Search Results (189)

Background/Objectives: Familial hyperaldosteronism type IV (FH-IV) is an extremely rare, clinically heterogeneous condition representing the least characterized familial subtype of primary aldosteronism (PA) caused by germline gain-of-function CACNA1H mutations. Despite growing molecular insights, optimal diagnostic and therapeutic strategies remain poorly defined. This systematic review aims to synthesize available evidence regarding the clinical, biochemical, and genetic characteristics of FH-IV, and to evaluate the efficacy of current pharmacological and surgical treatments. Methods: A systematic review was conducted in accordance with PRISMA guidelines and preregistered in PROSPERO (CRD420261324945). A comprehensive search of MEDLINE, Embase, and Web of Science identified studies reporting genetically confirmed FH-IV patients. Data concerning clinical phenotypes, diagnostic evaluations, treatment outcomes, and genetic backgrounds were extracted and analyzed. Results: The primary cohort included 31 fully characterized symptomatic patients, alongside 8 mutation-positive relatives (4 asymptomatic carriers and 4 symptomatic individuals). The genetic landscape was remarkably heterogeneous, encompassing 17 distinct CACNA1H mutations. Clinically, diagnosis was frequently delayed, often complicated by atypical normokalaemic presentations and misleading adrenal imaging. Surgical treatment was generally ineffective, frequently resulting in persistent or recurrent hypertension and biochemical dysregulation. Pharmacologically, patients often required multiple antihypertensive drugs, most frequently a combination of mineralocorticoid receptor antagonists (MRAs) and calcium channel blockers (CCBs). Conclusions: FH-IV is best conceptualized as a systemic adrenal channelopathy. While standard screening parameters are usually elevated, atypical biochemical profiles and misleading structural imaging can complicate the diagnostic process. Optimal management relies on multigene Next-Generation Sequencing (NGS) panels for definitive diagnosis and cascade screening of relatives. Finally, while the combination of MRAs and CCBs is commonly used in PA, it represents a valuable therapy for FH-IV, with dual L-/T-type CCBs emerging as a potential disease-specific option. Full article

Background: Breast cancer and gynecological malignancies, including cervical, ovarian, and endometrial cancers, remain leading causes of cancer incidence and mortality among women worldwide. This study investigated hereditary predisposition rates in women diagnosed with breast or gynecological cancer, focusing on the effect of age on germline pathogenic/likely pathogenic (P/LP) variant detection. We sought to determine whether younger age at diagnosis should be used as a criterion for patient selection for genetic testing. Methods: A total of 9084 consecutive females with breast cancer or gynecological tumors underwent germline NGS-based genetic testing (52 cancer-relevant genes) at Genekor laboratory from 2020–2026. Multivariable logistic regression evaluated factors associated with P/LP variant detection, adjusting for tumor type and family history. Results: Overall P/LP prevalence was approximately 20% (one in five patients), with tumor-specific rates of 19.24% in breast cancer, 27.59% in ovarian cancer, and 26.67% in endometrial cancer. P/LP prevalence declined significantly with age from 24.37% in patients <40 years to 15.90% in those ≥70 years, while Variants of Uncertain Significance (VUS) remained stable (40–43%). P/LP patients had earlier diagnosis (median 45 vs. 46 years, p < 0.001), driven predominantly by high-risk genes (13.87% in <40 y vs. 7.11% in ≥70 y). BRCA1 showed stronger age enrichment than BRCA2 (8.14% vs. 3.16% in <40 y; median diagnosis 43 vs. 45 years). Age remained independently associated with P/LP detection in multivariable analysis, with an 18% reduction in odds per 10-year increase for any P/LP (OR 0.82, 95% CI 0.78–0.86) and a stronger 28% reduction for high-risk variants (OR 0.72, 95% CI 0.67–0.78). Family history also independently predicted P/LP detection (OR 1.40, 95% CI 1.19–1.66). Conclusions: Although derived from a referral-based (and thus selected) population, these findings show that while younger patients have a higher prevalence of high-risk P/LP variants, clinically actionable findings are present across all age groups, including those ≥70 years. These results suggest that reliance on age alone to determine eligibility for genetic testing may be insufficient. Broadening access to testing beyond strict age-based criteria could improve the identification of hereditary cancer risk and inform patient management, although further evaluation in less selected populations is warranted. Full article

