scholarly journals Validation of Genomic and Transcriptomic Models of Homologous Recombination Deficiency in a Real-World Pan-Cancer Cohort

2021 ◽  
Author(s):  
Benjamin D Leibowitz ◽  
Bonnie V Dougherty ◽  
Joshua SK Bell ◽  
Joshuah Kapilivsky ◽  
Jackson Michuda ◽  
...  
Keyword(s):  
Gene Expression ◽  
Homologous Recombination ◽  
Performance Metrics ◽  
Statistical Tests ◽  
Homologous Recombination Deficiency ◽  
Mutational Status ◽  
Pathway Gene ◽  
A Genome ◽  
Cancer Types ◽  
Tumor Types

Background: With the introduction of DNA-damaging therapies into standard of care cancer treatment, there is a growing need for predictive diagnostics assessing homologous recombination deficiency (HRD) status across tumor types. Following the strong clinical evidence for the utility of DNA-sequencing-based HRD testing in ovarian cancer, and growing evidence in breast cancer, we present analytical validation of the Tempus|HRD-DNA test. We further developed, validated, and explored the Tempus|HRD-RNA model, which uses gene expression data from 16,470 RNA-seq samples to predict HRD status from formalin-fixed paraffin-embedded (FFPE) tumor samples across numerous cancer types. Methods: Genomic and transcriptomic profiling was performed using next-generation sequencing from Tempus|xT, Tempus|xO, Tempus|xE, Tempus|RS, and Tempus|RS.v2 assays on 48,843 samples. Samples were labeled based on their BRCA1, BRCA2 and selected Homologous Recombination Repair (HRR) pathway gene (CDK12, PALB2, RAD51B, RAD51C, RAD51D) mutational status to train and validate HRD-DNA, a genome-wide loss-of-heterozygosity biomarker, and HRD-RNA, a logistic regression model trained on gene expression, using several performance metrics and statistical tests. Results: In a sample of 2,058 breast and 1,216 ovarian tumors, BRCA status was predicted by HRD-DNA with F1-scores of 0.98 and 0.96, respectively. Across an independent set of 1,363 samples across solid tumor types, the HRD-RNA model was predictive of BRCA status in prostate, pancreatic, and non-small cell lung cancer, with F1-scores of 0.88, 0.69, and 0.62, respectively. Conclusions: We predict HRD-positive patients across many cancer types and believe both HRD models may generalize to other mechanisms of HRD outside of BRCA loss. HRD-RNA complements DNA-based HRD detection methods, especially for indications with low prevalence of BRCA alterations.

scholarly journals Utility of Homologous Recombination Deficiency Biomarkers Across Cancer Types

2021 ◽  
pp. 1270-1280
Author(s):  
Shiro Takamatsu ◽  
J.B. Brown ◽  
Ken Yamaguchi ◽  
Junzo Hamanishi ◽  
Koji Yamanoi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Homologous Recombination ◽  
Expression Profiles ◽  
Chemical Exposure ◽  
Clinical Samples ◽  
Precision Oncology ◽  
Tp53 Mutations ◽  
Pathway Gene ◽  
Cancer Types ◽  
Gene Alterations

PURPOSE 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. METHODS We 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. RESULTS Biallelic 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. CONCLUSION This 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.

scholarly journals Pan-cancer landscape of homologous recombination deficiency

2020 ◽  
Author(s):  
Luan Nguyen ◽  
John Martens ◽  
Arne Van Hoeck ◽  
Edwin Cuppen
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Cancer Genomics ◽  
Strand Break ◽  
Diagnostic Value ◽  
Cancer Type ◽  
Brca1 And Brca2 ◽  
Homologous Recombination Deficiency ◽  
A Genome ◽  
Pan Cancer

AbstractHomologous recombination deficiency (HRD) results in impaired double strand break repair and is a frequent driver of tumorigenesis. Here, we developed 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 revealed HRD was most frequent in ovarian and breast cancer, followed by pancreatic and prostate cancer. Biallelic inactivation of BRCA1, BRCA2, RAD51C or PALB2 was the most common genetic cause of HRD, with RAD51C and PALB2 inactivation resulting in BRCA2-type HRD. While the specific genetic cause of HRD was cancer type specific, biallelic inactivation was 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).

scholarly journals Identification of a Novel Gene Model-Based Homologous Recombination Deficiency Score to Improve Survival Prediction of TNBC.

