Identification of biomarkers complementary to homologous recombination deficiency for improving the clinical outcome of ovarian serous cystadenocarcinoma.
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ABSTRACT:
SUBMITTER: Shi Z
PROVIDER: S-EPMC8131501 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Homologous recombination repair (HRR) pathway deficiency (HRD) is involved in the tumorigenesis and progression of high-grade serous ovarian carcinoma (HGSOC) as well as in the sensitivity to platinum chemotherapy drugs. In this study, we obtained data from The Cancer Genome Atlas (TCGA) on HGSOC and identified scores for the loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions, and calculated the HRD score. We then investigated the relationships among the score, genetic/epigenetic alterations in HRR-related genes, and the clinical data. We found that BRCA1/2 mutations were enriched in the group with HRD scores ?63. Compared with the groups with scores ?62, this group had a good prognosis; we thus considered HRD scores ?63 to be the best cutoff point for identifying HRD cases in HGSOC. Classification of HGSOC cases by the HRD status revealed a better prognosis for HRD cases caused by genetic alterations (genetic HRD) than those caused by epigenetic changes and those caused by undetermined reasons (p?=?0.0002). Among cases without macroscopic residual tumors after primary debulking surgery, 11 of 12 genetic HRD cases survived after the median observation period of 6.6 years, showing remarkably high survival rates (p?=?0.0059). In conclusion, HGSOC can be classified into subtypes with different prognoses according to HRD status. This classification could be useful for personalized HGSOC treatment.
| S-EPMC7026096 | biostudies-literature
Project description:Homologous recombination deficiency (HRD) is a common molecular signature of genomic instability and has been shown to be a biomarker for targeted therapies. However, there is a lack of studies on the role of HRD changes in lung adenocarcinoma (LUAD) transcriptomics. HRD scores were determined using single nucleotide polymorphism (SNP) array data from LUAD patients from The Cancer Genome Atlas (TCGA) database. Transcriptional data from patients with different scores were analyzed to identify biomarkers associated with HRD. Candidate biomarkers were validated using Gene Expression Omnibus (GEO)-sourced datasets and an immunotherapy cohort. According to the bulk transcriptome and clinical characteristics of 912 LUAD patients and Single-cell RNA-seq of 9 LUAD patients from TCGA and GEO databases, we observed increased MS4A6A expression in HRD tumors; high MS4A6A expression predicted improved survival outcomes. Furthermore, a comprehensive analysis of the tumor immune microenvironment (TIME) revealed a positive correlation between MS4A6A expression and neoantigen loading and immune cell infiltration. Additionally, the immunotherapy cohort confirmed the possibility of using MS4A6A as a biomarker. Collectively, we suggest that MS4A6A is associated with HRD and provide a new perspective toward identifying promising biomarkers for immunotherapy.
| S-EPMC10496994 | biostudies-literature
Project description:Ovarian serous cystadenocarcinoma is a common malignant tumor of female genital organs. Treatment is generally less effective as patients are usually diagnosed in the late stage. Therefore, a well-designed prognostic marker provides valuable data for optimizing therapy. In this study, we analyzed 303 samples of ovarian serous cystadenocarcinoma and the corresponding RNA-seq data. We observed the correlation between gene expression and patients' survival and eventually established a risk assessment model of five factors using Cox proportional hazards regression analysis. We found that the survival time in high-risk patients was significantly shorter than in low-risk patients in both training and testing sets after Kaplan-Meier analysis. The AUROC value was 0.67 when predicting the survival time in testing set, which indicates a relatively high specificity and sensitivity. The results suggest diagnostic and therapeutic applications of our five-gene model for ovarian serous cystadenocarcinoma.
| S-EPMC4949334 | biostudies-literature
Project description:BackgroundHomologous recombination deficiency (HRD) is shown to predict response to DNA-damaging therapies in patients with high-grade serous ovarian cancer (HGSOC); however, changes in HRD during progression remains unknown.MethodsHRD scores were evaluated in paired primary and/or recurrent HGSOC samples (N = 107) from 54 patients with adjuvant platinum-based chemotherapy. BRCA1/2 mutation, BRCA1 methylation, loss of heterozygosity (LOH), and HRD scores were characterised using tumour DNA-based next-generation sequencing assays.ResultsAmong 50 evaluable pairs (N = 100 samples), high intra-patient correlation in HRD score was observed (r2 = 0.93). BRCA1/2 mutations, BRCA1/2 LOH, and HRD were maintained between primary and recurrent samples, except for one pair in which a BRCA1 reversion mutation was identified in the recurrent sample. Despite the reversion, both samples were classified as having high HRD scores ( ≥ 42). All samples with BRCA1/2 mutations exhibited high HRD scores; however, high HRD scores were more prevalent than BRCA1/2 mutations (55% vs. 30%, respectively).ConclusionMarkers of HRD were maintained between the primary and recurrent samples, regardless of other genomic changes that occurred during recurrence. HRD score/markers in primary tumours may be valuable and adequate for selection of platinum-based therapy and/or poly-ADP-ribose-polymerase (PARP) inhibitors in recurrent HGSOC.