The Papanicolaou (Pap) smear, a cornerstone of cervical cancer prevention, has emerged as a compelling, though unconventional, biospecimen for the detection of ovarian cancer (OC). This structured narrative review synthesizes the evolving evidence on the utility of cervicovaginal cytology and molecular analysis of Pap test material for OC detection. While conventional cytology provides a proof of concept, its sensitivity is low, ranging from incidental detection of OC in 0.004% of routine screens to 19.3% in patients with known OC. Specific cytologic findings, however, carry significant predictive value: atypical glandular cells (AGC) confer a two-fold increased OC risk, and psammoma bodies (PB) are strongly associated with serous malignancies. Driven by the sensitivity limitations of morphology, the field has undergone a paradigm shift towards molecular detection. Foundational studies confirmed tumor-derived DNA, including hallmark TP53 mutations, is detectable in Pap samples years before diagnosis, though sensitivity is constrained by low DNA abundance and confounded by background clonal mutations. To overcome this, strategies have expanded to target broader genomic signatures, such as somatic copy number alterations (EVA test: 75% sensitivity, 96% specificity), and multi-gene mutation panels (PapSEEK: 33–45% sensitivity). The most promising advances lie in multi-omic approaches, particularly DNA methylation biomarkers, which have demonstrated sensitivities up to 81% with high specificity. Collectively, this evidence argues against repurposing the Pap test as a standalone OC screen but supports its strategic integration into a risk-stratified clinical algorithm. We propose a “reflex-to-molecular” model where high-risk cytology (e.g., AGC, PB) automatically triggers advanced molecular testing on the same sample. This model efficiently leverages existing infrastructure to triage high-risk women for definitive diagnostics. Prospective validation of this integrated approach is the essential next step toward transforming this test into a sentinel for malignancies of the upper female reproductive tract. Full article

Hereditary breast cancer (BC) remains unexplained in a substantial proportion of families who test negative for BRCA1/2 and other known susceptibility genes. To contribute to the genomic characterization of these unresolved cases, we generated a whole-genome sequencing (WGS) dataset from six women belonging to two unrelated high-risk families, each comprising three sisters diagnosed with BC. All participants had previously received negative results in conventional multigene panel testing. WGS was performed on peripheral blood DNA using the Illumina NovaSeq platform, followed by variant calling against GRCh38 and the comprehensive annotation of single-nucleotide variants, indels, and structural variants. For each family, we identified shared ClinVar-annotated variants, rare exonic or splice-site alterations, and intronic variants located within a curated set of 286 cancer-related genes. The dataset includes per-patient VCF files, copy number variation annotations, and family-level variant summaries. Raw and processed data are publicly available through the Sequence Read Archive and Zenodo. This resource supports variant reinterpretation, exploration of regulatory and intronic regions, and methodological benchmarking in the study of familial BC beyond established susceptibility genes. Full article

Background: High-grade serous ovarian carcinoma (HG-SOC) remains the most lethal gynecological malignancy, largely due to intrinsic or acquired resistance to platinum-based chemotherapy. Although large-scale sequencing studies have delineated the genomic landscape of HG-SOC, clinically actionable biomarkers predictive of platinum response and outcome are still lacking. This study aimed to identify genomic alterations associated with platinum sensitivity, resistance, or refractoriness, and to assess their prognostic relevance. Methods: Tumor DNA from 24 HG-SOC patients with optimal cytoreductive resection, classified as platinum-sensitive (n = 9), platinum-resistant (n = 8), or platinum-refractory (n = 7) underwent targeted next-generation sequencing of 409 cancer-associated genes. Somatic variants were filtered and classified for oncogenicity using established criteria incorporating predicted functional impact, REVEL scores, and population allele frequencies. Associations between mutational profiles, platinum response, and overall survival (OS) were evaluated using Kaplan–Meier and Cox regression analyses. Key findings were validated in the TCGA ovarian serous carcinoma (TCGA-OV) dataset using survival analyses. Results: A total of 1367 protein-altering somatic variants across 301 genes were identified. While TP53 mutations were ubiquitous, platinum-resistant and platinum-refractory tumors showed enrichment of pathogenic alterations affecting DNA repair, transcriptional regulation, epigenetic modification, and oncogenic signaling, including FANCA, ATF1, MAF, NCOA2, PIK3CA, and TET1. Mutations in these genes were associated with reduced overall survival in exploratory analyses (median 2.5–9 months vs. 27.5–45 months). Multivariate analysis identified FANCA and ATF1 as potential independent predictors in exploratory modeling. In the TCGA-OV cohort, patients harboring pathogenic variants in a multi-gene panel derived from this study (excluding BRCA1/2) exhibited significantly worse survival compared with both BRCA1/2-mutated cases and the overall cohort. Conclusions: This exploratory study identifies a set of genomic alterations converging on transcriptional and epigenetic regulation, DNA repair, and oncogenic signaling that are associated with platinum resistance and adverse prognosis in HG-SOC. Independent validation in TCGA supports the potential clinical relevance of this mutational signature. These findings warrant further validation in larger prospective cohorts and functional studies to clarify their role as biomarkers of aggressive disease and therapeutic vulnerability. Full article

