SEARCH · PubMed Health

Results for “somatic instability”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources

PubMed2025

Resolving a century-old enigma: potato 'Bolters' originate from instability of the StCDF1.3 allele.

Potato bolters are caused by excision of a transposon from the StCDF1.3 allele, resulting in a somatic mutant with late maturity. Somatic mutations during vegetative propagation can lead to novel genotypes, known as sports. In cultivated potato (Solanum tuberosum), a recurring sport type, called 'Bolters', is characterized by vigorous haulms and prolonged flowering. Bolters emerge spontaneously during potato cultivation. While deviating phenotypes are typically rogued during clonal propagation, certain bolters have been selected as sub-clonal strains. Their delayed maturity results in a longer growing season and higher yield, in particular when cultivated under short daylengths. Despite their prevalence and agronomical benefits, the genetic basis of bolters has remained unresolved 160 years after their first description in the literature. We investigated whether allelic variation at the StCDF1 locus, a central regulator of potato life cycle, underlies the bolter phenotype. We describe 34 bolters from eight cultivars. Bolters are isogenic with their parent varieties and carried new StCDF1 alleles. These arose from excision events of the Class II TIR transposon disrupting the StCDF1.3 allele conferring early maturity. Among the newly formed alleles, we predominantly identified StCDF1.2 variants, characterized by a 7-nucleotide insertion and associated with a mild effect on early maturity. We also found novel variants, including StCDF1.7, with a 6-nucleotide in-frame insertion, which appears to confer an even milder shortening of the life cycle. Based on this knowledge, we propose that selecting bolters represents a promising breeding strategy to expand the cultivation range of elite varieties and to enhance allelic diversity at a key regulatory locus.

Solanum tuberosum↗

PubMed2025

Panorama of Chromosomal Instability in Lung Cancer.

Lung cancer is a highly heterogeneous disease primarily driven by tobacco smoking. About 20% of lung cancers occur among patients who have never smoked (LCINS) with differences in patient ancestry, sex, tumor histology, and clinical features. Our understanding of chromosomal instability in lung cancer, especially LCINS, is still limited. Here, we perform a comprehensive study of 182,429 somatic structural variations (SVs) detected in 1,209 whole-genome sequenced lung cancers, of which 864 LCINS. SVs are more abundant in tumors from patients who have smoked (LCSS); however, they are more complex and play more important roles in tumorigenesis in LCINS. EGFR mutations and KRAS mutations profoundly and independently shape the SV landscape. EGFR-mutant tumors have higher SV burden and more cancer-driving SVs. In contrast, KRAS mutations are associated with lower SV burden and less driver SVs. We decompose 16 SV signatures for both complex and simple SVs that likely represent divergent molecular mechanisms. The SV breakpoints have distinct distributions across the genome depending on the signatures due to mutagenic mechanisms and positive selection. Many established cancer-driving genes are recurrently rearranged by multiple SV signatures suggesting functional convergence of these genome instability mechanisms.

Journal Article↗

PubMed2024

ERCC2 mutations alter the genomic distribution pattern of somatic mutations and are independently prognostic in bladder cancer.

Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n = 343) and mutant (n = 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.

Humans↗

PubMed2025

Differences of clinical features, prognosis and genetic mutations in Chinese patients with malignant melanoma and additional primary tumours.

BACKGROUND: The differences in the clinical features, prognosis and genetic mutations in Chinese patients with malignant melanoma (MM) and additional primary tumours remain unclear. METHODS: A retrospective analysis was conducted on patients with malignancies in Fujian Cancer Hospital from January 2007 to September 2022, end follow-up in September 2023. Clinical data were gathered, survival analysis was performed, and genetic mutations were detected. RESULTS: There were 58 of 1223 melanoma patients with melanoma and additional primary tumours, an incidence of 4.74%. Acral MM was the most common subtype (26/58), 23 (39.66%) patients had concomitant digestive tumours. Patients who had MM as their first primary tumour (MMFP) had shorter tumour occurrence intervals (9.93 vs. 57.78 months, p = .008) but longer melanoma survival (MM-OS) than the non-MMFP group (100.43 vs. 18.93 months, p = .015). Patients with cancer family histories were more likely to have pathogenic and likely pathogenic (P/LP) mutations (2/5 vs. 4/25). The somatic BRAF gene mutation was frequently observed in MM tissue (8/19, 42.11%). Three patients had whole-genome doubling and microsatellite instability-high (MSI-H). The COSMIC2 signature 3 was significantly higher in the P/LP group. CONCLUSIONS: The frequency of MM and additional primary tumours is about 5% in Chinese populations. Patients with melanoma diagnosed first have longer melanoma survival. Digestive system tumours were the most concomitant; a digestive examination is advisable, especially for those with an expected overall survival (OS) greater than 10 months. Meanwhile, patient's family cancer history should be followed up in detail, along with completion of germline P/LP mutation and somatic mutation testing, all of which may provide valuable support for further treatment.

