Search Results (165)

Although BRCA1 and BRCA2 remain the backbone for germline DNA testing of patients with breast cancer (BC) or ovarian cancer (OC), there are a number of other genes with proven or potential clinical significance. PALB2 is associated with an elevated risk of BC, whereas pathogenic variants (PVs) in RAD51C, RAD51D, and BRIP1 are mainly relevant to OC development. Some germline findings are helpful in guiding therapeutic decisions: for example, PALB2, RAD51C, and RAD51D germline PVs render tumors sensitive to PARP inhibitors (PARPi), whereas cancers arising in PTEN heterozygotes are likely to be responsive to AKT down-regulators. CHEK2, ATM, BLM, and NBN PVs result in only a two-fold or even lower excess of cancer risk. However, the incorporation of these genes in DNA testing panels may occasionally lead to the identification of individuals with biallelic germline inactivation; these patients have a severe disease phenotype and thus require intensive medical intervention. The accumulation of data on “non-BRCA” BC- and OC-predisposing genes is complicated due to the rarity of their alterations, significant interethnic variations in population frequency of relevant PVs, heterogeneity of disease subtypes, etc. The use of extended gene panels, which pool together both clinically validated cancer-associated genes and “candidate” genes with potential but unproven significance, is likely to be a prevailing diagnostic approach in the next few years; therefore, proper attitudes towards accumulation and interpretation of genetic data are important. Full article

Background/Objectives: Standard hereditary breast cancer gene panels fail to identify causative variants in some patients meeting hereditary breast and ovarian cancer (HBOC) criteria. This exploratory, hypothesis-generating study characterised germline variants in MCPH1, functionally related DNA damage response genes, and selected low-evidence candidate genes in breast cancer patients with uninformative standard panel results. Methods: A total of 185 patients meeting NCCN/ACMG criteria, with normal 42-gene panel and BRCA1/2/PALB2 MLPA results, underwent second-tier targeted sequencing. Group 1 comprised MCPH1 and related genes (TP53BP1, MDC1, TOPBP1, UBE2N, RAD52); Group 2 consisted of Genomics England PanelApp candidates (ATRIP, ESR1, PPM1D, RAD54L, RRAS2, XRCC2). No ethnically matched control cohort was available. Variants were classified per ACMG 2015 guidelines and confirmed by Sanger sequencing. Results: Rare variants meeting reporting criteria were identified in 20/185 patients (10.8%): one likely pathogenic (LP) MCPH1 frameshift deletion (c.1869_1870del) in a luminal B invasive ductal carcinoma patient, nineteen variants of uncertain significance (VUS), and one unconfirmed copy number variant. ATRIP was the most frequently implicated Group 2 gene (4 patients), including a homozygous variant; RAD54L variants were identified in three patients, including the only male breast cancer case. Conclusions: These descriptive findings identify MCPH1, ATRIP, MDC1, TOPBP1, and RAD54L as candidates warranting evaluation in case–control studies with ancestry-matched cohorts, functional validation, and family segregation analysis before any consideration for panel inclusion. Full article

Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality owing to late diagnosis, aggressive tumor biology, and limited clinically useful early diagnostic and prognostic biomarkers. This study provides an exploratory evaluation of the expression profile, survival associations, co-expressed genes, functional association networks, and regulatory relationships of MEAK7 (KIAA1609/TLDC1) in pancreatic cancer using multi-platform bioinformatic approaches. We conducted a comprehensive multi-platform bioinformatic analysis using multiple publicly available datasets and platforms, including TCGA/GTEx, GEO, GEPIA3, HPA, CPTAC/UALCAN, TNMplot, Kaplan–Meier Plotter, DoSurvive, TIMER 3.0, STRING, TargetScan, miRDB, ENCORI and lncRNADisease. Gene expression patterns, survival associations, immune cell infiltration and regulatory non-coding RNA networks were systematically investigated. A STRING-derived protein functional association network was evaluated. MEAK7 expression patterns were additionally assessed in external GEO datasets, including GSE62165, GSE71729, and GSE183795. In summary, MEAK7 expression was elevated in pancreatic cancer compared with normal pancreatic tissues, was detectably expressed across multiple pancreatic cancer cell lines, and was increased in patient-derived PDAC samples. ROC analysis showed that MEAK7 expression discriminated PDAC tumor tissues from adjacent non-tumor pancreatic tissues, with an AUC of 0.795 (95% CI: 0.719–0.871) indicating exploratory transcriptomic discrimination rather than clinical diagnostic performance. Exploratory survival analyses showed that elevated MEAK7 expression was associated with unfavorable overall survival and disease-free outcomes, while multivariable Cox analyses showed that this association persisted after adjustment for the covariates available within the analyzed dataset. GEO-based analyses supported increased MEAK7 expression in early-stage pancreatic cancer samples, although metastatic expression patterns varied across datasets. Correlation and interaction analyses revealed positive associations between MEAK7 and PDAC-related genes, including CTTN, CDCP1, SMARCA4, SFN, and PALB2, as well as high-confidence STRING functional associations with V-ATPase components and RNASEK. Furthermore, MEAK7 was positively correlated with lncRNA UCA1 and negatively correlated with miR-582-5p. Collectively, these findings identify reproducible expression and survival-associated patterns involving MEAK7 across the analyzed datasets and provide a hypothesis-generating framework for further investigation of its potential biological role in PDAC. Experimental studies and prospectively characterized patient cohorts are required before any clinical, prognostic, diagnostic, or therapeutic implications can be established. Full article

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. Full article

Background: The growing awareness of breast cancer’s molecular diversity has not changed the technical foundations of surgery itself, but it has profoundly reshaped how surgeons think about surgery. Rather than molecular biology prescribing specific surgery, it is the surgeon’s interpretation of biological behavior—tumor subtype, genomic risk, treatment responsiveness—that influences surgical timing, extent, and feasibility. This is particularly important in the developing world, where mastectomy continues to be the default surgery, not always because it is required, but because biological nuance is underutilized in surgical planning. This review integrates existing evidence, guidelines, and real-world clinical experience to show how a surgeon who understands tumor biology can meaningfully expand safe breast conservation, de-escalate axillary surgery, and align operative choices with systemic therapy. In essence, molecular biology becomes a lens through which surgeons can practice more personalized, precise, and less invasive surgery, without compromising oncologic safety. Recent findings: We present evidence-based algorithms focusing on Luminal A, Luminal B, HER2-positive, and triple-negative subtypes, while discussing the nuances of multifocal and multicentric disease, metaplastic histologies, and discordant lesion management. The review addresses axillary management in the molecular era, specifying the appropriateness of sentinel lymph node biopsy, targeted axillary dissection, or completion axillary dissection, and how subtype-specific nodal responses to neoadjuvant therapy can guide de-escalation strategies. Through clinical vignettes, we exemplify how molecular integration into surgical planning can modify clinical courses, enabling oncoplastic conservation in downstaged tumors and justifying definitive resection in chemo-resistant cases. We examine the implications of germline and somatic genetic testing on surgical decision-making, particularly in relation to BRCA1/2 and PALB2 mutation carriers, alongside ethical and practical counseling considerations. Additionally, we review emerging biomarkers—such as circulating tumor DNA and immune and radiomic signatures—and propose research priorities for their incorporation into surgical trials. Conclusions: Effective implementation necessitates enhanced surgeon education, standardized assays, and multidisciplinary coordination to promote equitable access, consistent utilization of biology-driven algorithms, and rigorous quality oversight. This review furnishes breast surgeons with a pragmatic framework for translating molecular knowledge into multidisciplinary, patient-centered care pathways that optimize oncological safety, aesthetic outcomes, and overall quality of life. Full article

