Homologous recombination deficiency in ovarian cancer and beyond

2016 ◽  
Vol 4 (2) ◽  
pp. 17-22
Author(s):  
Ilary Ruscito ◽  
Susana Banerjee
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Cell Transformation ◽  
Parp Inhibitors ◽  
Molecular Signature ◽  
Current Evidence ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Homologous Recombination Deficiency ◽  
Response To Chemotherapy

It has been well established that failure in the homologous recombination repair (HRR) mechanism for DNA double strand repair causes genomic instability and increases the risk for cell transformation. Mutations in BRCA1 and BRCA2 are currently known to be the most frequent responsible for homologous recombination deficiency (HRD) but HRD can occur through other processes including mutations and epigenetic aberration of HRD-related genes and the indirect interaction of BRCA proteins with other proteins involved in the DNA repair. Current efforts in this field are concentrating in identifying an HRD molecular signature able to predict response to chemotherapy and PARP inhibitors, thus allowing to extend novel targeted treatments beyond germline BRCA mutated ovarian cancer patients. The aim of this brief review is to summarize the current evidence regarding HRD beyond germline BRCA mutations and therapeutic approaches.

scholarly journals Tumour Versus Germline BRCA Testing in Ovarian Cancer: A Single-Site Institution Experience in the United Kingdom

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 547
Author(s):  
Iolia Akaev ◽  
Siavash Rahimi ◽  
Olubukola Onifade ◽  
Francis John Edward Gardner ◽  
David Castells-Rufas ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Unknown Origin ◽  
Parp Inhibitors ◽  
Serous Carcinoma ◽  
High Grade ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Epithelial Cancers ◽  
Pathogenic Variants ◽  
Pathogenic Mutations

The aim of this audit was to evaluate the usefulness and serviceability of testing for pathogenic mutations in BRCA1 or BRCA2 (BRCA1/2) genes in ovarian cancer (OC) patients. One hundred and thirty-five patients with more common histological sub-types of OC were retrospectively identified between 2011 and 2019. The fail rate of the molecular analysis was 7.4% (10/135). One hundred and twenty-five records were evaluated: 99 (79.2%) patients had wild-type BRCA (both somatic and germline); tumour BRCA1/2 (tBRCA1/2) pathogenic mutations were found in 20 (16%) patients with distribution between BRCA1 and BRCA2 being 40% and 60%, respectively; 13 (10.4%) patients with pathogenic variants had germline mutations; and tBRCA1/2 with variant of unknown significance (VUS), in the absence of pathogenic BRCA1 or BRCA2 variants, was detected in 6 (4.8%) patients. Our data show that expanding the molecular service to the routine first-tumour testing for patients with OC will potentially increase the detection rate of BRCA mutations, thereby providing early benefits of PARP inhibitors therapy. The tumour testing service should continue to be offered to newly diagnosed patients with high-grade epithelial cancers, including high-grade serous carcinoma, but also with carcinosarcomas and poorly-differentiated metastatic adenocarcinomas of unknown origin.

scholarly journals PARP Inhibitors in Ovarian Cancer: The Route to “Ithaca”

Diagnostics ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 55 ◽  
Author(s):  
Boussios ◽  
Karathanasi ◽  
Cooke ◽  
Neille ◽  
Sadauskaite ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Current Evidence ◽  
Repair Pathway ◽  
Significant Efficacy

Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Early studies have shown significant efficacy for PARP inhibitors in patients with germline breast related cancer antigens 1 and 2 (BRCA1/2) mutations. It has also become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this treatment. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The choice of which PARP inhibitor is mainly based upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of patients most likely to benefit from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The aim of this review is to describe the current evidence for PARP inhibitors in ovarian cancer, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolution of resistance.

scholarly journals PARP inhibitors for BRCA wild type ovarian cancer; gene alterations, homologous recombination deficiency and combination therapy

2019 ◽  
Vol 49 (8) ◽  
pp. 703-707 ◽  
Author(s):  
Koji Matsumoto ◽  
Meiko Nishimura ◽  
Takuma Onoe ◽  
Hideki Sakai ◽  
Yusaku Urakawa ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Cancer Susceptibility ◽  
Checkpoint Inhibitors ◽  
Parp Inhibitors ◽  
Current Status ◽  
Wild Type ◽  
Homologous Recombination Deficiency ◽  
Cancer Susceptibility Genes ◽  
Gene Alterations