Adult↗

PubMed1979

Error propagation in viable cells.

Error propagation is the process, predicted by theoretical models, whereby errors in translating the genetic code will beget fresh errors in successive generations. It has been postulated that error propagation may underly the mortality of cells which display clonal senescence. We have demonstrated the occurrence of error propagation in viable cells of E. coli during growth in a low concentration of streptomycin, a drug which promotes ribosomal ambiguity. We monitored error propagation by measuring mistranslation of a specific UAA codon, and measured viability by direct enumeration of both live and dead cells through a sensitive microscopic technique. We find that the error frequency may be artificially increased by at least an order of magnitude without generating any detectable increase in the proportion of dead cells or of cells whose descendents are doomed to clonal senescence. The error frequency increases gradually over the course of a few generations, in qualitative agreement with the notion of error propagation, and eventually stabilizes at a constant value much higher than normal. The kinetics of this increase agree quantitatively with the Hoffman-Kirkwood and Holliday formulation of error propagation, for parameter values which dictate convergence to a stable error frequency. This convergent behaviour, under conditions of enhanced mistranslation, demonstrates that the normal parameters are well removed from the region of instability in error propagation; even an order of magnitude increase in mistranslation does not tip the translation system into the unstable mode which has been postulated to underly cell senescence. Thus, the error catastrophe theory of cell senescence cannot apply to the translation system of bacteria. We have reviewed experimental data on the fidelity of translation in somatic cells of higher organisms which militate against the notion that the translation system in these cell types could be much closer to the region of instability than in bacteria. These considerations controvert the error catastrophe theory of cell senescence.

Alkaline Phosphatase↗

PubMed2025

First clinical diagnosis of FAME3 via commercial Long-Read sequencing reveals mosaic repeat expansion in MARCHF6 gene.

Familial Adult Myoclonic Epilepsy type 3 (FAME3) is a rare autosomal dominant disorder characterized by cortical tremor and epilepsy, caused by a noncoding pentanucleotide repeat expansion (TTTTA/TTTCA)n in the MARCHF6 gene. Conventional genetic testing often fails to detect this expansion due to its repetitive structure and intronic location. We evaluated a 61-year-old woman with refractory myoclonic and generalized tonic-clonic seizures, whose prior genetic testing-including exome and genome sequencing-was non-diagnostic. Using PacBio HiFi long-read whole-genome sequencing and the tandem repeat genotyping tool TRGT, we identified a pathogenic MARCHF6 intronic expansion. The proband harbored one allele with 15 TTTTA repeats and a second allele with a compound expansion of 661 TTTTA and 12 TTTCA repeats. Three affected relatives shared similarly expanded alleles, but with increasing repeat size in the latter generations. Importantly, analysis using TRGT-instability revealed repeat mosaicism in all affected individuals, reflected by variability in motif counts across individual sequencing reads. This somatic heterogeneity may contribute to the phenotypic penetrance, variable expressivity and pleiotropism seen in FAME3 disease expression. To our knowledge, this is the first clinical diagnosis of FAME3 using a commercially available long-read sequencing platform, underscoring its diagnostic utility in resolving complex repeat expansion disorders and uncovering biologically relevant mosaicism.

Humans↗

PubMed1975

Genetic instability in Drosophila melanogaster: Mutable miniature (mu).

A new mutable gene, mutable miniature wing (mu), is described. This mutable gene mutates spontaneously at an inordinate rate both germinally and somatically. Two classes of reversions of mu have been found in approximately equal frequency: those to an allele with an intermediate phenotype (mi) and those to a subliminal allele (ms) equivalent to wild type in phenotype. Reversions appear to be mutationally stable. The chronology of genetic events leading to the discovery of mu implicates, but does not prove, the insertion of a "foreign" DNA segment as the basis of mutability.

Alleles↗

PubMed2025

DNA damage repair gene alterations influence the tumor immune microenvironment in advanced non-small cell lung cancer.