Background and Aim: Germline testing (GT) is increasingly relevant in pancreatic ductal adenocarcinoma (PDAC) because of therapeutic and familial implications. We evaluated real-world GT uptake, the diagnostic yield of pathogenic/likely pathogenic germline variants (P/LP), and their clinical implications. Methods: We retrospectively evaluated 674 consecutive patients with PDAC. GT was performed using targeted single-gene testing or multigene panels. Survival analyses among patients receiving platinum-based chemotherapy according to P/LP germline variant status in HRR-associated genes were exploratory. Results: Overall, 28.9% of patients underwent GT, increasing to 45.9% in 2021–2025 (p < 0.001). Results were available for 194 patients; 28 (14.4%) harbored P/LP variants, most commonly BRCA2 (4.6%) and ATM (3.1%). P/LP variants were identified in 6.8% of patients who did not meet classical referral criteria. Among the 28 carriers, 12 (42.9%) harbored BRCA1/2 or PALB2, variants with established therapeutic relevance, while eight (28.6%) carried ATM, FANCA, or FANCM, variants with potential therapeutic relevance. Of these 20 patients, 11 (55.0%) received matched therapy, and treatment was modified because of the germline result in six (30.0%). In exploratory analyses, among platinum-treated patients, carriers of P/LP germline variants in HRR-associated genes had longer PFS than non-carriers (23.9 vs. 4.8 months; log-rank p = 0.017), although only six HRR-associated variant carriers were included in this platinum-treated survival analysis. Conclusions: GT remained underused despite increasing implementation. Early systematic GT may identify clinically relevant variants missed by selective referral strategies and inform treatment, genetic counseling, and cascade testing. Survival findings require prospective validation. Full article

Background: Germline PALB2 variants are associated with hereditary breast cancer risk, but their clinical impact in Central Asian populations remains largely uncharacterized. This case study aims to evaluate the clinical significance of PALB2 variants in two Kazakh women with early-onset breast cancer. Methods: Molecular genetic testing identified germline PALB2 pathogenic variants (NM_024675.4:c.18_22delGAAGC and NM_024675.4:c.1034T>G) in two Kazakh women with early-onset invasive ductal carcinoma. Clinical courses, treatment responses, and outcomes were followed. Results: Neither patient had a reported family history of breast or other malignancies. Patient 1, a 26-year-old pregnant woman, was diagnosed with stage IIIB luminal B, HER2-negative invasive ductal carcinoma and received neoadjuvant chemotherapy, radical surgery, radiotherapy, endocrine therapy, and subsequent treatment for metastatic disease. Despite an initial response, she developed extensive skeletal metastases and died from metastatic breast cancer. Patient 2, a 33-year-old woman, presented with de novo stage IV luminal B, HER2-negative invasive ductal carcinoma with hepatic metastases. Following multimodal treatment, including chemotherapy, surgery, radiotherapy, endocrine suppression, and systemic therapy for disease progression, she experienced further metastatic spread and ultimately died from breast cancer-related complications. Conclusions: Both patients exhibited aggressive clinical courses characterized by early disease onset, metastatic progression, and poor outcomes despite comprehensive treatment. These cases highlight the potential clinical significance of germline PALB2 variants in apparently sporadic breast cancer and underscore the importance of genetic testing, risk assessment, and genetic counselling in young breast cancer patients, particularly in underrepresented. Full article