2021 ◽  
Author(s):  
Wenxiang Zhang ◽  
Bolun Ai ◽  
Xiangyi Kong ◽  
Xiangyu Wang ◽  
Jie Zhai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Homologous Recombination ◽  
Risk Score ◽  
Cox Regression ◽  
Roc Curves ◽  
Cox Regression Analysis ◽  
Homologous Recombination Deficiency ◽  
Ajcc Stage ◽  
Kaplan Meier

Abstract Background Triple-negative breast cancer (TNBC) is a specific histological type of breast cancer with a poor prognosis, early recurrence, which lacks durable chemotherapy responses and effective targeted therapies. We aimed to construct an accurate prognostic risk model based on homologous recombination deficiency (HRD) - gene expression profiles for improving prognosis prediction of TNBC. Methods Triple-negative breast cancer RNA sequencing data and sample clinical information were downloaded from the breast invasive carcinoma (BRCA) cohort in the Cancer Genome Atlas (TCGA) database. Combined with the HRD database, tumor samples were divided into two sets. We screened differentially expressed genes (DEGs) and then identified HRD-related prognostic genes using weighted gene co-expression network analysis (WGCNA) and Cox regression analysis. The least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were used to identifying key prognostic genes. Risk scores were calculated and compared with HRD score, Kaplan–Meier (KM) survival analysis were used to assess its prognostic power. GSE103091 dataset from GEO (Gene Expression Omnibus) database was used to validate the signature. Univariate and multivariate Cox regression were performed to independently verify the prognosis of the risk score. A nomogram was constructed and revealed by time-dependent ROC curves to guide clinical practice. Results We found that HRD tumor samples (HRD score > = 42) in TNBC patients were associated with poor overall survival (p = 0.027). We identified a total of 147 differential genes including 203 up-regulated and 213 down-regulated genes, among which 29 were prognosis-related genes. Through the LASSO method, 6 key prognostic genes ((MUCL1, IVL, FAM46C, CHI3L1, PRR15L, and CLEC3A) were selected and a 6-gene risk score was constructed. We found risk score was negatively associated with homologous recombination deficiency (HRD) scores (r = -0.22, p = 0.019). Compared with the low-risk group, Kaplan-Meier survival analysis shows that the high-risk group has an obvious poorer prognosis (P < 0.0001). Finally, we integrated the risk score model and clinical factors of TNBC (AJCC-stage, HRD score, T stage, and N stage) to construct a compound nomogram. Time-dependent ROC curves showed the risk score performed better in 1-, 3- and 5-year survival predictions compared with AJCC-stage. Conclusions Based on HRD gene expression data, our six HRD-related gene signature and nomogram could be practical and reliable tools for predicting OS in patients with TNBC.

scholarly journals Pan-cancer landscape of homologous recombination deficiency

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Luan Nguyen ◽  
John W. M. Martens ◽  
Arne Van Hoeck ◽  
Edwin Cuppen
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Cancer Genomics ◽  
Strand Break ◽  
Diagnostic Value ◽  
Cancer Type ◽  
Homologous Recombination Deficiency ◽  
Genome Wide ◽  
A Genome ◽  
Pan Cancer

Abstract 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).

scholarly journals TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer

2015 ◽  
Vol 33 (17) ◽  
pp. 1902-1909 ◽  
Author(s):  
Steven J. Isakoff ◽  
Erica L. Mayer ◽  
Lei He ◽  
Tiffany A. Traina ◽  
Lisa A. Carey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Clinical Trial ◽  
Homologous Recombination ◽  
Phase Ii ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Phase Ii Clinical Trial ◽  
End Points ◽  
Homologous Recombination Deficiency

