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Results for “Homologous Recombination Deficiency”

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PubMed2026

Prognostic significance of DNA damage response-related markers in esophageal squamous cell carcinoma using machine learning approaches.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) lacks reliable prognostic biomarkers. Homologous recombination deficiency (HRD) has been implicated in genomic instability across multiple cancers, but its prognostic significance in ESCC remains unexplored. This study aimed to evaluate HRD score as a prognostic biomarker and develop a machine learning-based predictive model for ESCC. METHODS: Transcriptomic and clinical data from 78 ESCC patients were obtained from The Cancer Genome Atlas (TCGA) and randomly split into training (70%) and test (30%) cohorts. Prognostic models were constructed using 112 machine learning algorithm combinations based on DNA damage response (DDR)-related genes. Gene set enrichment analysis (GSEA), somatic mutation profiling, and immune cell infiltration estimation via CIBERSORT were performed to characterize HRD-associated molecular features. RESULTS: High HRD scores were significantly associated with poorer overall survival (P<0.05). Among 112 algorithm combinations, the survival support vector machine (Survival-SVM) model demonstrated optimal performance [training concordance index (C-index): 0.741; test C-index: 0.708], identifying six hub genes: PARP1, MBD4, TELO2, NSMCE3, SMUG1, and BABAM1. A nomogram incorporating risk score (RS) and clinical variables achieved strong predictive accuracy for 1- to 3-year survival [area under the curve (AUC) >0.7]. High-HRD tumors exhibited distinct mutational patterns (TP53 and TTN) and enriched glutathione metabolism and cytochrome P450 pathways. Immune infiltration analysis revealed significant differences in plasma cell and neutrophil infiltration between risk groups (P<0.05), suggesting HRD-associated immune microenvironment remodeling. CONCLUSIONS: We developed a novel HRD-based prognostic model incorporating six DDR-related genes that demonstrates robust predictive performance in ESCC. HRD score is identified as an independent prognostic factor associated with genomic instability, immune microenvironment alterations, and clinical outcomes. These findings provide a theoretical basis for personalized treatment strategies, including potential applications of PARP inhibitors and immunotherapy in ESCC.

Esophageal squamous cell carcinoma (ESCC)↗

PubMed2026

Rationale and Study Design of the GUIDANCE trial: A Multicenter Phase II Trial of Maintenance Durvalumab and Olaparib After Standard Fist Line Treatment (Carboplatin/Cisplatin, Etoposide, and Durvalumab) in HRD Positive Extensive Disease (ED) Small-cell Lung Cancer (SCLC) (AIO-TRK-0124/ass).

BACKGROUND: Small-cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis and limited therapeutic progress over recent decades. Although PD-L1 inhibitors have modestly improved survival, responses are not durable. There are no predictive biomarkers that would allow for a personalized treatment strategy. Targeting DNA damage repair deficiencies represents a promising treatment strategy in various solid tumors. Poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib have demonstrated efficacy in homologous recombination deficiency (HRD)-positive tumors, and preclinical data suggest synergistic activity with immune checkpoint blockade. METHODS: GUIDANCE is a biomarker-driven, multicenter, single-arm, open-label phase II trial evaluating maintenance therapy with durvalumab and olaparib in patients with advanced or metastatic SCLC without progression after first-line therapy with platinum, etoposide and durvalumab. Patients are prospectively selected for HRD based on homologous recombination repair gene alterations and/or a genomic instability score. Following central prescreening, 29 patients will be enrolled. Patients receive durvalumab (1500 mg every 4 weeks) and olaparib (300 mg twice daily) until progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) by RECIST 1.1. Secondary endpoints are overall survival, safety and tolerability. Exploratory analyses include circulating tumor DNA (ctDNA) monitoring of individual TP53 mutations, assessment of SLFN11 expression, and characterization of immune cell composition via multiplex immunohistochemistry. DISCUSSION: This trial investigates a chemotherapy-free, genomically stratified maintenance strategy targeting both DNA damage repair deficiency and immune evasion in SCLC. By integrating HRD-based patient selection with concurrent PARP and immune checkpoint inhibition, GUIDANCE aims to establish a more individualized therapeutic approach and to generate a signal for further evaluation in biomarker-defined patient populations. Trial registration number EuraCT 2024-512373-27-00.

