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

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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Association between molecular genetic markers of DNA repair and cell cycle control genes and response to platinum-based chemotherapy in ovarian cancer patients

Bulletin of Experimental Biology and Medicine ◽

10.47056/0365-9615-2021-171-6-745-750 ◽

2021 ◽

Vol 171 (6) ◽

pp. 745-750

Author(s):

T. M. Zavarikina ◽

◽

S. V. Khokhlova ◽

A. S. Tyulandina ◽

G. N. Khabas ◽

...

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Dna Repair ◽

Cancer Patients ◽

Genetic Markers ◽

Cell Cycle Control ◽

Molecular Genetic ◽

Molecular Genetic Markers ◽

Platinum Based Chemotherapy

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Immune System and DNA Repair Defects in Ovarian Cancer: Implications for Locoregional Approaches

International Journal of Molecular Sciences ◽

10.3390/ijms20102569 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2569 ◽

Cited By ~ 6

Author(s):

Alberto Farolfi ◽

Giorgia Gurioli ◽

Paola Fugazzola ◽

Salvatore Burgio ◽

Claudia Casanova ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Immune System ◽

Tumor Infiltrating Lymphocytes ◽

Parp Inhibitors ◽

Therapeutic Implications ◽

Dna Repair Mechanisms ◽

Platinum Based Chemotherapy ◽

Repair Mechanisms

In the last few years, substantial progress has been made in the treatment of ovarian cancer, with increased knowledge about the biology of the disease. Ovarian cancer is a neoplasm strongly linked to defects in DNA repair mechanisms, where deficiency in the homologous recombination (HR) system results in a better response of ovarian cancers to therapy, whether platinum-based chemotherapy, anthracyclines, or poly (ADP-ribose) polymerase (PARP) inhibitors. More recently, it has been demonstrated that different ovarian cancer histotypes may have different immunogenicity. Interestingly, defects in HR systems are associated more frequently with higher tumor infiltrating lymphocytes, providing a rationale for developing combination therapy with immune-modulating agents and PARP inhibitors. Again, locoregional therapies combining heat shock and chemotherapy delivery have been shown to induce an anticancer immune response in vitro. Thus, the potential for locoregional therapeutic approaches that may impact the immune system, perhaps in combination with immune-modulating agents or PARP inhibitors, needs to be further explored. With this premise, we reviewed the main biological and clinical data demonstrating a strict interplay between the immune system, DNA repair mechanisms, and intraperitoneal therapies in ovarian cancer, with a focus on potential future therapeutic implications.

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