Abstract After a brief summary of the current status of poly-ADP ribose polymerase (PARP) inhibitors for ovarian cancer, we summarize the current status of PARP inhibitors for BRCA wild type ovarian cancer, especially regarding gene alterations other than BRCA, homologous recombination deficiency (HRD), and combinations. Discussion of gene alterations other than BRCA include the results of multiple gene panels studying homologous recombination repair deficiency genes and cancer susceptibility genes, and influences of these alterations on efficacy of PARP inhibitors and cancer susceptibility. Discussions of HRD include the results of phase three trials using HRD assay, the definition of HRD assays, and the latest assays. Discussions of combinations include early phase trial results and ongoing trials combining PARP inhibitors with immune checkpoint inhibitors, anti-angiogenic agents, and triplets.

scholarly journals Homologous Recombination Deficiency Testing for BRCA-Like Tumors: The Road to Clinical Validation

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1004
Author(s):  
Marjolijn M. Ladan ◽  
Dik C. van Gent ◽  
Agnes Jager
Keyword(s):  
Homologous Recombination ◽  
Brca Mutation ◽  
Strand Break ◽  
Parp Inhibitors ◽  
Clinical Validation ◽  
Brca Mutations ◽  
Homologous Recombination Deficiency ◽  
The Road ◽  
Dna Double Strand Break ◽  
The Status

Germline BRCA mutations result in homologous recombination deficiency (HRD) in hereditary breast and ovarian cancer, as well as several types of sporadic tumors. The HRD phenotype makes these tumors sensitive to DNA double strand break-inducing agents, including poly-(ADP-ribose)-polymerase (PARP) inhibitors. Interestingly, a subgroup of cancers without a BRCA mutation also shows an HRD phenotype. Various methods for selecting patients with HRD tumors beyond BRCA-mutations have been explored. These methods are mainly based on DNA sequencing or functional characteristics of the tumor. We here discuss the various tests and the status of their clinical validation.

scholarly journals Lymphocyte-specific Protein Tyrosine Kinase Regulates Homologous Recombination (HR) DNA Repair and Targeting Enhances PARPi Utility in HR Proficient Ovarian Cancer

2021 ◽  
Author(s):  
Goutam Dey ◽  
Rashmi Bharti ◽  
Chad Braley ◽  
Ravi Alluri ◽  
Emily Esakov ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Parp Inhibitors ◽  
Specific Protein ◽  
Brca1 And Brca2 ◽  
Nonreceptor Tyrosine Kinase

AbstractPoly-ADP Ribose Polymerase (PARP) inhibitors are clinically approved for the treatment of homologous recombination (HR) repair deficient tumors. PARP targeted therapy has limited efficacy in HR-proficient cancer. In this study, we identified the non-receptor lymphocyte-specific protein tyrosine kinase (LCK) as a novel regulator of HR repair pathways in endometrioid epithelial ovarian cancer (eEOC). Inhibition of LCK attenuates the expression of RAD51, BRCA1, and BRCA2 proteins necessary for HR-mediated DNA repair. HR repair in eEOC cells is LCK dependent. Upon DNA damage LCK expression is increased, and autophosphorylated, activated LCK is localized in the nucleus. LCK inhibition impairs RAD51 foci formation but augments γH2AX formation during DDR indicating reduced ability to repair DNA damage. DNA damage leads to direct interaction of LCK with RAD51 and BRCA1. Finally, attenuation of LCK sensitized HR-proficient eEOC cells to PARP inhibitor. Collectively, the findings identify a mechanism for expanding utility of PARP inhibitors.Graphical AbstractIn BriefDey and colleagues identify the nonreceptor tyrosine kinase LCK as a mediator of homologous recombination directed DNA repair in ovarian cancer. The studies show that LCK inhibition (LCKi) is sufficient to augment Poly (ADP-Ribose) Polymerase inhibitor efficacy in Homologous Recombination (HR) proficient endometrioid ovarian cancer.HighlightsNonreceptor tyrosine kinase LCK regulates expression of HR repair proteins RAD51, BRCA1 and BRCA2.LCKi induces HR deficiency in endometrioid epithelial ovarian cancer.DNA damage leads to autophosphorylation of LCK and co-immunoprecipitation with RAD51 and BRCA1.LCKi potentiates PARP targeted therapy in HR proficient ovarian cancer and expands the utility of the highly successful PARP inhibitors in the clinic.Statement of significanceThis study identifies a novel regulator and signaling pathway for maintaining HR repair during DNA damage. It further demonstrates a new opportunity to increase the utility of PARP inhibitors in HR-proficient eEOC cells.