Purpose The identification of patients with metastatic triple-negative breast cancer (mTNBC) who are expected to benefit from platinum-based chemotherapy is of interest. We conducted a single-arm phase II clinical trial of single-agent platinum for mTNBC with biomarker correlates. Patients and Methods Patients with mTNBC received first- or second-line cisplatin (75 mg/m2) or carboplatin (area under the concentration-time curve 6) by physician's choice once every 3 weeks. Coprimary end points were objective response rate (RR) and response prediction by p63/p73 gene expression. Secondary and exploratory end points included toxicity assessment, RR in cisplatin versus carboplatin, and RR in molecularly defined subgroups, including BRCA1/2 mutation carriers. Results Patients (N = 86; 69 as first-line therapy) received cisplatin (n = 43) or carboplatin (n = 43). RR was 25.6% (95% CI, 16.8% to 36%) and was numerically higher with cisplatin (32.6%) than with carboplatin (18.7%). RR was 54.5% in patients with germline BRCA1/2 mutations (n = 11). In patients without BRCA1/2 mutations (n = 66), exploratory analyses showed that a BRCA-like genomic instability signature (n = 32) discriminated responding and nonresponding tumors (mean homologous recombination deficiency–loss of heterozygosity/homologous recombination deficiency–large-scale state transitions [HRD-LOH/HRD-LST] scores were 12.68 and 5.11, respectively), whereas predefined analysis by p63/p73 expression status (n = 61), p53 and PIK3CA mutation status (n = 53), or PAM50 gene expression subtype (n = 55) did not. Five of the six long-term responders alive at a median of 4.5 years lacked germline BRCA1/2 mutations, and two of them had increased tumor HRD-LOH/HRD-LST scores. Conclusion Platinum agents are active in mTNBC, especially in patients with germline BRCA1/2 mutations. A measure of tumor DNA repair function may identify patients without mutations who could benefit from platinum therapy agents. Prospective controlled confirmatory trials are warranted.

scholarly journals Higher prevalence of homologous recombination-deficiency in lung squamous carcinoma from African Americans

2019 ◽  
Author(s):  
Sanju Sinha ◽  
Khadijah A. Mitchell ◽  
Adriana Zingone ◽  
Elise Bowman ◽  
Neelam Sinha ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Copy Number ◽  
Squamous Carcinoma ◽  
The Cancer Genome Atlas ◽  
Multiple Cancer ◽  
Homologous Recombination Deficiency ◽  
Molecular Features ◽  
Incidence And Mortality ◽  
Cancer Types ◽  
Lung Squamous Carcinoma

AbstractTo improve our understanding of the longstanding disparities in incidence and mortality across multiple cancer types among minority populations, we performed a systematic comparative analysis of molecular features in tumors from African American (AA) and European American (EA) ancestry. Our pan-cancer analysis on the cancer genome atlas (TCGA) and a more focused analysis of genome-wide somatic copy number profiles integrated with tumor-normal RNA sequencing in a racially balanced cohort of 222 non-small cell lung cancers (NSCLC) reveals more aggressive genomic characteristics of AA tumors. In general, we find AA tumors exhibit higher genomic instability (GI), homologous recombination-deficiency (HRD) levels, and more aggressive molecular features such as chromothripsis across many cancer types, including lung squamous carcinoma (LUSC). GI and HRD levels are strongly correlated across AA tumors, indicating that HRD plays an important role in GI in these patients. The prevalence of germline HRD is higher in AA tumors, suggesting that the somatic differences observed have genetic ancestry origins. Finally, we identify AA-specific copy number-based arm, focal and gene level recurrent features in lung cancer, including a higher frequency of PTEN deletion and KRAS amplification and a lower frequency of CDKN2A deletion. These results highlight the importance of including minority and under-represented populations in genomics research and may have therapeutic implications.

scholarly journals Novel Insights into Epigenetic Regulation of IL6 Pathway: In Silico Perspective on Inflammation and Cancer Relationship

2021 ◽  
Vol 22 (18) ◽  
pp. 10172
Author(s):  
Saverio Candido ◽  
Barbara Maria Rita Tomasello ◽  
Alessandro Lavoro ◽  
Luca Falzone ◽  
Giuseppe Gattuso ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Epigenetic Regulation ◽  
Computational Analysis ◽  
The Cancer Genome Atlas ◽  
Post Translational Modifications ◽  
Pathway Gene ◽  
Cancer Genome Atlas ◽  
Cancer Types ◽  
Tumor Types

IL-6 pathway is abnormally hyperactivated in several cancers triggering tumor cell growth and immune system inhibition. Along with genomic mutation, the IL6 pathway gene expression can be affected by DNA methylation, microRNAs, and post-translational modifications. Computational analysis was performed on the Cancer Genome Atlas (TCGA) datasets to explore the role of IL6, IL6R, IL6ST, and IL6R transmembrane isoform expression and their epigenetic regulation in different cancer types. IL6 was significantly modulated in 70% of tumor types, revealing either up- or down-regulation in an approximately equal number of tumors. Furthermore, IL6R and IL6ST were downregulated in more than 10 tumors. Interestingly, the correlation analysis demonstrated that only the IL6R expression was negatively affected by the DNA methylation within the promoter region in most tumors. Meanwhile, only the IL6ST expression was extensively modulated by miRNAs including miR-182-5p, which also directly targeted all three genes. In addition, IL6 upregulated miR-181a-3p, mirR-214-3p, miR-18a-5p, and miR-938, which in turn inhibited the expression of IL6 receptors. Finally, the patients’ survival rate was significantly affected by analyzed targets in some tumors. Our results suggest the relevance of epigenetic regulation of IL6 signaling and pave the way for further studies to validate these findings and to assess the prognostic and therapeutic predictive value of these epigenetic markers on the clinical outcome and survival of cancer patients.