PURPOSE: DNA damage response and repair (DDR) gene alterations contribute to genomic instability and increased tumor immunogenicity, yet their clinical significance in non-small cell lung cancer (NSCLC) remains unclear. Using a large real-world dataset, we evaluated the prevalence of DDR alterations and their relation to the tumor immune microenvironment in metastatic NSCLC. EXPERIMENTAL DESIGN: We retrospectively analyzed real-world data from patients with metastatic NSCLC using the Tempus AI database. Tumors were sequenced with Tempus xT DNA and xR RNA assays and classified based on the presence (DDRmt) or absence (DDRwt) of a pathogenic somatic alteration or copy number deletion in a DDR pathway gene. Associations between DDR alterations and immune cell infiltration, PD-L1 immunohistochemistry, tumor mutational burden (TMB), and microsatellite instability (MSI-H) were examined. RESULTS: Among 14,127 patients (median age = 67, 49% female), 5,276 (37%) were DDRmt. There was a higher prevalence of current/former smokers in the DDRmt group (86% vs. 82%; p<0.001). DDRmt tumors were more likely to have higher levels of TMB (median: 5.4 vs. 4.6; p<0.001), MSI-H (1.1 % vs. <0.1 %; p<0.001), and infiltrating CD8+ T cells (p=0.003) compared to DDRwt tumors. A lower frequency of macrophages (p<0.001) were observed among DDRmt compared with DDRwt tumors with no difference in PDL1 positivity. CONCLUSIONS: Among patients with metastatic NSCLC, 37% present with DDRmt tumors characterized by higher TMB, frequency of MSI-H, and changes in immune cell infiltrates. These findings provide insight into the immunogenic landscape of DDR-altered NSCLC and may inform biomarker selection and therapeutic strategies.

Humans↗

PubMed2026

Exploiting the weak link: Ataxia-Telangiectasia Mutated dysfunction in oesophagogastric tumours.

ATM (ataxia-telangiectasia mutated) is a central regulator of the DNA damage response, coordinating double-strand break repair, checkpoint control, and cell fate decisions. Its disruption drives genomic instability and has been implicated across multiple tumour types. In oesophagogastric cancers, ATM alterations occur in a clinically relevant subset of cases, encompassing both somatic and germline events, and are associated with distinct molecular features including reduced co-occurrence with TP53 mutations and elevated homologous recombination deficiency scores. This narrative review synthesises published literature and publicly available genomic databases to examine ATM biology, the spectrum of ATM alterations across oesophageal adenocarcinoma, oesophageal squamous cell carcinoma, and gastric cancer subtypes, and the challenges of defining true ATM deficiency. The therapeutic implications of ATM dysfunction are evaluated across radiotherapy, platinum-based chemotherapy, ATR inhibition, and PARP inhibition. ATM alterations are detected in approximately 6% of tumours pan-cancer and in up to 10% of oesophagogastric cases. Defining ATM deficiency remains challenging, as immunohistochemistry, next-generation sequencing, and functional assays each carry distinct limitations. ATR inhibition emerges as the most consistently supported therapeutic strategy, with converging preclinical and early clinical evidence across oesophagogastric models. By contrast, available data do not support treating ATM deficiency as equivalent to BRCA-like homologous recombination deficiency, and PARP inhibitor monotherapy has not demonstrated consistent benefit. Prospective validation of functional ATM assays, histology-stratified trial design, and integration of genomic, protein-level, and functional evidence represent key priorities for translating ATM-guided strategies into oesophagogastric cancer practice.

Humans↗

PubMed2026

Bayesian Integration of Tumor Mutational Signatures and Somatic Features Refines Pathogenicity Assessment of Germline Mismatch Repair Variants.

Variants of uncertain significance (VUS) in mismatch repair (MMR) genes represent a persistent bottleneck in germline interpretation for Lynch syndrome, creating a critical opportunity to leverage tumor biology to refine pathogenicity assessment. Although tumor features such as microsatellite instability (MSI) and immunohistochemistry (IHC) are routinely evaluated, they are typically interpreted separately from germline classification, and their quantitative contribution within ACMG/AMP frameworks remains poorly defined. We therefore analyzed paired germline and tumor sequencing data from 1110 tumors across 1073 patients with colorectal or endometrial cancer to determine whether mismatch repair-deficient (MMR-d) mutational signatures can be quantitatively integrated into Bayesian germline variant interpretation. Using COSMIC single-base substitution signatures, tumors were classified as MMR-d or MMR proficient, and an empirically derived likelihood ratio (LR) quantified the association between MMR-d signatures and pathogenic germline MMR variants. The presence of an MMR-d signature increased the likelihood of an underlying pathogenic germline MMR variant approximately eightfold (LR ≈ 8; log10 LR ≈ 0.90), whereas its absence provided moderate-to-strong benign evidence (LR ≈ 0.156; log10 LR ≈ -0.81). Applying this integrative framework to 45 germline MMR VUS, joint modeling of tumor mutational signatures with additional somatic and variant-level evidence resulted in clinically significant reclassification of 38 (84.4%) variants, including three reclassified as pathogenic or likely pathogenic and 35 as likely benign. A total of 16 downgraded variants were independently downgraded by Invitae. These findings demonstrate that tumor mutational signatures can be formally incorporated into Bayesian germline interpretation, transforming tumor data into quantitative pathogenicity evidence and offering a principled strategy to reduce VUS burden in hereditary cancer genetics.