Poly(ADP-ribose) polymerase inhibitors (PARPis) have demonstrated remarkable efficacy in tumors carrying BRCA1/2 pathogenic variants (PVs) through the mechanism of synthetic lethality. PVs in other homologous recombination (HR) genes may also impair homologous recombination repair and confer sensitivity to PARPis; however, their predictive value remains uncertain and appears to vary according to the affected gene and tumor type. We review and critically discuss the current evidence regarding the predictive value of non-BRCA HR gene pathogenic variants as biomarkers of PARPi sensitivity across ovarian, breast, prostate, and pancreatic cancers. A narrative review was conducted between October 2023 and December 2025, first identifying pivotal clinical trials of PARP inhibitors across ovarian, breast, prostate, and pancreatic cancers, followed by a targeted search of PubMed, Embase, Web of Science, and Google Scholar for relevant preclinical and clinical studies. Seventeen clinical studies and multiple preclinical reports were analyzed regarding genomic frequency, HRD association, and treatment response. Preclinical studies consistently demonstrated increased PARPi sensitivity in models with alterations in several non-BRCA HR genes. Clinical evidence, however, was heterogeneous. PALB2 demonstrated the strongest and most consistent association with PARPi benefit across tumor types, while RAD51C and RAD51D also showed clinically meaningful activity, particularly in ovarian cancer. In contrast, evidence supporting PARPi sensitivity in tumors harboring ATM, CHEK2, CDK12, and several other HR gene alterations remained limited or inconsistent. Differences in gene function, biallelic inactivation, variant type, and current limitations of HRD companion diagnostic assays likely contribute to the observed variability in clinical response. Non-BRCA HR gene alterations represent promising predictive biomarkers for PARPi therapy but should not be considered a homogeneous group. Future biomarker-driven studies integrating comprehensive genomic profiling and functional assessment of homologous recombination deficiency are needed to refine patient selection and optimize the clinical application of PARPis beyond BRCA1/2-associated cancers. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a rising incidence and a poor prognosis that largely reflects late-stage diagnosis. Although most cases are sporadic, approximately 5–10% of PDACs occur in the context of inherited cancer susceptibility, including hereditary pancreatic cancer (HPC) syndromes and familial pancreatic cancer (FPC). Germline pathogenic variants in genes involved in DNA damage repair, cell-cycle regulation, and genomic stability—such as BRCA1, BRCA2, PALB2, ATM, CDKN2A, STK11, mismatch repair genes, and TP53—contribute to PDAC risk and may influence disease biology. This review provides an overview of the genetic landscape of hereditary and FPC, focusing on established cancer predisposition syndromes and emerging susceptibility genes. Current evidence regarding the prevalence, penetrance, and clinical relevance of germline pathogenic variants (PGVs) is summarized, together with the challenges associated with identifying individuals at increased risk. Contemporary recommendations for germline genetic testing, including the use of multigene panel approaches and limitations in real-world implementation, are also discussed. In addition, surveillance strategies for PDAC in high-risk individuals (HRI) are reviewed, and the available data on the outcomes and limitations of surveillance programs are examined. Finally, the therapeutic implications of inherited alterations, particularly in DNA repair-deficient PDAC, are outlined with reference to genotype-informed systemic treatment approaches. Full article

Metastatic pancreatic ductal adenocarcinoma (PDAC) is typically treated with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel (GnP), but the choice between regimens remains largely empirical. This narrative review summarizes biomarkers with potential to inform first-line selection in metastatic PDAC, emphasizing genomic and transcriptomic correlates of differential benefit. Recent head-to-head trials, particularly Pancreatic Adenocarcinoma Signature Stratification for Treatment (PASS-01) and GENERATE (Japan Clinical Oncology Group [JCOG] 1611), indicate that modified FOLFIRINOX (mFOLFIRINOX) is not uniformly superior to GnP, strengthening the rationale for biomarker-guided selection. The strongest evidence favoring platinum-based/FOLFIRINOX strategies involves homologous recombination repair deficiency (HRD), especially alterations in germline breast cancer gene 1/2 (BRCA1/2) or partner and localizer of BRCA2 (PALB2), as well as broader genomic scar signatures. Transcriptomic subtype and GATA-binding protein 6 (GATA6) expression are promising but remain unsettled because retrospective data favor classical/GATA6-high disease for FOLFIRINOX, whereas PASS-01 suggested better outcomes with GnP in classical tumors. Candidate biomarkers favoring GnP include high human equilibrative nucleoside transporter 1 (hENT1), low class III β-tubulin (TUBB3) expression, and exploratory phosphatidylinositol 3-kinase (PI3K)/KIT/NOTCH pathway mutation signals. Comprehensive molecular profiling also identifies actionable alterations that may redirect patients to targeted therapy or clinical trials rather than standard chemotherapy alone. Importantly, no biomarker has yet been prospectively validated in a biomarker-stratified randomized trial with regimen selection as the primary endpoint; all biomarker-regimen associations described in this review should therefore be considered hypothesis-generating rather than practice-defining. Nevertheless, the convergence of genomic, transcriptomic, and organoid-based approaches makes biologically informed first-line selection increasingly feasible in metastatic PDAC. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with rising incidence and a 5-year survival rate of 13%. Late presentation, early metastasis, and intrinsic resistance constrain the efficacy of cytotoxic chemotherapy, which remains the backbone of PDAC treatment, with only modest survival gains and resistance nearly universal. Although KRAS mutations dominate tumour biology (~90% of cases), PDAC is a heterogeneous disease with distinct molecular subtypes that confer differential therapeutic vulnerabilities. Advances in comprehensive molecular profiling have catalysed a paradigm shift toward precision oncology in PDAC. In KRAS-mutant PDAC, mutation-specific inhibitors have established proof-of-concept, particularly in KRAS G12C disease, while next-generation approaches including KRAS G12D inhibitors, RAS-“ON” inhibitors, proteolysis-targeting chimeras (PROTACs), and KRAS-targeted vaccine strategies are expanding the therapeutic landscape. Combination strategies targeting upstream and downstream effectors of the RAS–MAPK pathway are also being explored to enhance the depth and durability of response. In parallel, KRAS-wild-type PDAC has emerged as a molecularly distinct subgroup enriched for rare but actionable alternative oncogenic fusion drivers including NRG1, NTRK, RET, ALK, and FGFR. Additional molecularly directed strategies targeting HER2 alterations, BRAF mutations, EGFR-dependent signalling, and tumour-selectively exposed surface antigens such as CLDN18.2 are under investigation across PDAC irrespective of KRAS mutation status. Synthetic lethal approaches, including targeting the PRMT5/CDKN2A/MTAP axis, represent a further emerging therapeutic strategy. Germline homologous recombination repair defects, particularly involving BRCA1/2 and PALB2, further define clinically important subsets with sensitivity to platinum chemotherapy and PARP inhibition. This review summarises current and emerging targeted and molecularly directed therapeutic strategies in PDAC, emphasising the importance of molecular stratification and recent advances shaping precision oncology in this historically treatment-refractory disease. Full article