scholarly journals Inferring Homologous Recombination Deficiency of Ovarian Cancer From the Landscape of Copy Number Variation at Subchromosomal and Genetic Resolutions

2021 ◽  
Vol 11 ◽  
Author(s):  
Meng Zhang ◽  
Si-Cong Ma ◽  
Jia-Le Tan ◽  
Jian Wang ◽  
Xue Bai ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Copy Number Variation ◽  
Copy Number ◽  
The Cancer Genome Atlas ◽  
Homologous Recombination Deficiency ◽  
Number Variation ◽  
Cancer Genome Atlas ◽  
Tumor Types ◽  
Pan Cancer

BackgroundHomologous recombination deficiency (HRD) is characterized by overall genomic instability and has emerged as an indispensable therapeutic target across various tumor types, particularly in ovarian cancer (OV). Unfortunately, current detection assays are far from perfect for identifying every HRD patient. The purpose of this study was to infer HRD from the landscape of copy number variation (CNV).MethodsGenome-wide CNV landscape was measured in OV patients from the Australian Ovarian Cancer Study (AOCS) clinical cohort and &gt;10,000 patients across 33 tumor types from The Cancer Genome Atlas (TCGA). HRD-predictive CNVs at subchromosomal resolution were identified through exploratory analysis depicting the CNV landscape of HRD versus non-HRD OV patients and independently validated using TCGA and AOCS cohorts. Gene-level CNVs were further analyzed to explore their potential predictive significance for HRD across tumor types at genetic resolution.ResultsAt subchromosomal resolution, 8q24.2 amplification and 5q13.2 deletion were predominantly witnessed in HRD patients (both p &lt; 0.0001), whereas 19q12 amplification occurred mainly in non-HRD patients (p &lt; 0.0001), compared with their corresponding counterparts within TCGA-OV. The predictive significance of 8q24.2 amplification (p &lt; 0.0001), 5q13.2 deletion (p = 0.0056), and 19q12 amplification (p = 0.0034) was externally validated within AOCS. Remarkably, pan-cancer analysis confirmed a cross-tumor predictive role of 8q24.2 amplification for HRD (p &lt; 0.0001). Further analysis of CNV in 8q24.2 at genetic resolution revealed that amplifications of the oncogenes, MYC (p = 0.0001) and NDRG1 (p = 0.0004), located on this fragment were also associated with HRD in a pan-cancer manner.ConclusionsThe CNV landscape serves as a generalized predictor of HRD in cancer patients not limited to OV. The detection of CNV at subchromosomal or genetic resolution could aid in the personalized treatment of HRD patients.

scholarly journals The chromatin remodeler ALC1 underlies resistance to PARP inhibitor treatment

2020 ◽  
Vol 6 (51) ◽  
pp. eabb8626
Author(s):  
Szilvia Juhász ◽  
Rebecca Smith ◽  
Tamás Schauer ◽  
Dóra Spekhardt ◽  
Hasan Mamar ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Dna Lesions ◽  
End Joining ◽  
Multiple Tumor ◽  
Genome Wide ◽  
A Genome ◽  
Inhibitor Resistance ◽  
Tumor Types

Poly(ADP-ribose) polymerase (PARP) inhibitors are used in the treatment of BRCA-deficient cancers, with treatments currently extending toward other homologous recombination defective tumors. In a genome-wide CRISPR knockout screen with olaparib, we identify ALC1 (Amplified in Liver Cancer 1)—a cancer-relevant poly(ADP-ribose)-regulated chromatin remodeling enzyme—as a key modulator of sensitivity to PARP inhibitor. We found that ALC1 can remove inactive PARP1 indirectly through binding to PARylated chromatin. Consequently, ALC1 deficiency enhances trapping of inhibited PARP1, which then impairs the binding of both nonhomologous end-joining and homologous recombination repair factors to DNA lesions. We also establish that ALC1 overexpression, a common feature in multiple tumor types, reduces the sensitivity of BRCA-deficient cells to PARP inhibitors. Together, we conclude that ALC1-dependent PARP1 mobilization is a key step underlying PARP inhibitor resistance.

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