| S-EPMC6219476 | biostudies-literature
Project description:Background: The homologous recombination (HR) pathway defects in cancers induced abrogation of cell cycle checkpoints, resulting in the accumulation of DNA damage, mitotic catastrophe, and cell death. Cancers with BRCA1/2 loss and other accumulation of similar genomic scars resulting in HRD displayed increased sensitivity to chemotherapy. Our study aimed to explore HRD score genetic mechanisms and subsequent clinical outcomes in human cancers, especially ovarian cancer. Methods: We analyzed TCGA data of HRD score in 33 cancer types and evaluated HRD score distribution and difference among tumor stages and between primary and recurrent tumor tissues. A weighted gene co-expression network analysis (WGCNA) was performed to identify highly correlated genes representing essential modules contributing to the HRD score and distinguish the hub genes and significant pathways. We verified HRD status predicting roles in patients' overall survival (OS) with univariate and multivariate Cox regression analyses and built the predicting model for patient survival. Results: We found that the HRD score increased with the rise in tumor stage, except for stage IV. The HRD score tended to grow up higher in recurrent tumor tissue than in their primary counterparts (p = 0.083). We constructed 15 co-expression modules with WGCNA, identified co-expressed genes and pathways impacting the HRD score, and concluded that the HRD score was tightly associated with tumor cells replication and proliferation. A combined HRD score ≥42 was associated with shorter OS in 33 cancer types (HR = 1.010, 95% CI: 1.008-1.011, p < 0.001). However, in ovarian cancer, which ranked the highest HRD score among other cancers, HRD ≥42 cohort was significantly associated with longer OS (HR = 0.99, 95% CI: 0.98-0.99, p < 0.0001). We also built a predicting model for 3 and 5 years survival in HGSC patients. Conclusion: A quantitative HRD score representing the accumulated genomic scars was dynamically increasing in proliferating tumor cells since the HRD score was tightly correlated to tumor cell division and replication. We highlighted HRD score biomarker role in prognosis prediction of ovarian cancer.
| S-EPMC8640082 | biostudies-literature
Project description:Homologous recombination deficiency (HRD) has become an important prognostic and predictive biomarker for patients with high-grade serous ovarian cancer who may benefit from poly-ADP ribose polymerase inhibitors (PARPi) and platinum-based therapies. HRD testing provides relevant information to personalize patients' treatment options and has been progressively incorporated into diagnostic laboratories. Here, we assessed the performance of an in-house HRD testing system deployable in a diagnostic clinical setting, comparing results from two commercially available next-generation sequencing (NGS)-based tumor tests (SOPHiA DDMTM HRD Solution and AmoyDx® (HRD Focus Panel)) with the reference assay from Myriad MyChoice® (CDx). A total of 85 ovarian cancer samples were subject to HRD testing. An overall strong correlation was observed across the three assays evaluated, regardless of the different underlying methods employed to assess genomic instability, with the highest pairwise correlation between Myriad and SOPHiA (R = 0.87, p-value = 3.39 × 10-19). The comparison of the assigned HRD status to the reference Myriad's test revealed a positive predictive value (PPV) and negative predictive value (NPV) of 90.9% and 96.3% for SOPHiA's test, while AmoyDx's test achieved 75% PPV and 100% NPV. This is the largest HRD testing evaluation using different methodologies and provides a clear picture of the robustness of NGS-based tests currently offered in the market. Our data shows that the implementation of in-house HRD testing in diagnostic laboratories is technically feasible and can be reliably performed with commercial assays. Also, the turnaround time is compatible with clinical needs, making it an ideal alternative to offer to a broader number of patients while maintaining high-quality standards at more accessible price tiers.
| S-EPMC10648202 | biostudies-literature
Project description:Ovarian cancer is the second most prevalent gynecologic malignancy, and ovarian serous cystadenocarcinoma (OSCA) is the most common and lethal subtype of ovarian cancer. Current screening methods have strong limits on early detection, and the majority of OSCA patients relapse. In this work, we developed and cross-validated a method for detecting gene expression biomarkers able to discriminate OSCA tissues from healthy ovarian tissues and other cancer types with high accuracy. A preliminary ranking-based approach was applied, resulting in a panel of 41 over-expressed genes in OSCA. The RNA quantity gene expression of the 41 selected genes was then cross-validated by using NanoString nCounter technology. Moreover, we showed that the RNA quantity of eight genes (ADGRG1, EPCAM, ESRP1, MAL2, MYH14, PRSS8, ST14 and WFDC2) discriminates each OSCA sample from each healthy sample in our data set with sensitivity of 100% and specificity of 100%. For the other three genes (MUC16, PAX8 and SOX17) in combination, their RNA quantity may distinguish OSCA from other 29 tumor types.