Common bunt of wheat (Tilletia spp.) remains a significant threat to wheat production in low-input and organic farming systems, where chemical seed treatments are restricted or avoided. Host resistance represents a key component of sustainable disease control, but its effective deployment requires detailed knowledge of race-specific virulence and the genetic basis of resistance. In this study, we analysed the reaction of a large and diverse wheat germplasm collection to current European populations of common bunt and mapped the underlying resistance genes using SNP-based approaches. A total of 2731 wheat accessions were phenotyped from 2012 to 2025 using up to 42 purified bunt races with well-defined virulence profiles. Based on phenotypic responses to race-specific resistance patterns, accessions were grouped and compared with established differential lines. A total of 1504 selected accessions were genotyped using Illumina 26k SNP arrays, and resistance loci were identified by genome-wide association studies followed by fine mapping using recombination analysis. All classical Bt resistance genes from Bt1 to Bt10 and Bt13 and BtZ were mapped to defined physical intervals, and the genomic positions of 18 additional race-specific resistance genes were identified in a panel of germplasm. Our results confirm that several historically defined Bt genes, including Bt11 and Bt12, represent multi-gene resistance complexes rather than single loci. Also, genes established as separate genes may possibly be identical, including Bt4 being identical to Bt6, Bt10 being identical to BtZ, and Bt9 possibly being identical to one of the genes in the Bt11 complex. These findings highlight the need for a revised nomenclature of genes and a differential set of varieties. The identified resistance haplotypes provide an improved tool for marker-assisted selection and support the development of wheat cultivars with durable resistance to common bunt. Full article

Major depressive disorder (MDD) affects over 330 million people globally, yet up to 30% of patients fail initial pharmacotherapy due to genetic variability in drug metabolism. This narrative review synthesizes evidence on pharmacogenomic (PGx) guided approaches for MDD, emphasizing their integration with POC diagnostics and engineering solutions. Approximately 40–50% of patients carry actionable variants in CYP2C19 or CYP2D6, which govern the metabolism of selective serotonin reuptake inhibitors. Landmark trials (GUIDED, PRIME Care, GAPP-MDD) and meta-analyses demonstrate that PGx-informed prescribing modestly but significantly improves remission and response rates, particularly in treatment-resistant depression. Established guidelines from CPIC and the Dutch Pharmacogenetics Working Group provide actionable recommendations for CYP2D6 and CYP2C19 phenotypes. Emerging POC platforms, including Genomadix Cube and Genedrive, now deliver CYP2C19 results within one hour, supporting rapid clinical decisions. However, psychiatric-specific implementation data remain limited compared to cardiology; current POC devices lack multi-gene capabilities, and most studies underrepresent diverse populations. Persistent barriers include variable reimbursement, limited clinician education, and fragmented electronic health record integration. Future directions include pre-emptive genotyping, expanded multi-gene panels, and embedded clinical decision support. With continued engineering innovation and rigorous validation, PGx-guided care holds promise for reducing the trial-and-error burden and advancing precision psychiatry. Full article