Humans↗

PubMed2026

Integrating germline and tumor sequencing to improve hereditary cancer diagnosis and care.

A subset of cancers arises due to inherited germline pathogenic variants in specific genes, known as hereditary cancers. These genes typically include tumor suppressors, DNA repair and replication fidelity genes, and occasionally oncogenes. In most hereditary cancer syndromes, Knudson's two-hit hypothesis applies, where a second somatic event inactivates the remaining allele of a tumor suppressor or DNA repair gene, leading to tumorigenesis. Advancements in genome-wide sequencing have significantly enhanced our understanding of the mutational processes involved in hereditary cancers. In particular, the assessment of microsatellite instability (MSI), tumor mutational burden (TMB), and mutational signatures has emerged as a powerful tool for the identification of hereditary tumors. Tumors with high or ultra-high TMB often reflect underlying DNA repair deficiencies, while specific mutational signatures can pinpoint the defective pathway. These tumor mutational features are especially informative in syndromes involving mismatch repair (MMR), homologous recombination (HR), base excision repair (BER), nucleotide excision repair (NER), and polymerase proofreading. Moreover, tumor sequencing aids in the interpretation of germline variants, identifies somatic mosaicism, and helps differentiate hereditary from sporadic cancers. Additionally, tumor molecular features associated with DNA repair deficiencies offer insights into personalized therapies, such as the use of PARP inhibitors for BRCA1/2-deficient tumors and immune checkpoint inhibitors for MMR- and polymerase proofreading-deficient cancers. Tumor profiling also uncovers actionable mutations in oncogenes like RET and VHL, which can be targeted with specific therapies. This review explores the integration of tumor molecular features with germline genetic data to refine diagnosis, risk assessment, and therapeutic strategies in hereditary cancer.

Humans↗

PubMedDate not supplied

[Genome organization in eukaryotes].

The review discussed problems of genome organization in the chromosomes of eukaryotes based on the data of genetical and molecular-biological studies. Particular attention is paid to the peculiarities of organization of genetic material in Drosophila. The main (euchromatic) part of the genome is considered as the totality of separate functional units (chromomere, gene loci), which have in the average a higher excess of DNA compared to the sized of the structural gene. The possible ways of internal organization of these units and the role of different types of DNA sequences in their function are discussed. The features of organization and function of the heterochromatic regions of chromosomes consisting of simple sequences of satellite DNA and tandemly repeated genes (polygenes), that code for general cellular functions (similar to the ribosomal genes) are considered. The instability of the number and even the sites of localization of polygenes in the chromosome, which can be determined by the peculiarities of their functions during differentiation of somatic cells is notes.

Animals↗

PubMed1978

Unusual in vivo rearrangements of the Y chromosome with mitotic instability in vitro.

An unusual structural rearrangement of the Y chromosome resulting in seven different cell lines was found in a male infant with coronal synostosis as the only major clinical symptom. At least three different events must have occurred to explain the patient's karyotype: nondisjunction, chromosome breakage followed by translocation, and tetraploidization followed by somatic recombination. In addition, the structurally abnormal Y chromosome appeared to be unstable in vitro.

Cells, Cultured↗

PubMed2026

Mobile elements in pituitary neuroendocrine tumors: integrative evidence and future directions.

Mobile genetic elements (MGEs), including LINE-1 retrotransposons, Alu and SVA elements, and human endogenous retroviruses (HERVs), constitute nearly half of the human genome and are increasingly understood to influence multiple dimensions of cancer evolution. Yet, pituitary neuroendocrine tumors (PitNETs) remain almost absent from mobilome research, despite exhibiting genomic and epigenetic contexts permissive to retroelement activation. In this review, we synthesize current evidence linking MGEs to PitNET biology and delineate unresolved but testable mechanisms. Structural genomic studies demonstrate that Alu-mediated non-allelic homologous recombination contributes to germline mutagenesis in MEN1 and AIP, reinforcing the notion that repetitive DNA architecture shapes PitNET predisposition. Transcriptomic analyses reveal global derepression of transposable elements and LINE-1 hypomethylation in subsets of tumors, while mechanistic connections to chromatin instability emerge from recurrent ATRX/DAXX deficiency and TP53 inactivation, both established repressors of retroelements. Furthermore, the retrocopy-derived long non-coding RNA RPSAP52 exemplifies how mobilome-origin transcripts can be co-opted as oncogenic regulators in PitNETs, acting through HMGA2-dependent proliferative networks. Preliminary data also suggest endogenous retroviral activation, with consistent upregulation of HERV envelope genes across distinct tumor subtypes. Nevertheless, no study has yet systematically mapped somatic mobile-element insertions (MEIs), quantified LINE-1 protein activity, or profiled HERV expression at locus resolution in PitNETs. Mobilome biology represents a tractable and conceptually rich frontier with diagnostic, prognostic, and therapeutic potential in pituitary tumorigenesis.