DNA-damage repair↗

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↗

PubMed1992

Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells.

apoE-deficient mice have been created by homologous recombination in ES cells. On a low fat, low cholesterol chow diet these animals have plasma cholesterol levels of 494 mg/dl compared with 60 mg/dl in control animals, and when challenged with a high fat Western-type diet, these animals have plasma cholesterol levels of 1821 mg/dl compared with 132 mg/dl in controls. This marked hypercholesterolemia is primarily due to elevated levels of very low and intermediate density lipoproteins. At 10 weeks of age, apoE-deficient mice have already developed atherosclerotic lesions in the aorta and coronary and pulmonary arteries. apoE-deficient mice are a promising small animal model to help understand the role of apoE in vivo and the genetic and environmental determinants of atherosclerosis.

Animals↗

PubMed1990

Generation of capsule-deficient Neisseria meningitidis strains by homologous recombination.

Capsule-deficient mutants of Neisseria meningitidis serogroup B strain B1940 were constructed by allelic replacement using the plasmids pMF120 and pMF121, which contain the flanking regions of the gene locus for the biosynthesis pathway of the group B meningococcal capsular polysaccharide. Southern blot analysis of chromosomal DNA of the capsule-deficient meningococcal strains confirmed the generation of large deletions in the chromosomal cps gene complex. The same strategy proved useful in constructing meningococcal strains with capsular types A, C, W135, Y and Z.

Alleles↗

PubMed2005

Homozygous germ line mutation in exon 27 of murine Brca2 disrupts the Fancd2-Brca2 pathway in the homologous recombination-mediated DNA interstrand cross-links' repair but does not affect meiosis.

The role of the region encoded by exon 27 of the Brca2 gene in DNA repair was studied in cells and tissues from Brca2Delta27/Delta27 mice. The COOH-terminal truncated Brca2 localized to the nucleus in primary mouse embryo fibroblasts from Brca2Delta27/Delta27 mice. Fluorescence-activated cell sorting (FACS) analysis demonstrated that these fibroblasts were hypersensitive to mitomycin C-induced cross-links, but not to double-strand breaks (DSBs) induced by irradiation. The gammaH2AX appearance kinetics and comet assay showed that DSBs were repaired through non-homologous end joining pathways, while interstrand cross-links were not repaired due to deficient homologous recombination pathways. Immunoprecipitation experiments showed that Fancd2 did not coprecipitate with the mutated Brca2. There were also no detectable Rad51-positive foci formed in these cells after damage. On the other hand, we did not find any difference during gametogenesis in mice harboring exon 27 truncating mutation of the Brca2 gene and control mice, and in both cases, Rad51 localized to the recombination foci. Our results suggest that exon 27 of murine Brca2 is crucial for the interaction of Brca2 and Fancd2 in Rad51-mediated recombination in response to DNA damage, but that this interaction is not taking place in the homologous recombination during meiosis.

Animals↗

PubMed1995

Biological effects of combined inactivation of plasminogen activator and plasminogen activator inhibitor-1 gene function in mice.

