DNA-repair pathway inhibitors for the treatment of ovarian cancer

AbstractSome familial ovarian cancer (OC) could be due to rare risk alleles in genes that each account for a relatively small proportion of cases not due to BRCA1 and BRCA2, major risk genes in the homologous recombination (HR) DNA repair pathway. We report a new candidate OC risk allele, FANCI c.1813C>T in a Fanconi anemia (FA) gene that plays a role upstream of the HR DNA repair pathway. This variant was identified by whole exome sequencing of a BRCA1 and BRCA2 mutation-negative French Canadian (FC) OC family from a population exhibiting founder effects. In FCs, the c.1813C>T allele was detected in 7% (3/43) of familial and 1.6% (7/439) of sporadic OC cases; and in 3.7% (3/82) of familial breast cancer (BC) cases with a family history of OC and in 1.9% (3/158) of BC only families. This allele was significantly associated with FC BRCA1 and BRCA2 mutation-negative OC families (OR=5.6; 95%CI=1.6-19; p=0.006). Although FANCI c.1813C>T was detected in 2.5% (74/2950) of cancer-free FC females, carriers had a personal history of known OC risk reducing factors, and female/male carriers were more likely to have reported a first-degree relative with OC (ρ=0.037; p=0.011). Eight rare potentially pathogenic FANCI variants were identified in 3.3% (17/516) of Australian OC cases, including 10 carriers of FANCI c.1813C>T. Potentially pathogenic FANCI variants were significantly more common in AUS OC cases with a family history of OC than in isolated OC cases (p=0.027). The odds ratios (OR) were >3 for carriers of any of the seven rarest FANCI alleles, and 1.5 for c.1813C>T. Data from the OC Association Consortium revealed that the ORs for the c.1813C>T allele were highest for the most common OC subtypes. Localization of FANCD2, part of the FANCI-FANCD2 (ID2) binding complex in the FA pathway, to sites of induced DNA damage was severely impeded in cells expressing the p.L605F isoform. This isoform was expressed at a reduced level; unstable by formaldehyde or mitomycin C treatment; and exhibited sensitivity to cisplatin but not to olaparib (a poly [ADP-ribose] polymerase inhibitor). By tissue microarray analyses, FANCI protein was robustly expressed in fallopian tube epithelial cells but expressed at low-to-moderate levels in 88% (83/94) of high-grade serous carcinoma OC samples. This is the first study to describe potentially pathogenic variants in OC in a member of the ID2 complex of the FA DNA repair pathway. Our data suggest that potentially pathogenic FANCI variants may modify OC risk in cancer families.

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

Diagnostics ◽

10.3390/diagnostics9020055 ◽

2019 ◽

Vol 9 (2) ◽

pp. 55 ◽

Cited By ~ 16

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.

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Abstract 324: SIK2 inhibitors regulate DNA repair pathway and sensitize ovarian cancer to PARP1 inhibitors

10.1158/1538-7445.am2018-324 ◽

2018 ◽

Author(s):

Zhen Lu ◽

Wequn Mao ◽

Lan Pang ◽

Janice M. Santiago-O'Farrill ◽

Haling Yang ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Repair Pathway ◽

Parp1 Inhibitors

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Re: A DNA Repair Pathway-Focused Score for Prediction of Outcomes in Ovarian Cancer Treated with Platinum-Based Chemotherapy

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djs363 ◽

2012 ◽

Vol 104 (19) ◽

pp. 1514-1514

Author(s):

O. A. Stefansson ◽

A. Villanueva ◽

A. Vidal ◽

L. Marti ◽

M. Esteller

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Repair Pathway ◽

Platinum Based Chemotherapy

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A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene

Genome Medicine ◽

10.1186/s13073-021-00998-5 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Caitlin T. Fierheller ◽

Laure Guitton-Sert ◽

Wejdan M. Alenezi ◽

Timothée Revil ◽

Kathleen K. Oros ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Cell Lines ◽