Humans↗

PubMed2025

Evolutionary fingerprints of epithelial-to-mesenchymal transition.

Mesenchymal plasticity has been extensively described in advanced epithelial cancers; however, its functional role in malignant progression is controversial1-5. The function of epithelial-to-mesenchymal transition (EMT) and cell plasticity in tumour heterogeneity and clonal evolution is poorly understood. Here we clarify the contribution of EMT to malignant progression in pancreatic cancer. We used somatic mosaic genome engineering technologies to trace and ablate malignant mesenchymal lineages along the EMT continuum. The experimental evidence clarifies the essential contribution of mesenchymal lineages to pancreatic cancer evolution. Spatial genomic analysis, single-cell transcriptomic and epigenomic profiling of EMT clarifies its contribution to the emergence of genomic instability, including events of chromothripsis. Genetic ablation of mesenchymal lineages robustly abolished these mutational processes and evolutionary patterns, as confirmed by cross-species analysis of pancreatic and other human solid tumours. Mechanistically, we identified that malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division. Thus, EMT favours the emergence of genomic-unstable, highly fit tumour cells, which strongly supports the concept of cell-state-restricted patterns of evolution, whereby cancer cell speciation is propagated to progeny within restricted functional compartments. Restraining the evolutionary routes through ablation of clones capable of mesenchymal plasticity, and extinction of the derived lineages, halts the malignant potential of one of the most aggressive forms of human cancer.

Animals↗

PubMed2026

Reframing early gastric carcinogenesis through lineage, niche, and evolution.

Early gastric cancer is still commonly conceptualized as the endpoint of a linear sequence from chronic gastritis to intestinal metaplasia, dysplasia, and invasion. Yet recent single-cell, spatial, genomic, and functional studies indicate that this model incompletely captures the biology of early gastric carcinogenesis. Malignant potential is established progressively within a precancerous gastric field already shaped by somatic evolution, chronic inflammatory injury, and epithelial lineage distortion. Within this field, progression is concentrated in a restricted set of precursor states, particularly incomplete, hybrid, and stem-like metaplastic populations that display plasticity, persistence, and increasing compatibility with a supportive microenvironment. Fibroblast niche remodeling, immune protection loss, endothelial rewiring, genomic instability, epigenetic drift, and selective retention of advantageous molecular alterations further promote malignant commitment. In parallel, diffuse gastric cancer appears to follow a distinct route that may arise independently of conventional intestinal metaplasia through E-cadherin-deficient epithelial transformation and downstream chromatin reprogramming. Here, we synthesize recent evidence to propose an updated framework for early gastric carcinogenesis based on field evolution, lineage instability, ecosystem support, and pathway divergence. Rather than replacing the classical Correa cascade, this framework seeks to refine it by shifting the unit of risk assessment from histologic stage alone to biologically defined precursor states shaped by lineage instability, clonal persistence, niche permissiveness, and pathway-specific molecular constraints. This perspective shifts the emphasis of prevention from detecting smaller cancers to identifying and intercepting biologically committed precursor states before invasion occurs.

Humans↗

PubMed1978

Analysis of banding patterns and mosaic configurations in a case of ring chromosome 15.

Cytogenetic studies on lymphocytes from a 14-year-old mentally retarded girl with somatic anomalies suggestive of a chromosomal abnormality revealed a ring chromosome 15. The long arm of the defective chromosome is broken at band q24 or q25. The silver staining technique for nucleolus organizer regions showed that the ring had lost the achromatic stalk and the satellite. The chromosomal mosaicism resulting from the structural instability of the ring chromosome was analyzed and compared with 6 cases reported in the literature. It is proposed that the clinical manifestations in the different patients with ring chromosome 15 result from both the deficiency in the long arm and the mosaic configurations.

Adolescent↗

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)↗