Mice with combined homozygous deficiency of tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) (T-U-), of t-PA and plasminogen activator inhibitor-1 (PAI-1) (T-P-), of u-PA and PAI-1 (U-P-) or of t-PA, u-PA, and PAI-1 (T-U-P-) were generated by inbreeding of mice with the respective deficiencies. Homologous recombination at the t-PA, u-PA and PAI-1 locus was verified by Southern blot analysis of genomic tail tip DNA, and confirmed by measurement of antigen levels in plasma or urine. T-P- and U-P- mice were apparently healthy and fertile. T-U- mice showed extensive fibrin deposition with calcification in the liver, whereas T-U-P- mice were significantly (p < 0.001) less affected. Spontaneous in vivo clot lysis measured 4 h after injection of a 125I-fibrin-labeled clot prepared from plasma of wild-type (WT) mice into the jugular vein, was (mean +/- SEM of n experiments) 2 +/- 1% (n = 8) for T-P-, 49 +/- 6% (n = 9) for U-P-, 1 +/- 1% (n = 4) for T-U- and 3 +/- 3% (n = 3) for T-U-P- mice, as compared to 32 +/- 4% (n = 10) for WT, 1 +/- 0% (n = 7) for T-, 30 +/- 5% (n = 5) for U- and 58 +/- 10% (n = 6) for P- mice. Plasminogen-dependent lysis of 125I-fibrin-labeled matrix and of 3H-proline-labeled subendothelial matrix (mean +/- SEM; n = 4 to 6) was lower with thioglycollate-stimulated macrophages obtained from U-P- mice (22 +/- 7% and 5 +/- 1%, respectively), as compared to WT mice (57 +/- 14% and 18 +/- 5%, respectively) and T-P- mice (87 +/- 6% and 27 +/- 4%, respectively). A similar decrease was previously observed with U- mice, but not with T- or P- mice. Thus, the phenotype of mice with combined deficiency of t-PA and PAI-1 or of u-PA and PAI-1 is similar to the phenotype observed in mice with single deficiency of the plasminogen activator. Additional deletion of PAI-1 does not affect viability, fertility, macrophage function or thrombolytic potential of the single deficient mice. Additional deletion of PAI in mice with combined deficiency of t-PA and u-PA does not restore the deficient in vivo fibrinolytic capacity, but significantly reduces the thrombotic phenotype, as revealed by fewer, smaller and less calcified fibrin deposits in the liver.

Animals↗

PubMed2025

Integrating necroptosis and immune landscapes: a multi-omics-derived NecropImmScore stratifies prognosis and therapy in ovarian cancer.

BACKGROUND: Ovarian cancer (OC) remains the deadliest gynecologic malignancy, largely due to its immunosuppressive tumor microenvironment (TME) and resistance to therapy. Necroptosis, a regulated lytic cell death pathway mediated by the RIPK1-RIPK3-MLKL axis, can trigger immunogenic cell death, but its specific role in shaping the OC immune landscape and its clinical translation potential are posorly understood. METHODS: We employed multi-omics analysis (transcriptomics, genomics, clinical data) from TCGA-OV (n = 380), ICGC OV-AU, and IMvigor210 cohorts, combined with rigorous in vitro functional validation using OC cell lines (SKOV3, HEY), macrophages (THP-1 derived), and T cells (Jurkat). Computational immunology approaches (ESTIMATE, CIBERSORT, ssGSEA) quantified immune infiltration. We identified MLKL-associated immune genes, performed survival analysis (Kaplan-Meier, Cox regression), and constructed a necroptosis-immune signature (NecropImmScore) using consensus clustering and PCA of 102 prognostic genes. Drug sensitivity was predicted via pRRophetic and CellMiner. RESULTS: MLKL emerged as a protective prognostic biomarker (p = 0.018), significantly correlated with enhanced immune infiltration (ImmuneScore, StromalScore, ESTIMATEScore; p < 2.22e-16), M1 macrophage polarization (p = 0.006), activated CD4 + T cells (p = 0.003), and elevated immune checkpoint expression (PD-L1, CTLA4, LAG3, TIGIT). In vitro, MLKL overexpression in OC cells promoted M1 polarization (p < 0.05), activated Jurkat T cells (upregulated CCR4/5/7/9, CD69, CD3D/E, GZMB; p < 0.05), and induced key chemokines (CXCL9/10/11/13) critical for immune cell recruitment. Integration of MLKL-related and immune-related DEGs (n = 632) revealed enrichment in T-cell activation, chemokine signaling, and antigen presentation pathways (FDR < 0.05). Consensus clustering based on 102 survival-associated genes defined three molecular subtypes (Clusters A-C) with divergent survival (p = 0.019), necroptosis activity, and immune infiltration (Cluster C: best prognosis, highest MLKL/ImmuneScore). The derived NecropImmScore robustly stratified patients: high-score correlated with superior overall survival (TCGA: p < 0.001; ICGC: p = 0.014), inflamed TME phenotype, elevated checkpoint expression, and improved response to anti-PD-L1 in IMvigor210. Critically, high NecropImmScore predicted higher BRCA1 mutation frequency (AUC = 0.802), synergy with BRCA1 status for prognosis, higher homologous recombination deficiency (HRD) score, sensitivity to cisplatin (p = 0.014), paclitaxel (p = 0.016), gemcitabine (p = 0.017), and provided superior prognostic stratification when combined with TMB and HRD score (p < 0.001). CONCLUSION: This study establishes MLKL as a master regulator of anti-tumor immunity in OC, driving chemokine-mediated immune cell recruitment and TME reprogramming. The novel NecropImmScore is a multifaceted biomarker that effectively predicts prognosis, immunotherapy response, BRCA1 deficiency, and chemosensitivity, offering significant potential for guiding precision therapeutic strategies in OC.

