ExpHRD: an individualized, transcriptome-based prediction model for homologous recombination deficiency assessment in cancer
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ABSTRACT:
SUBMITTER: Lee J
PROVIDER: S-EPMC11241885 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:ObjectiveHomologous recombination deficiency (HRD) is the main mechanism of tumorigenesis in some cancers. HRD causes abnormal double-strand break repair, resulting in genomic scars. Some scoring HRD tests have been approved as companion diagnostics of polyadenosine diphosphate-ribose polymerase (PARP) inhibitor treatment. This study aimed to build an HRD prediction model using gene expression data from various cancer types.MethodsThe cancer genome atlas data were used for HRD prediction modeling. A total of 10,567 cases of 33 cancer types were included, and expression data from 5128 out of 20,502 genes were included as predictors. A penalized logistic regression model was chosen as a modeling technique.ResultsThe area under the curve of the receiver operating characteristic curve of HRD status prediction was 0.98 for the training set and 0.93 for the test set. The accuracy of HRD status prediction was 0.93 for the training set and 0.88 for the test set.ConclusionsOur study suggests that the HRD prediction model based on penalized logistic regression using gene expression data can be used to select patients for treatment with PARP inhibitors.
| S-EPMC9676333 | biostudies-literature
Project description:Defects in genes involved in the DNA damage response cause homologous recombination repair deficiency (HRD). HRD is found in a subgroup of cancer patients for several tumor types, and it has a clinical relevance to cancer prevention and therapies. Accumulating evidence has identified HRD as a biomarker for assessing the therapeutic response of tumor cells to poly(ADP-ribose) polymerase inhibitors and platinum-based chemotherapies. Nevertheless, the biology of HRD is complex, and its applications and the benefits of different HRD biomarker assays are controversial. This is primarily due to inconsistencies in HRD assessments and definitions (gene-level tests, genomic scars, mutational signatures, or a combination of these methods) and difficulties in assessing the contribution of each genomic event. Therefore, we aim to review the biological rationale and clinical evidence of HRD as a biomarker. This review provides a blueprint for the standardization and harmonization of HRD assessments.
| S-EPMC10928375 | biostudies-literature
Project description:Homologous recombination deficiency (HRD) renders cancer cells vulnerable to unrepaired double-strand breaks and is an important therapeutic target as exemplified by the clinical efficacy of poly ADP-ribose polymerase (PARP) inhibitors as well as the platinum chemotherapy drugs applied to HRD patients. However, it remains a challenge to predict HRD status precisely and economically. Copy number alteration (CNA), as a pervasive trait of human cancers, can be extracted from a variety of data sources, including whole genome sequencing (WGS), SNP array, and panel sequencing, and thus can be easily applied clinically. Here we systematically evaluate the predictive performance of various CNA features and signatures in HRD prediction and build a gradient boosting machine model (HRDCNA) for pan-cancer HRD prediction based on these CNA features. CNA features BP10MB[1] (The number of breakpoints per 10MB of DNA is 1) and SS[ > 7 & <=8] (The log10-based size of segments is greater than 7 and less than or equal to 8) are identified as the most important features in HRD prediction. HRDCNA suggests the biallelic inactivation of BRCA1, BRCA2, PALB2, RAD51C, RAD51D, and BARD1 as the major genetic basis for human HRD, and may also be applied to effectively validate the pathogenicity of BRCA1/2 variants of uncertain significance (VUS). Together, this study provides a robust tool for cost-effective HRD prediction and also demonstrates the applicability of CNA features and signatures in cancer precision medicine.
| S-EPMC10188435 | biostudies-literature
Project description:Homologous recombination deficiency (HRD) results in impaired double strand break repair and is a frequent driver of tumorigenesis. Here, we develop a genome-wide mutational scar-based pan-cancer Classifier of HOmologous Recombination Deficiency (CHORD) that can discriminate BRCA1- and BRCA2-subtypes. Analysis of a metastatic (n = 3,504) and primary (n = 1,854) pan-cancer cohort reveals that HRD is most frequent in ovarian and breast cancer, followed by pancreatic and prostate cancer. We identify biallelic inactivation of BRCA1, BRCA2, RAD51C or PALB2 as the most common genetic cause of HRD, with RAD51C and PALB2 inactivation resulting in BRCA2-type HRD. We find that while the specific genetic cause of HRD is cancer type specific, biallelic inactivation is predominantly associated with loss-of-heterozygosity (LOH), with increased contribution of deep deletions in prostate cancer. Our results demonstrate the value of pan-cancer genomics-based HRD testing and its potential diagnostic value for patient stratification towards treatment with e.g. poly ADP-ribose polymerase inhibitors (PARPi).
| S-EPMC7643118 | biostudies-literature
Project description:Homologous recombination DNA-repair deficiency (HRD) is a common driver of genomic instability and confers a therapeutic vulnerability in cancer. The accurate detection of somatic allelic imbalances (AIs) has been limited by methods focused on BRCA1/2 mutations and using mixtures of cancer types. Using pan-cancer data, we revealed distinct patterns of AIs in high-grade serous ovarian cancer (HGSC). We used machine learning and statistics to generate improved criteria to identify HRD in HGSC (ovaHRDscar). ovaHRDscar significantly predicted clinical outcomes in three independent patient cohorts with higher precision than previous methods. Characterization of 98 spatiotemporally distinct metastatic samples revealed low intra-patient variation and indicated the primary tumor as the preferred site for clinical sampling in HGSC. Further, our approach improved the prediction of clinical outcomes in triple-negative breast cancer (tnbcHRDscar), validated in two independent patient cohorts. In conclusion, our tumor-specific, systematic approach has the potential to improve patient selection for HR-targeted therapies.