Background/Objectives: Male breast cancer (MBC) is rare, accounting for less than 1% of all breast cancers. Given its low incidence, male breast cancer (MBC) remains understudied; this 33-year Serbian cohort was assessed for clinicopathological features, therapeutic approaches, genetic alterations, and survival. Methods: We retrospectively analyzed MBC patients diagnosed between 1991 and 2024 at the Institute for Oncology and Radiology of Serbia. Data included demographics, tumor characteristics, and stage, treatment, hormone receptor and HER2 status, Ki-67 index, genetic testing, and survival. Results: A total of 191 patients were identified (median age 66). Family history was negative in 91% and positive in 5.8%. T2 tumors were most frequent (36%), and 96% presented without metastasis. Mastectomy with axillary or sentinel lymph node dissection was performed in 78.5%. Neoadjuvant chemotherapy and radiotherapy were administered in 5.8% and 8.4%. Estrogen receptor positivity was 72%, progesterone receptor 88%, HER2 overexpression 11.0%, and triple-negative tumors 2.6% (40% with axillary involvement). High Ki-67 (≥15%) was recorded in 28.8%. Adjuvant chemotherapy, radiotherapy, and hormone therapy were given in 36%, 58%, and 68%. Among 37 genetically tested patients, seven had pathogenic variants (BRCA1, BRCA2, CHEK2, PALB2). Disease recurrence occurred in 30%. Median follow-up was 53 months. Median disease-free survival (DFS) was 82 months (1-, 2-, 5-, 10-year DFS: 87%, 73%, 57%, 39%). Median overall survival (OS) 131 months (1-, 2-, 5-, 10-year OS: 95%, 93%, 73%, 53%). Conclusions: This long-term cohort highlights the predominance of hormone-receptor positivity, the infrequency of germline mutations, and moderate survival rates, informing patient management and guiding future studies. Full article