An optimized homologous recombination deficiency (HRD) algorithm ASGAD for predicting PARP inhibitor response in ovarian cancer patient.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e17077-e17077
Author(s):  
Yang Jiao ◽  
Dong Ju Chen ◽  
Bo Liu ◽  
Pei Meng ◽  
Lei Sun ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Cancer Patient ◽  
Large Scale ◽  
Clustering Algorithm ◽  
Ovarian Cancer Patient ◽  
Parp Inhibitor ◽  
Gynecologic Cancer ◽  
Parp Inhibitors ◽  
Homologous Recombination Deficiency

e17077 Background: Homologous recombination deficiency (HRD) results less efficient and error-prone DNA double strand break (DSB) repair, thus causes genomic in stability and impacts on cancer susceptibility to Poly‐(ADP‐Ribose)‐Polymerase (PARP) inhibitors. Evaluating HRD level in gynecologic cancer patients is becoming far more important and influential, so far, there is no standard method to be used in clinical. Methods: Here, we optimized an HRD score algorithm, termed as ASGAD, which combines three classic factors, including loss of heterozygosity score (LOH), telomeric allelic imbalance score (TAI), large-scale state transition score (LST), along with tumor ploidy to predict PARP inhibitor response in ovarian cancer patient. Results: Traditional global optimization strategy for purity and ploidy calculation is usually sensitive to initial values and may lead to incorrect convergences. Here we designed a two-step optimization manner to avoid this problem. Firstly, a density-based clustering algorithm was applied on BAF and CN, and the genotype was assigned to the most legible cluster. Then the rectified BAF and CN was calculated and used to find the maximum likelihood genotype of each segment. The segmentation processed was also improved by applying a series of statistical test to merge similar adjacent segments. The accuracy of allele-specific copy-number detection is significantly improved vie this algorithm, deriving stable and reliable HRD scores especially on aneuploid and hyperploid tumor cases. In this study, we assessed ASGAD algorithm in almost 150 ovarian cancer patient samples, who had treated with platinum effectively. BRCA1/2 deficient was defined as either one deleterious mutation in BRCA1/2, with LOH in the wild type copy or two deleterious mutations in the same gene. The results showed that the 19/23 BRCA1/2 deficient samples are also HRD-high, giving the sensitivity of 82.61%. Besides, we identify 58 HRD-high samples with intact BRCA1/2, who might benefit from PARP inhibitors, by the ASGAD algorithm. Interestingly, we analyzed 4 HRD-high samples by using whole-exome sequencing (WES), and found other HR genes mutations in these samples, including PARP4, FANCM, MSH2, MSH6, ATR, POLD1. Conclusions: The expanded use of PARP inhibitors in HRD tumors using the ASGAD algorithm requires more validation.

scholarly journals How to measure homologous recombination deficiency in ovarian cancer

2017 ◽  
Vol 5 (1) ◽  
pp. 15-20 ◽  
Author(s):  
Claudia Marchetti ◽  
Iain A. McNeish
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Somatic Mutations ◽  
Parp Inhibitors ◽  
Important Advance ◽  
Brca1 And Brca2 ◽  
Homologous Recombination Deficiency ◽  
Repair Pathways ◽  
Defective Dna Repair ◽  
Important Therapeutic Target

Defective DNA repair via homologous recombination (HR) is common in ovarian high grade serous carcinomas, and homologous recombination deficiency (HRD) represents an important therapeutic target in epithelial ovarian cancers (EOCs). The development of poly(ADP ribose) polymerase (PARP) inhibitors (PARPi) has been an important advance in the treatment of HR-deficient EOCs with the potential to change daily clinical practice. However, while germline and somatic mutations in BRCA1 and BRCA2 are still the most important mechanisms of HRD, alterations in other DNA repair pathways might also contribute to defective HR. In this review, we focus on current and emerging approaches for identifying and targeting HR-deficient EOCs, and discuss the challenges associated with these approaches.

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