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 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).

A transcriptomic model for homologous recombination deficiency in prostate cancer

2021 ◽  
Author(s):  
Adam B. Weiner ◽  
Yang Liu ◽  
Matthew McFarlane ◽  
Pushpinder S. Bawa ◽  
Eric V. Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Homologous Recombination Deficiency

Abstract 2822: A pan-cancer analysis of inferred homologous recombination deficiency identifies potential platinum benefit in novel subtypes

2014 ◽  
Author(s):  
Andrea M. Marquard ◽  
Aron C. Eklund ◽  
Zhigang C. Wang ◽  
Andrea L. Richardson ◽  
Zoltan Szallasi ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Homologous Recombination Deficiency ◽  
Pan Cancer

Targeting resistant prostate cancer with ATR and PARP inhibition (TRAP trial): A phase II study.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS254-TPS254
Author(s):  
Zachery R. Reichert ◽  
Stephanie Daignault ◽  
Benjamin A. Teply ◽  
Michael Edward Devitt ◽  
Elisabeth I. Heath
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Acquired Resistance ◽  
Progression Free Survival ◽  
Strand Break ◽  
Circulating Tumor Dna ◽  
Parp Inhibition ◽  
Genes Encoding

TPS254 Background: Inhibition of poly(ADP-ribose) polymerase (PARP) shows promise in prostate cancer, but is limited to the ~20% of men with defects in genes encoding for DNA repair proteins BRCA1, BRCA2 or ATM (homologous recombination defect positive, HRD+). The effect is modest for HRD+ patients with a progression free survival of ~7 months. Pharmacologically simulating genetic DNA repair defects may expand who benefits to homologous recombination defect negative (HRD-) patients and improve HRD+ response. The ataxia telangiectasia and Rad3-related protein (ATR) is ideal with its roles in cell cycle regulation, replication fork resolution and both single and double strand break repair. Preclinical studies on HRD-/HRD+ cell lines support this. We hypothesize co-inhibition of ATR and PARP will respond regardless of HRD status. Methods: TRAP is a prospective, multi-institutional, phase 2 clinical trial testing AZD6738 combined with olaparib in HRD+ and HRD- mCRPC patients. Primary endpoint is the response rate (RR) by RECIST radiographic response or PSA decline ≥50% in 35 HRD- patients, with a secondary objective of RR in 12 HRD+ patients. HRD+ is mono/biallelic loss of ATM or biallelic loss of BRCA1/2. Tissue based sequencing is done unless completed prior in mCRPC, known BRCA germline loss, treating provider deems biopsy unsafe or biopsy fails. Those unable or failing biopsy are designated as HRD-, but BRCA1/2 and ATM are tested via circulating tumor DNA in a commercial test. Eligible patients must progress after ≥1 line of mCRPC therapy. Progression on a second generation anti-androgen (e.g. apalutamide), abiraterone or within 6 months of docetaxel in hormone sensitive disease are eligible. Treatment entails 160 mg PO daily of AZD6738 on days 1-7 and 300 mg PO BID of olaparib on days 1-28 of a 28-day cycle. Statistical analysis will provide RR with 95% binomial confidence intervals. Analysis of tumor specimens, circulating tumor cells and DNA will be performed for predictors of response and acquired resistance. The study is at four sites in the US, participates in the Prostate Cancer Clinical Trials Consortium, LLC, is managed by the University of Michigan and funded by AstraZeneca. Clinical trial information: NCT03787680.

scholarly journals Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer

2019 ◽  
Author(s):  
Zsofia Sztupinszki ◽  
Miklos Diossy ◽  
Marcin Krzystanek ◽  
Judit Borcsok ◽  
Mark Pomerantz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Next Generation Sequencing Data ◽  
Parp Inhibition ◽  
Sequencing Data ◽  
Mutational Signatures ◽  
Homologous Recombination Deficiency ◽  
Platinum Based Chemotherapy ◽  
Inhibitor Treatment

AbstractBackgroundProstate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. It is not clear, however, whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, rendering them sensitive to HR-directed therapies.To identify a more comprehensive set of prostate cancer cases with homologous recombination deficiency (HRD) including those cases that do not harbor mutations in known HR genes.HRD levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. Whole genome (n=311) and whole exome sequencing data (n=498) of both primary and metastatic prostate adenocarcinomas (PRAD) were analyzed.ResultsKnown BRCA-deficient samples showed robust signs of HR-deficiency associated mutational signatures. HRD-patterns were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR related genes. Patients with HRD signatures had a significantly worse prognosis than patients without signs of HRD.ConclusionsThese findings may expand the number of cases likely to respond to PARP-inhibitor treatment. Based on the HRD associated mutational signatures, 5-8 % of prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).

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 >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 < 0.0001), whereas 19q12 amplification occurred mainly in non-HRD patients (p < 0.0001), compared with their corresponding counterparts within TCGA-OV. The predictive significance of 8q24.2 amplification (p < 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 < 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.

Sign in / Sign up

Export Citation Format

Share Document