| S-EPMC9367275 | biostudies-literature
Project description:BackgroundHomologous Recombination Deficiency (HRD) is a predictive biomarker for ovarian cancer treated with PARP inhibitors or for breast cancer treated with first-line platinum-based chemotherapy. However, limited research is documented on platinum-based treatment prediction with HRD as a biomarker in ovarian cancer patients, especially in the Chinese population.MethodsWe investigated the association between HRD status and the response of platinum-based chemotherapy in 240 Chinese HGSOC patients.ResultsThe Pt-sensitive patients showed higher HRD scores than Pt-resistant ones, but this was not significant(median: 42.6 vs. 31.6, p = 0.086). (Pt)-sensitive rate was higher in HRD + BRCAm tumors and in HRD + BRCAwt tumors (HRD + BRCAm: 97%, p = 0.004 and HRD + BRCAwt: 90%, p = 0.04) compared with 74% in the HRD-BRCAwt tumors. We also found Pt-sensitive patients tend to be enriched in patients with BRCA mutations or non-BRCA HRR pathway gene mutations (BRCA: 93.6% vs 75.4%, p < 0.001; non-BRCA HRR: 88.6% vs 75.4%, p = 0.062). Patients with HRD status positive had significantly improved PFS compared with those with HRD status negative (median PFS: 30.5 months vs. 16.8 months, Log-rank p = 0.001). Even for BRCAwt patients, positive HRD was also associated with better PFS than the HRD-negative group (median: 27.5 months vs 16.8 months, Log-rank p = 0.010). Further, we found patients with pathogenic mutations located in the DNA-binding domain (DBD) of BRCA1 had improved FPS, compared to those with mutations in other domains. (p = 0.03).ConclusionsThe HRD status can be identified as an independent significance in Chinese HGSOC patients treated with first-line platinum-based chemotherapy.
| S-EPMC10015784 | biostudies-literature
Project description:Poly (ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapies have been found to be particularly effective in tumors that harbor deleterious germline or somatic mutations in the BRCA1 or BRCA2 genes, the products of which contribute to the conservative homologous recombination repair of DNA double-strand breaks. Nonetheless, several setbacks in clinical trial settings have highlighted some of the issues surrounding the investigation of PARP inhibitors, especially the identification of patients who stand to benefit from such drugs. One potential approach to finding this patient subpopulation is to examine the tumor DNA for evidence of a homologous recombination defect. However, although the genomes of many breast and ovarian cancers are replete with aberrations, the presence of numerous factors able to shape the genomic landscape means that only some of the observed DNA abnormalities are the outcome of a cancer cell's inability to faithfully repair DNA double-strand breaks. Consequently, recently developed methods for comprehensively capturing the diverse ways in which homologous recombination deficiencies may arise beyond BRCA1/2 mutation have used DNA microarray and sequencing data to account for potentially confounding features in the genome. Scores capturing telomeric allelic imbalance, loss of heterozygosity (LOH) and large scale transition score, as well as the total number of coding mutations are measures that summarize the total burden of certain forms of genomic abnormality. By contrast, other studies have comprehensively catalogued different types of mutational pattern and their relative contributions to a given tumor sample. Although at least one study to explore the use of the LOH scar in a prospective clinical trial of a PARP inhibitor in ovarian cancer is under way, limitations that result in a relatively low positive predictive value for these biomarkers remain. Tumors whose genome has undergone one or more events that restore high-fidelity homologous recombination are likely to be misclassified as double-strand break repair-deficient and thereby sensitive to PARP inhibitors and DNA damaging chemotherapies as a result of prior repair deficiency and its genomic scarring. Therefore, we propose that integration of a genomic scar-based biomarker with a marker of resistance in a high genomic scarring burden context may improve the performance of any companion diagnostic for PARP inhibitors.
| S-EPMC4053155 | biostudies-literature
Project description:Homologous recombination DNA repair deficiency (HRD) is associated with sensitivity to platinum and poly (ADP-ribose) polymerase inhibitors in certain cancer types, including breast, ovarian, pancreatic, and prostate. In these cancers, BRCA1/2 alterations and genomic scar signatures are useful indicators for assessing HRD. However, alterations in other homologous recombination repair (HRR)-related genes and their clinical significance in other cancer types have not been adequately and systematically investigated.MethodsWe obtained data sets of all solid tumors in The Cancer Genome Atlas and Cancer Cell Line Encyclopedia, and comprehensively analyzed HRR pathway gene alterations, their loss-of-heterozygosity status, and per-sample genomic scar scores, that is, the HRD score and mutational signature 3 ratio, DNA methylation profiles, gene expression profiles, somatic TP53 mutations, sex, and clinical or in vitro response to chemical exposure.ResultsBiallelic alterations in HRR genes other than BRCA1/2 were also associated with elevated genomic scar scores. The association between HRR-related gene alterations and genomic scar scores differed significantly by sex and the presence of somatic TP53 mutations. HRD tumors determined by a combination of indices also showed HRD features in gene expression analysis and exhibited significantly higher sensitivity to DNA-damaging agents than non-HRD cases in both clinical samples and cell lines.ConclusionThis study provides evidence for the usefulness of HRD analysis in all cancer types, improves chemotherapy decision making and its efficacy in clinical settings, and represents a substantial advancement in precision oncology.A comprehensive pan-cancer analysis on the clinical significance of homologous recombination deficiency.
| S-EPMC8373547 | biostudies-literature