Background: We previously pioneered a multigene mRNA test, qMIDS^V2, validated through an international multicohort study with geographically and ethnically diverse oral squamous cell carcinoma (OSCC) patients from Europe and Asia. This study aimed to repurpose the qMIDS^V2 test for nasopharyngeal carcinoma (NPC). A molecular test independent of Epstein–Barr virus (EBV) status would be clinically useful for risk stratification in NPC patients with undetectable or low levels of EBV. Methods: This study investigated a Chinese cohort of 62 participants (18 donated normal nasopharyngeal mucosa (NPM) and 44 donated NPC tissue samples). Messenger RNA levels of 16 genes in each sample were quantified using the qPCR method, and an algorithm computed a malignancy index for cancer risk stratification. Results: We identified a unique 10-gene panel (containing eight target genes, namely NEK2, INHBA, FOXM1, TOP2A, BIRC5, CXCL8, NR3C1, and IVL, relative to two reference genes, YAP1 and POLR2A, collectively named qMIDS^NPC) that demonstrated the best overall diagnostic performance in segregating NPM from NPC, with AUC = 0.909 and positive/negative predictive values of 91% PPV and 78% NPV, respectively. Furthermore, we demonstrated prognostic value of qMIDS^NPC in segregating NPM from NPC stage III + IV, with AUC = 0.936, 92% PPV, and 84% NPV. Conclusions: Here, we present a simple qPCR-based 10-gene mRNA test, qMIDS^NPC, with potential clinical utilities for rapid (1 h) prognostic stratification of NPC. Further studies involving geographically and ethnically independent NPC cohorts would be needed to validate the clinical use of qMIDS^NPC in non-endemic NPC populations. Full article

Background/Objectives: Traditional histopathologic grading of renal cell carcinoma (RCC) is subjective, is poorly reproducible, and fails to predict responses to modern targeted agents or immunotherapies. In the era of precision oncology, molecular pathology offers objective tools for individualized management. We aimed to characterize genomic alterations in clear-cell RCC (ccRCC) with venous tumor thrombus and to develop pathology-driven panels for personalized prognostic stratification, with exploratory assessment of their potential to predict therapeutic response. Methods: Formalin-fixed paraffin-embedded pT1 ccRCC samples with and without thrombus underwent whole-exome sequencing. Distinct somatic mutations and copy number variations were incorporated into multigene panels. External assessment was performed in TCGA and PAWG cohorts, assessing survival outcomes and therapeutic biomarkers including homologous recombination deficiency (HRD), tumor mutational burden (TMB), and microsatellite instability (MSI). Results: Thrombus cases showed unique genomic heterogeneity compared with matched controls. Three multigene panels were constructed. Across external datasets, including a 354-patient TCGA-KIRC ccRCC cohort, the panels provided consistent molecular stratification signals for overall, disease-specific, and progression-free survival, complementing established pathological risk factors. They were significantly associated with established therapy-related genomic biomarkers, including HRD, TMB, and MSI, showing high sensitivity and negative predictive value in identifying patients unlikely to harbor these biomarker-positive profiles. These findings support the panels’ prognostic utility, with exploratory evidence for their potential in therapy response prediction. Conclusions: Small ccRCC with thrombus harbors distinct molecular pathological features. The proposed pathology-driven panels, compatible with FFPE tissue, represent pathology-compatible genomic tools that may support modern precision pathology by improving molecular risk stratification and informing exploratory therapeutic biomarker assessment. Full article

Background/Objectives: EndoPredict is a second-generation prognostic assay for estrogen-receptor-positive, HER2-negative breast cancer that integrates molecular and clinical parameters for risk stratification. Multiple studies have reported its clinical utility, while differences in the proportion of patients classified as high- or low-risk have been observed across cohorts. This study aimed to characterize clinical, pathological, and demographic factors associated with these differences. Methods: We conducted a descriptive review of 17 published studies and analyzed a single-institution cohort of 140 patients. Associations between clinicopathological variables and high-risk classification were assessed, including tumor size, lymph node status, histological grade, Ki-67 expression, and reproductive and demographic factors. Differences in inclusion criteria and cohort characteristics were also examined. Results: Tumor size and lymph node involvement emerged as primary determinants of high-risk classification. A high histological grade and Ki-67 levels above 25% were significantly associated with high-risk status (p < 0.001). Conversely, age, age at menarche, menopausal status, Body Mass Index, progesterone receptor expression, molecular subtype, and histological type showed no significant association. A higher number of pregnancies correlated with a lower frequency of high-risk classification (p < 0.01). Heterogeneity in risk distribution across studies was largely attributable to differences in tumor size, nodal involvement, and histological grade. Additional variability was associated with inclusion criteria, sample selection, and regional demographic characteristics. Conclusions: Variability in EndoPredict risk classification reflects both tumor biological features and population-specific factors. These findings emphasize the importance of interpreting genomic risk scores within their clinical and demographic context and support the comparison of risk distributions across heterogeneous patient cohorts. Full article