Carrier Frequency ◽

Pathogenic Variant ◽

Fanconi Anaemia ◽

Repair Pathway ◽

French Canadian ◽

Pathogenic Variants ◽

Gene And Protein Expression

Abstract Background Familial ovarian cancer (OC) cases not harbouring pathogenic variants in either of the BRCA1 and BRCA2 OC-predisposing genes, which function in homologous recombination (HR) of DNA, could involve pathogenic variants in other DNA repair pathway genes. Methods Whole exome sequencing was used to identify rare variants in HR genes in a BRCA1 and BRCA2 pathogenic variant negative OC family of French Canadian (FC) ancestry, a population exhibiting genetic drift. OC cases and cancer-free individuals from FC and non-FC populations were investigated for carrier frequency of FANCI c.1813C>T; p.L605F, the top-ranking candidate. Gene and protein expression were investigated in cancer cell lines and tissue microarrays, respectively. Results In FC subjects, c.1813C>T was more common in familial (7.1%, 3/42) than sporadic (1.6%, 7/439) OC cases (P = 0.048). Carriers were detected in 2.5% (74/2950) of cancer-free females though female/male carriers were more likely to have a first-degree relative with OC (121/5249, 2.3%; Spearman correlation = 0.037; P = 0.011), suggesting a role in risk. Many of the cancer-free females had host factors known to reduce risk to OC which could influence cancer risk in this population. There was an increased carrier frequency of FANCI c.1813C>T in BRCA1 and BRCA2 pathogenic variant negative OC families, when including the discovery family, compared to cancer-free females (3/23, 13%; OR = 5.8; 95%CI = 1.7–19; P = 0.005). In non-FC subjects, 10 candidate FANCI variants were identified in 4.1% (21/516) of Australian OC cases negative for pathogenic variants in BRCA1 and BRCA2, including 10 carriers of FANCI c.1813C>T. Candidate variants were significantly more common in familial OC than in sporadic OC (P = 0.04). Localization of FANCD2, part of the FANCI-FANCD2 (ID2) binding complex in the Fanconi anaemia (FA) pathway, to sites of induced DNA damage was severely impeded in cells expressing the p.L605F isoform. This isoform was expressed at a reduced level, destabilized by DNA damaging agent treatment in both HeLa and OC cell lines, and exhibited sensitivity to cisplatin but not to a poly (ADP-ribose) polymerase inhibitor. By tissue microarray analyses, FANCI protein was consistently expressed in fallopian tube epithelial cells and only expressed at low-to-moderate levels in 88% (83/94) of OC samples. Conclusions This is the first study to describe candidate OC variants in FANCI, a member of the ID2 complex of the FA DNA repair pathway. Our data suggest that pathogenic FANCI variants may modify OC risk in cancer families.

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CtBP1/2 differentially regulate genomic stability and DNA repair pathway in high-grade serous ovarian cancer cell

Oncogenesis ◽

10.1038/s41389-021-00344-9 ◽

2021 ◽

Vol 10 (7) ◽

Author(s):

YingYing He ◽

Zhicheng He ◽

Jian Lin ◽

Cheng Chen ◽

Yuanzhi Chen ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Damage ◽

Dna Repair ◽

Dna Replication ◽

Genomic Stability ◽

High Grade ◽

Serous Ovarian Cancer ◽

Repair Pathway ◽

Serous Ovarian Carcinoma ◽

Skov3 Cells

AbstractThe C-terminal binding proteins (CtBPs), CtBP1 and CtBP2, are transcriptional co-repressor that interacts with multiple transcriptional factors to modulate the stability of chromatin. CtBP proteins were identified with overexpression in the high-grade serous ovarian carcinoma (HGSOC). However, little is known about CtBP proteins’ regulatory roles in genomic stability and DNA repair in HGSOC. In this study, we combined whole-transcriptome analysis with multiple research methods to investigate the role of CtBP1/2 in genomic stability. Several key functional pathways were significantly enriched through whole transcription profile analysis of CtBP1/2 knockdown SKOV3 cells, including DNA damage repair, apoptosis, and cell cycle. CtBP1/2 knockdown induced cancer cell apoptosis, increased genetic instability, and enhanced the sensitivity to DNA damage agents, such as γ-irradiation and chemotherapy drug (Carboplatin and etoposide). The results of DNA fiber assay revealed that CtBP1/2 contribute differentially to the integrity of DNA replication track and stability of DNA replication recovery. CtBP1 protects the integrity of stalled forks under metabolic stress condition during prolonged periods of replication, whereas CtBP2 acts a dominant role in stability of DNA replication recovery. Furthermore, CtBP1/2 knockdown shifted the DSBs repair pathway from homologous recombination (HR) to non-homologous end joining (NHEJ) and activated DNA-PK in SKOV3 cells. Interesting, blast through TCGA tumor cases, patients with CtBP2 genetic alternation had a significantly longer overall survival time than unaltered patients. Together, these results revealed that CtBP1/2 play a different regulatory role in genomic stability and DSBs repair pathway bias in serous ovarian cancer cells. It is possible to generate novel potential targeted therapy strategy and translational application for serous ovarian carcinoma patients with a predictable better clinical outcome.

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