Humans↗

PubMed2026

Pan-cancer analysis identifies APOC1 as a TAM-derived modulator of adaptive immune resistance and predictor of therapeutic response.

BACKGROUND: Apolipoprotein C1 (APOC1) has been implicated in several malignancies, yet its expression patterns, clinical significance, and immunomodulatory roles across cancer types remain poorly characterized. METHODS: We performed a comprehensive multi-omic analysis of APOC1 across 33 cancer types integrating transcriptomic, proteomic, genomic, epigenomic, and pharmacogenomic data from TCGA, GTEx, CPTAC, and multiple independent external cohorts. Immune infiltration was assessed using seven complementary algorithms. Spatial transcriptomics and single-cell RNA sequencing were employed to determine the cellular source of APOC1 expression. RESULTS: APOC1 upregulation in most cancers was associated with cancer type-specific prognosis. After adjustment for clinical covariates and macrophage infiltration, high APOC1 remained an independent adverse factor in KIRC, LGG, and STAD. APOC1 expression positively correlated with genomic instability hallmarks, including homologous recombination deficiency and aneuploidy, with these associations largely independent of immune infiltration; in contrast, associations with tumor mutational burden were substantially confounded by macrophage abundance. Immune infiltration analysis revealed a pattern consistent with adaptive immune resistance: APOC1 correlated positively with immune-activating signatures (STAT1, MHC-II, TCR signaling) and immunosuppressive M2 macrophages and Tregs, yet negatively with anti-tumor effectors (activated NK cells, dendritic cells). Spatial transcriptomics and single-cell RNA sequencing identified tumor-associated macrophages (TAMs) as the primary cellular source of APOC1, with transcripts co-localizing with CD68 in tissue sections. APOC1 expression correlated with multiple immune checkpoint molecules and was elevated in responders to immune checkpoint blockade, consistent with an inflamed yet regulated tumor microenvironment. Pharmacogenomic analyses revealed that APOC1-high tumors display distinct drug response profiles, characterized by resistance to MAPK pathway inhibitors and potential sensitivity to the HDAC inhibitor Entinostat. CONCLUSION: This pan-cancer analysis establishes APOC1 as a context-dependent biomarker and a TAM-derived modulator of adaptive immune resistance, with prognostic and therapeutic implications across malignancies. APOC1-expressing TAMs represent a potential target for combination immunotherapy strategies.

APOC1↗

PubMed2026

Expression patterns of potential targets for antibody-directed therapy in metastatic castration-resistant prostate cancer patients.

