have improved outcomes in patients with homologous recombination repair (HRR) alterations, particularly in BRCA2-mutated disease, their clinical benefit is limited by restricted patient selection, modest efficacy in non-BRCA HRR alterations, and the frequent emergence of resistance. These limitations highlight an unmet need for strategies that can both expand the therapeutic population and overcome PARPi resistance. Bipolar androgen therapy (BAT), which alternates between supraphysiological and near-castrate androgen exposure, has emerged as a paradoxical yet clinically active approach in mCRPC. Unlike conventional androgen deprivation strategies, preclinical evidence suggests that BAT induces acute androgen receptor-mediated DNA damage while simultaneously suppressing HRR gene expression. This dual effect may generate a transcription-coupled homologous recombination-deficient state that is independent of canonical baseline genomic HRR alterations, thereby potentially sensitizing tumors to PARP inhibition. Current clinical trials of BAT combined with PARP inhibitors suggest activity in both HRR-deficient and HRR-proficient disease. Collectively, these findings suggest a preliminary, hypothesis-generating conceptual framework in which BAT may expand the therapeutic scope of PARPis beyond genomically defined HRR-mutated tumors and may help counteract mechanisms of PARPi resistance in mCRPC.

PARP inhibitor↗

PubMed2026

RNA splicing evidence enables robust classification of BRCA1 exon 18 variants: Results from the ENIGMA consortium.

The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) research consortium conducted a comprehensive study to characterize spliceogenic variants in BRCA1 exon 18. The absence of systematic RNA-based assessment for these variants has led to inconsistent interpretation, limiting accurate classification and management of individuals and their families. The splicing profile of 166 variants was assessed using minigene assays; 32 were additionally analyzed in blood-derived RNA from 51 individuals and 18 in mouse embryonic stem cell (mESC)-based assays to evaluate homology-directed repair (HDR) capacity. mRNA assessment by RT-PCR in blood samples and minigene assays showed a significant positive correlation, with splicing analysis in mESCs displaying highly concordant results. The mESC-based HDR assay showed that the in-frame exon 18 skipping (Δ18) transcript encodes a non-functional protein lacking rescue activity. Linear regression analysis using mESC splicing and functional data indicated that ≥59% of full-length (FL) levels and <34% of Δ18 were associated with benign HDR activity. These thresholds differ from those recommended by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) specifications for applying BP7_strong(RNA): >30% functional transcripts or <70% non-functional transcripts. Incorporation of RNA splicing evidence into variant interpretation increased pathogenic (28.6%-31.7%) and benign (3.7%-24.4%) classifications while reducing likely pathogenic (19.5%-17.7%), uncertain (18.9%-8.5%), and likely benign (29.3%-17.7%) categories. Experimental mRNA profiling impacted the interpretation of 34% of variants and resolved uncertainty in approximately 10% of cases. Exon 18 skipping was less tolerated, indicating that the degree of splice perturbation required to impair BRCA1 function may depend on the nature of the resulting non-functional transcript.

Humans↗

PubMed2026

Reinforcement learning-based dynamic ensemble for missense variant effect prediction and tiered prioritization of VUS.

BACKGROUND: Accurate classification of missense variants remains a challenging task despite major advances in genomics. Numerous computational models have been developed to assist in variant classification, but often require repeated integration and benchmarking efforts. Ensemble methods have been proposed to overcome the limitations of single predictors, but mostly rely on fixed, predefined weights that constrain their ability to capture interactions among predictive signals. METHODS: We present GenixRL, a dynamic ensemble framework that reformulates model fusion as a reinforcement learning optimization problem. GenixRL uses a Q-learning agent to learn a policy that dynamically weights the probabilistic outputs of complementary predictors, including BayesDel (addAF and noAF), ClinPred, and MetaRNN. Replacing static weighting with policy learning allows GenixRL to adaptively identify optimal weightings and substantially improve classification accuracy. RESULTS: In benchmark evaluation against 25 state-of-the-art predictors, GenixRL achieved an AUROC of 0.9644 on an independent ClinVar dataset. On saturation genome editing assays for BRCA1 and BRCA2, GenixRL achieved the best performance and ranked highest on 14 of 17 clinically significant genes in a zero-shot evaluation. Applied to uncertain and conflicting ClinVar variants, GenixRL enabled tiered, evidence-based prioritization of hundreds of thousands of variants as likely pathogenic or pathogenic with high confidence, supported by orthogonal population evidence from gnomAD. CONCLUSION: GenixRL advances pathogenicity prediction for missense variants and provides an adaptive ensemble that sorts variants of uncertain significance into tiered candidates for expert curation and functional validation.