The increasing accumulation of end-of-life tires has motivated the development of sustainable construction materials incorporating recycled rubber for acoustic insulation applications. This study proposes a data-driven framework for predicting the weighted airborne sound reduction index ($R_w$) of recycled rubber–polyurethane composite panels based on a limited experimental dataset. Specimens with varying granulometric composition, material density, and polyurethane adhesive dosage were evaluated in accordance with EN ISO 10140-2:2010 and EN ISO 717-1:2013. To address data scarcity, a regression-oriented SMOTE strategy was applied exclusively to the training set to preserve statistical representativeness and avoid data leakage. Test set representativeness was ensured by systematically evaluating numerous data splits and adopting the one that maximized multivariate statistical consistency. A hierarchical modeling approach was adopted, ranging from classical regression models to tree-based ensemble methods and multigene symbolic regression. Model performance was evaluated using R², RMSE, MAE, and MAPE on an independent test set. The highest accuracy and robustness were obtained using symbolic regression, with R² values close to 0.99 and minimal prediction errors. Shapley value analysis and PDP/ICE plots identified material density as the dominant predictor of $R_w$, followed by polyurethane adhesive dosage, while granulometric composition exhibited a weaker influence. The proposed framework provides an accurate and interpretable tool for the preliminary design and optimization of recycled rubber acoustic panels. Full article

Antimicrobial resistance (AMR) in poultry-associated Escherichia coli (E. coli) is a persistent One Health concern, particularly when ESBL/pAmpC determinants co-occur with resistance to multiple antimicrobial classes. Between March and October 2024, we investigated commensal E. coli from three interconnected compartments of the poultry production chain in Bosnia and Herzegovina (parent-breeder flocks, commercial broiler farms, hatchery-associated material). A total of 333 samples were examined, and 99 E. coli isolates were recovered (29.7%). Phenotypic characterization included ESBL confirmation, disk diffusion susceptibility testing, and EUVSEC broth microdilution. Targeted real-time PCR assays were used to screen key ESBL/pAmpC-associated genes and selected carbapenemase and plasmid-mediated colistin resistance targets within the targeted panel. ESBL phenotypes were detected in 52/99 isolates (52.5%), and multidrug resistance was highly prevalent across compartments (93/99; 93.9%). ESBL/pAmpC-associated genes were detected in 91/99 isolates (91.9%), with bla_TEM predominating. Gene pattern analysis indicated that bla_TEM occurred most frequently as a single determinant and as part of the predominant multi-gene combinations, most notably bla_TEM + bla_CMY and bla_TEM + bla_CTX-M, while bla_SHV was sporadic. Carbapenemase genes (bla_KPC, bla_NDM, bla_GES, bla_OXA-48) and mcr-1 to mcr-9 were not detected. Overall, our findings indicate a substantial ESBL/MDR burden throughout the poultry production chain, supporting the need for strengthening antimicrobial stewardship and biosecurity measures across both farms and hatcheries. Full article

Introduction: Epilepsy syndromes show marked clinical and genetic heterogeneity, with numerous functionally diverse genes involved in their etiology. Next-generation sequencing (NGS) has facilitated the identification of many monogenic epilepsy syndromes and enables earlier, more accurate diagnosis in pediatric patients. Materials and Methods: This study analyzes the molecular profiles of 87 pediatric patients with various forms of epilepsy in whom pathogenic or likely pathogenic variants were identified. Next-generation sequencing (NGS) using multi-gene epilepsy panels or whole-exome sequencing (WES) was performed. Results: A total of 88 pathogenic or likely pathogenic variants were detected in 48 epilepsy-related genes; 30 variants occurred de novo. SCN1A and KCNQ2 were the most frequent contributors (12.6% and 9.2%, respectively). The highest percentage of positive diagnoses (48%) was observed in patients with developmental and epileptic encephalopathy (DEE), with variants identified in genes including ALG13, ATP1A2, CACNA1A, CDKL5, CHD2, GABRG2, ITPA, KCNQ2, PCDH19, SCN1A, SCN2A, SCN3A, SCN8A, SMC1A, SPTAN1, STXBP1, and UBA5. Pathogenic variants in ANKRD11 were found in four patients with KBG syndrome, while other genes appeared sporadically. Conclusions: Targeted massively parallel sequencing is an effective diagnostic tool for pediatric epilepsy. The presence of numerous single-case findings highlights the high genetic heterogeneity of epilepsy. This approach enabled more precise diagnoses that would not have been achieved through clinical evaluation alone, underscoring the importance of genetic testing for prognosis and treatment planning in pediatric patients with unexplained epilepsy. Full article