INTRODUCTION: Survival in metastatic castration-resistant prostate cancer (mCRPC) patients remains limited and treatment is complicated by tumor heterogeneity. As antibody-based therapeutics emerge, identifying actionable antigen targets and patient subgroups most likely to benefit is essential. MATERIALS & METHODS: Gene expression of 62 antibody-targetable proteins was analyzed in 296 mCRPC biopsies. These genes encode proteins targeted by approved or investigational antibody-based cancer therapeutics. Associations between target expression with genomic classifications and transcriptomic subtypes were evaluated. Target expression was also assessed in tumors with low expression of established mCRPC targets. Subgroup-specific targets were validated in an independent cohort and single-cell transcriptomics. RESULTS: Established targets KLK2, FOLH1 (PSMA) and STEAP1 showed the highest median expression across the cohort. Target expression did not correlate with genomic classifications, including homologous recombination deficiency, microsatellite instability, CDK12, TP53, PTEN or AR alterations Target expression did associate with transcriptomic subtypes: CRPC-AR (driven by androgen receptor-signaling) and CRPC-SCL (stem cell-like features, AP-1/YAP/TAZ-driven), displayed the highest expression of multiple targets, including KLK2, FOLH1, and SLC44A4. CRPC-NE (neuroendocrine phenotype) showed heterogeneous expression, with high CD46 expression, whereas CRPC-WNT (Wnt-signaling driven) generally showed low target expression. Notably, CD46 was highly expressed in tumors with low KLK2, FOLH1, and STEAP1 expression, a subgroup associated with poor prognosis. CONCLUSIONS: Although several antibody targets showed broad expression in mCRPC-tumors, expression varied by transcriptomic subtype. Subgroups such as CRPC-WNT expressed fewer targets, suggesting the need for alternative therapeutic strategies. CD46 emerged as a promising target, with wide expression across multiple subtypes, including clinically challenging CRPC-NE and mCRPC tumors lacking expression of established targets.

Humans↗

PubMed2026

Paired Exome-Based Comprehensive Genomic Profiling and Germline Genetic Testing for Unselected Patients With Colorectal Cancer in a Multicenter Prospective Study.

BACKGROUND AND AIMS: Comprehensive genomic profiling (CGP) for tumors and germline genetic testing (GGT) inform precision therapy and clinical management of patients with colorectal cancer (CRC), and evidence is growing in support of universal paired CGP-GGT patient testing. However, the utility of combining CGP and GGT for early-stage CRC (ESC) and early-onset CRC (EOC) is unclear. METHODS: We performed a prospective, multisite study featuring GGT using an 80+ gene next-generation sequencing platform and exome-based CGP among CRC patients (unselected for age, stage, family history) receiving care at Mayo Clinic Cancer Centers between April 1, 2018, and March 31, 2020. RESULTS: A total of 150 CRC patients had GGT and exome-based CGP performed. ESC patients had an enrichment of high microsatellite instability and high tumor mutation burden. High microsatellite instability was also enriched in those with smoking history, and in tumors with mutated BRAF, homologous recombination deficiency, or at least 1 variant in the rat sarcoma virus pathway. Moreover, patients with smoking history were enriched in BRAF and other Tier 1 or 2 variants overall. Sixteen percent of patients harbored a pathogenic germline variant, most frequent being in Lynch syndrome genes. Paired GGT and CGP testing had high rates of clinically significant findings (≈70%) with the most frequent being high tumor mutation burden status. Pathway and mutational signature analysis revealed frequent CGP mutations in DNA repair and cell cycle pathways. CONCLUSION: These data suggest that universal, combined GGT-CGP increases clinical utility for EOC and ESC patients. This is key for EOC patients who tend to experience poorer outcomes. CGP-GGT expedites germline resolution for tumor mutations in hereditary cancer genes, reducing delays and facilitating identification of relevant therapies, clinical trials, and management recommendations.

Colorectal Cancer↗

PubMed2025

Epstein-Barr Virus-Associated Gastric Cancer: A Histopathologic Study With Comprehensive Molecular Profiling.