| S-EPMC9800569 | biostudies-literature
Project description:BackgroundThe homologous recombination deficiency (HRD) test is an important tool for identifying patients with epithelial ovarian cancer (EOC) benefit from the treatment with poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi). Using whole exome sequencing (WES)-based platform can provide information of gene mutations and HRD score; however, the clinical value of WES-based HRD test was less validated in EOC.MethodsWe enrolled 40 patients with EOC in the training cohort and 23 in the validation cohort. The WES-based HRD score was calculated using the scarHRD software. We first evaluated the concordance of the HRD status defined by the Myriad MyChoice CDx and then assessed the value of HRD on clinical prognosis in patients with EOC.ResultsThe HRD score defined by the WES-based test was positively correlated with that of the Myriad MyChoice® CDx test (r = 0.82, p < 0.01) in the training cohort. In compared to HRD status of Myriad test, the sensitivity, specificity, positive predictive value, and negative predictive value of the WES-based HRD test were 93.5% (29/31), 77.8% (7/9), 93.5% (29/31), and 77.8% (7/9), respectively. Patients with positive HRD status defined by WES-based scarHRD test and Myriad MyChoice® CDx test were both highly associated with platinum sensitive response (both Fisher's exact test, p = 0.002) as well as the superior progression-free survival (both log-rank p = 0.002). The multi-variate Cox regression model incorporated with optimal debulking surgery showed that the recurrence risk was decreased in the patients with positive HRD status, either defined by Myriad MyChoice® CDx test (Hazard ratio (HR) 0.33, 95% confidence interval (CI) 0.14-0.79, p = 0.013) or WES-based test Myriad MyChoice® CDx test (HR 0.34, 95% CI 0.14-0.80, p = 0.014). Nine patients had mutations in the genes involved in HR DNA repair, and all of them were positive for HRD. In the validation group, 23 patients were defined as positive HRD by WES-based testing. Six positive HRD patients and 5 negative HRD patients received maintenance PARPi. The median responsive interval of PARPi was 17 months in positive HRD patients and 3 months in negative HRD patients.ConclusionThe WES-based test is a potential option for determining the HRD status in EOC patients, and desires for further validation in large-scale cohorts.
| S-EPMC11780812 | biostudies-literature
Project description:Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique tumor responsiveness to HR-dependent DNA damage triggered by certain treatments (platinum chemotherapy and PARP inhibitors). While pathogenic mutations in HR genes are a major driver of this sensitivity, another layer of diverse tumor intrinsic and extrinsic factors regulate the HR deficiency (HRD) phenotype. Defining the mechanisms that drive HRD may guide the development of novel strategies and therapeutics to induce treatment sensitivity in non-HRD tumors. Here, we discuss the complexity underlying HRD in pancreatic cancer and highlight implications for identifying and treating this distinct subset of patients.
| S-EPMC8466888 | biostudies-literature
Project description:Homologous recombination (HR) is a highly accurate DNA repair mechanism. Several HR genes are established cancer susceptibility genes with clinically actionable pathogenic variants (PVs). Classically, BRCA1 and BRCA2 germline PVs are associated with significant breast and ovarian cancer risks. Patients with BRCA1 or BRCA2 PVs display worse clinical outcomes but respond better to platinum-based chemotherapies and poly-ADP ribose polymerase inhibitors, a trait termed "BRCAness." With the advent of whole-exome sequencing and multigene panels, PVs in other HR genes are increasingly identified among familial cancers. As such, several genes such as PALB2 are reclassified as cancer predisposition genes. But evidence for cancer risks remains unclear for many others. In this review, we will discuss cancer predispositions and treatment implications beyond BRCA1 and BRCA2, with a focus on 24 HR genes: 53BP1, ATM, ATR, ATRIP, BARD1, BLM, BRIP1, DMC1, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RIF1, RMI1, RMI2, RPA1, TOP3A, TOPBP1, XRCC2, and XRCC3. IMPLICATIONS FOR PRACTICE: This review provides a comprehensive reference for readers to quickly identify potential cancer predisposing homologous recombination (HR) genes, and to generate research questions for genes with inconclusive evidence. This review also evaluates the "BRCAness" of each HR member. Clinicians can refer to these discussions to identify potential candidates for future clinical trials.
| S-EPMC8417864 | biostudies-literature
Project description:The use of mutation analysis of homologous recombination repair (HRR) genes to estimate PARP-inhibition response may miss a larger proportion of responding patients. Here, we provide preclinical models for castration-resistant prostate cancer (CRPC) that can be used to functionally predict HRR defects. In vitro, CRPC LNCaP sublines revealed an HRR defect and enhanced sensitivity to olaparib and cisplatin due to impaired RAD51 expression and recruitment. Ex vivo-induced castration-resistant tumor slice cultures or tumor slice cultures derived directly from CRPC patients showed increased olaparib- or cisplatin-associated enhancement of residual radiation-induced γH2AX/53BP1 foci. We established patient-derived tumor organoids (PDOs) from CRPC patients. These PDOs are morphologically similar to their primary tumors and genetically clustered with prostate cancer but not with normal prostate or other tumor entities. Using these PDOs, we functionally confirmed the enhanced sensitivity of CRPC patients to olaparib and cisplatin. Moreover, olaparib but not cisplatin significantly decreased the migration rate in CRPC cells. Collectively, we present robust patient-derived preclinical models for CRPC that recapitulate the features of their primary tumors and enable individualized drug screening, allowing translation of treatment sensitivities into tailored clinical therapy recommendations.
| S-EPMC10257417 | 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