A group of experts of different specialties involved in the care of prostate cancer (PCa) patients participated in the ENFOCA2 project, promoted by the Spanish Oncology Genitourinary Group (SOGUG), with the aim to review, discuss, and summarize current relevant aspects related to screening, diagnosis, imaging, risk-based approach, and molecular characterization of PCa. A multidisciplinary team (MDT) approach is essential to ensure that patients receive evidence-based care, promoting shared decision-making, and tailoring treatment to the patient’s unique values and preferences. Population-based screening based on risk-stratified algorithms is needed to overcome the limitations of opportunistic screening for detecting clinically significant PCa. Next-generation imaging (NGI) methods, such as prostate-specific membrane antigen (PSMA) PET/CT alone or combined with multiparametric MRI (mpMRI), have a promising role in different scenarios of the diagnostic process due to their high sensitivity. The diagnostic yield of mpMRI should be improved, especially for assessing extraprostatic extension. The use of specific molecular probes as imaging markers for MRI could improve the staging of metastatic disease. Protocols for germline testing developed by international societies, such as the European Association of Urology (EAU) and the National Comprehensive Cancer Network (NCCN), should be adapted at local levels, with BRCA1/2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2, EPCAM, and HOXB13 as the genes to be investigated. Genomic classifier tools help identifying aggressiveness of cancers and aid in personalized treatment decision-making. Joint efforts of multidisciplinary physicians are crucial to improve health outcomes for patients with PCa across the spectrum of this disease. Full article

Background: Poly(ADP-ribose) polymerase inhibitors (PARPi) have transformed cancer therapy for patients harbouring homologous recombination repair (HRR) deficiencies, notably BRCA1/2 mutations. However, resistance to PARPi remains a clinical challenge, with restoration of BRCA1 function via hypomorphic variants representing an understudied scenario. Methods: Here, we engineered a doxycycline-inducible BRCA1 expression system in the BRCA1-mutant, triple-negative breast cancer cell line MDAMB436, permitting controlled analysis of functionally distinct BRCA1 hypomorphs in vitro and in vivo. Results: Among multiple BRCA1 variants generated—including RING, coiled-coil, and BRCT domain mutants—only overexpression of the ∆exon11 hypomorph robustly conferred resistance to olaparib and carboplatin, with drug sensitivity correlating to ∆exon11 expression levels. While ∆exon11 BRCA1 mediated HRR restoration, its efficiency was consistently lower than full-length BRCA1, as measured by RAD51 foci formation and interaction with repair partners such as PALB2. In vivo, tumours expressing Δexon11 BRCA1 exhibited only partial resistance to olaparib compared to those expressing full-length BRCA1. Importantly, the combination of olaparib and the ATR inhibitor, ceralasertib, overcame ∆exon11-mediated resistance, impairing RAD51 foci formation in ∆exon11-expressing cells. Conclusions: Our findings identify a dose-dependent, hypomorphic HRR restoration by ∆exon11 BRCA1, help explain the variable resistance observed in BRCA1-mutant pre-clinical models expressing this hypomorph, and propose ATR inhibition in combination with PARPi as a clinical strategy to counteract therapeutic resistance mediated by ∆exon11 BRCA1 hypomorphs. Full article

Objectives: The molecular characterization of male breast cancer (MaBC) has long been understudied, primarily due to its rare occurrence. Clinical management of MaBC remains profoundly challenging, with current therapeutic strategies largely extrapolated from female breast cancer protocols. Methods: Through panel-based sequencing targeting BRCA1, BRCA2, and PALB2 variants, we delineated the genomic landscape of 96 MaBC cases. Subsequent whole-exome sequencing (WES) of 84 BRCA1/2- and PALB2-mutation-negative MaBC patients, compared against 4480 healthy controls, revealed compelling findings. Results: Pathogenic variants in BRCA1/2 and PALB2 were identified in 14.6% (14/96) of MaBC cases, with BRCA2 mutations predominating at 12.5% (n = 12). Notably, one patient harbored the BRCA1 c.4015G > T stop-gained mutation, while another exhibited the PALB2 c.481_482dupGA alteration. Our analysis further uncovered 170 pathogenic/likely pathogenic mutations, with RAD50, DMD, ARSA, and ABCC6 demonstrating recurrent mutations in MaBC. Conclusions: As the inaugural germline genomic investigation of MaBC in a Han Chinese population, this work reveals clinically actionable alterations with diagnostic and therapeutic implications. These discoveries not only advance our understanding of MaBC’s molecular architecture but also underscore the critical need for dedicated research into this malignancy. Full article