A subset of gastric cancers (GCs) is linked to Epstein-Barr virus (EBV) infection. This study aims to characterize the histopathological and molecular features of EBV-associated GCs (EBVaGCs), focusing on predictive biomarkers and genomic and transcriptomic analysis. A total of 35 primary EBVaGCs were considered. The presence of EBV was confirmed with in situ hybridization. Immunohistochemical analyses for HER2, PD-L1, claudin 18.2, and mismatch repair proteins were performed. Genomic and transcriptomic profiles were assessed using AmoyDx Master Panel, which can identify single-nucleotide variants, InDels, and copy number variations on 571 hot genes, as well as microsatellite status, tumor molecular burden, and homologous recombination deficiency at the DNA level; however, at the RNA level, it identifies rearrangements/fusions in 45 genes and also quantifies the expression of 2396 cancer-related transcripts. The following histotypes were identified: carcinoma with lymphoid stroma (CLS; 69%), tubular (20%), and mixed (11%). Most cases were associated with atrophic gastritis (71%), and only 11% with dysplasia. The vast majority (94%) of EBVaGCs expressed EBV-encoded RNA in all tumor cells. Mismatch repair deficiency and HER2 overexpression were each observed in 6% of cases, whereas all tumors had a PD-L1-combined positive score ≥10. Sixty-six percent of cases showed moderate/strong claudin 18.2 expression in ≥75% of cancer cells. The most frequently altered genes were PIK3CA (41%) and ARID1A (17%). Transcriptomic analysis revealed substantial differential gene expression between EBVaGCs and EBV-negative controls, with upregulation of genes involved in antigen presentation, natural killer cell-mediated cytotoxicity, and cytokine-cytokine receptor interaction in EBVaGCs. Within EBVaGC, CLS showed higher expression of immune-related transcripts and higher PD-L1 expression than other histotypes. This study establishes EBVaGC as a distinct molecular class, with a distinctive profile of genomic alterations and expression of predictive biomarkers, and also with a unique immune microenvironment with enhanced cytotoxic activity. The findings highlight EBV's role in early tumor development and EBVaG-CLS as a distinct subgroup within EBVaGC, characterized by unique morphologic features and a pronounced immune activation profile.

Humans↗

PubMed2026

Exploiting DNA damage tolerance for precision oncology.

Unresolved DNA lesions trigger replication stress, forcing cancer cells to hijack DNA damage tolerance (DDT) networks, specifically translesion synthesis (TLS) and template switching, to sustain replication. While DDT prevents lethal fork collapse, error-prone TLS drives mutagenesis, tumor evolution, chemoresistance and radioresistance. Proliferating cell nuclear antigen post-translational modifications dynamically govern pathway selection. Cancer cells exploit this plasticity, creating actionable vulnerabilities such as postreplicative single-stranded DNA gaps. Emerging inhibitors targeting TLS polymerases, upstream regulators such as ubiquitin-specific peptidase 1 (USP1), and critical protein-protein interactions offer unprecedented opportunities for precision oncology. By integrating DDT inhibition with biomarkers such as homologous recombination deficiency and tumor mutational burden, we can drive synthetic lethality, sensitize tumors to genotoxic agents, suppress treatment-induced mutagenesis, and potentially enhance responses to immunotherapy.

DDT↗

PubMed2005

Structure, flexibility, and repair of two different orientations of the same alkyl interstrand DNA cross-link.

Interstrand DNA cross-links are the principal cytotoxic lesions produced by chemotherapeutic bifunctional alkylating agents. Using an N(4)C-ethyl-N(4)C interstrand DNA cross-link to mimic this class of clinically important cancer chemotherapeutic agents, we have characterized the repair, structure, and flexibility of DNA that contains this cross-link in two different orientations. Plasmid DNAs in which the cytosines of single CpG or GpC steps are covalently linked were efficiently processed by repair proficient and homologous recombination deficient strains of Escherichia coli. Repair in a nucleotide excision repair (NER) deficient strain was less efficient overall and displayed a 4-fold difference between the two cross-link orientations. Both the structure and flexibility of DNA containing these cross-links were examined using a combination of (1)H NMR, restrained molecular dynamics simulations, and atomic force microscopy (AFM). The NMR structure of a decamer containing a CpG interstrand cross-link shows the cross-link easily accommodated within the duplex with no disruption of hydrogen bonding and only minor perturbations of helical parameters. In contrast, disruptions caused by the GpC cross-link produced considerable conformational flexibility that precluded structure determination by NMR. AFM imaging of cross-link-containing plasmid DNA showed that the increased flexibility observed in the GpC cross-link persists when it is embedded into much larger DNA fragments. These differences may account for the different repair efficiencies seen in NER deficient cells.