Background/Objectives: Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by pathogenic variants in the adenomatous polyposis coli (APC) gene. Its attenuated form (AFAP) is characterized by fewer colorectal polyps and later onset of colorectal cancer. We aimed to characterize the molecular effects of a novel APC gene variant (NM_000038.6: c.1620_1624delinsT) identified in a patient with AFAP. Methods: A 56-year-old man with the AFAP phenotype underwent germline testing via a multigene NGS panel, which identified a novel APC gene variant (NM_000038.6: c.1620_1624delinsT). In silico analyses predicted disruption of the canonical donor splice site and a frameshift followed by the introduction of a premature stop codon. The transcriptional impact of the identified APC gene variant was investigated by mRNA analysis. Results: mRNA analysis revealed two distinct APC transcripts: the first transcript led to a truncated protein (p.Leu540PhefsTer8), and the second transcript lacked exon 12, resulting in an in-frame 26 amino acid deletion of APC protein (p.Ala517_Gly542del). The transcript lacking exon 12 was more abundant than the transcript with a premature stop codon, likely due to degradation through nonsense-mediated decay. Conclusions: The APC gene variant (NM_000038.6: c.1620_1624delinsT) exhibits a dual transcriptional effect, revealing its pathogenic role in AFAP. This study highlights the diagnostic value of combined DNA–RNA germline testing for improving the clinical classification of novel APC gene variants and their genotype–phenotype correlations in FAP. Full article

Background: Germline alterations in DNA damage repair (DDR) genes represent a clinically important subset of prostate cancer (PCa), but real-world data from Middle Eastern and Turkish populations remain limited. We evaluated the prevalence and clinicopathologic associations of germline DDR variants in a single-center Turkish cohort. Methods: We retrospectively analyzed 122 men with histologically confirmed PCa who underwent germline multigene panel testing. Variants were classified according to ACMG/ClinVar criteria. Patients were grouped as pathogenic/likely pathogenic (P/LP), variants of uncertain significance (VUS), or variant-negative. Patients were grouped as variant-positive (P/LP or VUS/uncategorized) or clinically actionable variant–negative (benign/likely benign or no variant detected). Group comparisons used t-tests, chi-square or Fisher’s exact tests as appropriate. Results: The median age at diagnosis was 65.2 years (mean 64.6 ± 8.78). Overall, 37 patients (30.3%) carried at least one germline variant, including 12 (9.8%) with P/LP alterations and 24 (19.7%) with VUS; one patient (0.8%) harbored an uncategorized variant. The most frequently affected genes were CHEK2 (n = 8), BRCA1 (n = 6), BRCA2 (n = 6), ATM (n = 5), and APC (n = 4). Variant-positive status increased from 10.8% in ISUP 1–2 to 21.6% in ISUP 3 and 76.0% in ISUP 4–5, although this trend was not statistically significant (p = 0.391). Mean age at diagnosis and the prevalence of metastatic disease did not differ between variant-positive and clinically actionable variant–negative patients (64.2 vs. 65.7 years, p = 0.390; 66.7% vs. 64.6%, p = 0.842). Truncating DDR variants (RAD50, BRCA2, MSH3, NBN, CHEK2, ATM) occurred predominantly in ISUP 4–5 tumors. Conclusions: Germline DDR alterations—most notably in BRCA2, CHEK2, and ATM—were present in a substantial subset of Turkish men with PCa and showed a non-significant trend toward clustering in higher-grade disease. The high prevalence of VUS reflects limited genomic annotation in under-represented populations and underscores the need for longitudinal reinterpretation. These data support the clinical value of incorporating germline DDR testing into risk assessment and familial counseling, while larger cohorts integrating somatic profiling are needed to refine genotype–phenotype associations. Full article