Mutation, Missense↗

PubMed2026

Genomic profiling by circulating tumor DNA in patients with hormone receptor-positive/HER2-negative advanced breast cancer: Prevalence of actionable mutations across treatment lines.

INTRODUCTION: Plasma next-generation sequencing (NGS) is endorsed by ESMO as an alternative to tissue testing in advanced hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2- mBC), particularly after progression on endocrine therapy plus CDK4/6 inhibitors. However, prospective real-world data across distinct therapeutic contexts remain limited. PATIENTS AND METHODS: In this prospective observational study conducted within a nationwide cancer network in Brazil, centralized plasma NGS, and tissue NGS when available, was performed in two independent cohorts: prior to initiation of first-line endocrine therapy in the metastatic setting (Cohort 1) and at progression on endocrine therapy plus a CDK4/6 inhibitor (Cohort 2). The primary objective was to evaluate plasma-detected ESR1 mutation prevalence across these therapeutic contexts, and secondarily to assess other actionable drivers detected by plasma or tissue NGS. RESULTS: Among 86 collected plasma samples, 72 (84%) had evaluable NGS results (Cohort 1, n = 37; Cohort 2, n = 35). ESR1 mutations were identified in 18.9% of patients in Cohort 1 and 40.0% in Cohort 2, mostly at low variant allele fractions (<0.5%), corresponding to an absolute prevalence difference of 21.1 percentage points (95% CI, -0.2 to 40.3; P value=0.07). When considering any actionable alteration detected by plasma, including ESR1, PIK3CA, AKT1, PTEN, BRCA1, BRCA2, and ERBB2, prevalences were 43.2% and 68.6%, respectively (P value=0.04). Only four patients had ESR1 mutations identified in tissue, three in metastatic samples. Plasma-tissue concordance was higher for PIK3CA mutations (85.1%). CONCLUSION: Plasma NGS identified clinically meaningful ESR1 mutation rates across both contexts, supporting guideline-endorsed plasma-based genomic profiling in HR+/HER2- mBC.

CDK4/6 inhibitors↗

PubMed2026

Clinically actionable genomic alterations in breast cancer brain metastases.

BACKGROUND: Breast cancer brain metastases (BCBMs) represent a critical unmet clinical need in metastatic breast cancer (MBC) and the identification of novel therapeutic targets is urgently needed in this context. In this study, we describe clinically actionable targets in BCBMs using comprehensive genomic profiling. PATIENTS AND METHODS: Genomic DNA was extracted from formalin-fixed paraffin-embedded archival BCBM samples and analyzed using the commercially available Agilent SureSelect V6 whole exome sequencing (WES) kit and an Illumina NovaSeq 6000 platform. Pathogenic alterations were classified as actionable alterations (AAs) if they met the updated MBC or tumor-agnostic ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) I or II criteria of the ESCAT scale. RESULTS: WES data from 56 BCBM samples were available [33.9% hormone receptor (HR)-negative/human epidermal growth factor receptor (HER)2-negative; 25.0% HR-positive/HER2-negative; and 38% HER2-positive]. ESCAT I/II AAs were detected in 76.8% (n = 43) of all BCBMs and the most frequently detected AAs were in genes involved in the homologous recombination repair pathway (BRCA1/BRCA2/PALB2; 53.6% overall). Biallelic inactivation of BRCA1, BRCA2, or PALB2 was observed in 19.6% of samples, with higher rates in HER2-negative BCBMs (26% in HR-negative /HER2-negative and 21% in HR-positive/HER2-negative). ESCAT I/II PIK3CA/AKT1/PTEN pathway alterations were present in 48.2% of samples and, in particular, in 50% of HR-positive/HER2-negative BCBMs. No ESR1 mutation was detected in HR-positive/HER2-negative BCBMs. The prognostic impact of previously described AAs was evaluated overall and according to breast cancer subtype. Twenty-three BCBMs (41%) were classified as HER2-positive; among these, 3 (13%) presented a hotspot PIK3CA mutation and 7 (30%) presented a PTEN deletion. Among patients with HER2-positive BCBMs, the identification of a hotspot PIK3CA mutation was significantly associated with worse prognosis. CONCLUSIONS: ESCAT I/II actionable genomic alterations are frequent in BCBMs, highlighting the potential for genomically targeted treatments in this setting.

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