Alkylating Agents↗

PubMed2026

Integrated signatures define mutational processes in prostate cancer.

Prostate cancer follows a long and heterogeneous disease course with incompletely understood aetiology1. Here we dissect the mutational processes shaping the genomes of 959 donors from the Pan Prostate Cancer Group and assess their clinical relevance. By integrating de novo extracted single-base substitution, insertion-deletion and copy-number signatures with six novel complex structural variant signatures, we identify eight integrated mutational footprints (IMFs) that collectively explain the mutational processes in 85% of primary prostate cancer genomes. IMFs were strongly influenced by regional biases in the genome, most prevalently androgen receptor-mediated mutagenesis and replication stress. Four IMFs, present in 37% of primary tumours, were significantly associated with shorter time to metastasis. These included reactive oxygen-species-driven mutagenesis and both canonical and non-canonical homologous recombination deficiency, the latter being enriched in patients of African ancestry. Extending to the metastatic setting, we found that IMFs predicted sensitivity to androgen receptor pathway inhibitors. Taken together, our study delineates the aetiologies and mutational processes that drive the genomic and clinical heterogeneity of prostate cancer, introduces IMFs as a unifying framework, and highlights their potential to improve both risk stratification and biomarker-guided treatment selection.

Journal Article↗

PubMed1997

Plasminogen and plasminogen activators protect against renal injury in crescentic glomerulonephritis.

The plasminogen/plasmin system has the potential to affect the outcome of inflammatory diseases by regulating accumulation of fibrin and other matrix proteins. In human and experimental crescentic glomerulonephritis (GN), fibrin is an important mediator of glomerular injury and renal impairment. Glomerular deposition of matrix proteins is a feature of progressive disease. To study the role of plasminogen and plasminogen activators in the development of inflammatory glomerular injury, GN was induced in mice in which the genes for these proteins had been disrupted by homologous recombination. Deficiency of plasminogen or combined deficiency of tissue type plasminogen activator (tPA) and urokinase type plasminogen activator (uPA) was associated with severe functional and histological exacerbation of glomerular injury. Deficiency of tPA, the predominant plasminogen activator expressed in glomeruli, also exacerbated disease. uPA deficiency reduced glomerular macrophage infiltration and did not significantly exacerbate disease. uPA receptor deficiency did not effect the expression of GN. These studies demonstrate that plasminogen plays an important role in protecting the glomerulus from acute inflammatory injury and that tPA is the major protective plasminogen activator.

Animals↗

PubMed2026

nf-core/pacsomatic: a scalable somatic analytic pipeline using PacBio HiFi data.

MOTIVATION: Pacific Biosciences (PacBio) HiFi long-read sequencing enables robust characterization of complex genomic regions, repetitive elements, and structural variants (SVs) that are often inaccessible to short-read technologies. To fully leverage HiFi reads to advance cancer genomics and epigenetics, researchers require an end-to-end, scalable and optimized bioinformatics workflow. The nf-core framework meets this need by providing rigorously tested, community-curated pipelines that ensure reproducibility, transparency, and broad compatibility across computational environments. RESULTS: We present nf-core/pacsomatic, an automated Nextflow DSL2 pipeline designed for comprehensive paired tumor-normal somatic analysis using PacBio HiFi data. The workflow includes steps for read alignments against reference genome, somatic SNV/indel, SV, and CNV calling, CpG methylation profiling and differential methylation region (DMR) detection. Additional downstream modules support functional annotation, mutational signature analysis, tumor purity and ploidy estimation, and homologous recombination deficiency (HRD) assessment. Utilizing nf-core's modular design and containerized execution, nf-core/pacsomatic provides a stable framework for the reproducible discovery of biological insights. AVAILABILITY: nf-core/pacsomatic is available under the MIT License at nf-core (https://nf-co.re/pacsomatic) and github (https://github.com/nf-core/pacsomatic).

Software↗

PubMed2026

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

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

Humans↗