DNA damage response and repair in ovarian cancer: Potential targets for therapeutic strategies

Mirza-Aghazadeh-Attari, Mohammad; Ostadian, Caspian; Saei, Amir Ata; Mihanfar, Ainaz; Darband, Saber Ghazizadeh; Sadighparvar, Shirin; Kaviani, Mojtaba; Kafil, Hossein Samadi; Yousefi, Bahman; Majidinia, Maryam

doi:10.1016/j.dnarep.2019.06.005

Cited by 41 publications

(31 citation statements)

References 338 publications

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“…Among existing DNA repair pathways, six pathways are implicated in OvC. In general, defective homologous recombination repair (HR), non-homologous end-joining (NHEJ), mismatch repair (MMR), base excision repair (BER), and disorders in nucleotide excision repair (NER) are typically reflected in OvC origin, pathogenesis and response to chemotherapy [20,24], whereas direct reversal of lesions is in connection with OvC addressed scarcely. Interestingly, there is sufficient evidence on the participation of all DNA repair pathways in ovarian tumorigenesis due to complex exposures from environment [25,26].…”

Section: Main Molecular Hallmarks Of Ovarian Cancer and Association Wmentioning

confidence: 99%

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

Tomášová

Čumová

Šeborová

et al. 2020

Cancers

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There is ample evidence for the essential involvement of DNA repair and DNA damage response in the onset of solid malignancies, including ovarian cancer. Indeed, high-penetrance germline mutations in DNA repair genes are important players in familial cancers: BRCA1, BRCA2 mutations or mismatch repair, and polymerase deficiency in colorectal, breast, and ovarian cancers. Recently, some molecular hallmarks (e.g., TP53, KRAS, BRAF, RAD51C/D or PTEN mutations) of ovarian carcinomas were identified. The manuscript overviews the role of DNA repair machinery in ovarian cancer, its risk, prognosis, and therapy outcome. We have attempted to expose molecular hallmarks of ovarian cancer with a focus on DNA repair system and scrutinized genetic, epigenetic, functional, and protein alterations in individual DNA repair pathways (homologous recombination, non-homologous end-joining, DNA mismatch repair, base- and nucleotide-excision repair, and direct repair). We suggest that lack of knowledge particularly in non-homologous end joining repair pathway and the interplay between DNA repair pathways needs to be confronted. The most important genes of the DNA repair system are emphasized and their targeting in ovarian cancer will deserve further attention. The function of those genes, as well as the functional status of the entire DNA repair pathways, should be investigated in detail in the near future.

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Section: Main Molecular Hallmarks Of Ovarian Cancer and Association Wmentioning

confidence: 99%

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

Tomášová

Čumová

Šeborová

et al. 2020

Cancers

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“…Among the most-significant cancer-associated alterations, aberrations in the DNA damage response (DDR) play a major role in OCs. The constituent pathways of the DDR include DNA repair machinery, cell cycle checkpoints, and apoptotic pathways; mutations in any components of these pathways are involved in the ovarian cancer initiation and progression as well as in resistance to therapy [ 95 ]. Fitness genes identified by the dropout CRISPR-Cas9 screening in ovarian cancer cell lines include key-genes involved in the cell cycle checkpoint regulation, components of the mismatch repair (MMR) system that recognize and repair DNA abnormalities, members of the homologous recombination (HR) and nucleotide excision repair (NER) pathways (see Table 2 and Figure 1 ).…”

Section: Functional Pathways Affected By Oc Fitness Genesmentioning

confidence: 99%

“…The NER system plays a key role in OC for its prognostic value and in response to treatment. Among fitness genes belonging to the NER pathway we identified some crucial factors, whose mutations are strongly correlated to cancerous phenotype, such as POLE, RPA3, and ERCC genes [ 95 ]. Excision repair cross-complementing DNA-helicases ERCC2 and ERCC3 belong to the transcription factor IIH complex and unwind DNA strands that flank the damaged site.…”

Section: Functional Pathways Affected By Oc Fitness Genesmentioning

confidence: 99%

“…MMR is critical for the detection of DNA damages as deficiency in this pathway could lead to uncontrolled proliferation. Loss of function in the hub genes of the MMR pathway have been identified in 29% of ovarian cancers and their mutations correlate with the neoplasm stage [ 95 ]. In Figure 1 some of the functional pathways specifically related to DNA damage repair mechanisms are reported as an example; in particular nucleotide excision repair ( Figure 1 a), DNA mismatch repair ( Figure 1 b), and homologous recombination ( Figure 1 c) have been depicted, with fitness genes specifically correlated and physical interactions among the different proteins involved in the pathways.…”

Section: Functional Pathways Affected By Oc Fitness Genesmentioning

confidence: 99%

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An Overview of Candidate Therapeutic Target Genes in Ovarian Cancer

Alexandrova

Pecoraro

Sellitto

et al. 2020

Cancers

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Ovarian cancer (OC) shows the highest mortality rate among gynecological malignancies and, because of the absence of specific symptoms, it is frequently diagnosed at an advanced stage, mainly due to the lack of specific and early biomarkers, such as those based on cancer molecular signature identification. Indeed, although significant progress has been made toward improving the clinical outcome of other cancers, rates of mortality for OC are essentially unchanged since 1980, suggesting the need of new approaches to identify and characterize the molecular mechanisms underlying pathogenesis and progression of these malignancies. In addition, due to the low response rate and the high frequency of resistance to current treatments, emerging therapeutic strategies against OC focus on targeting single factors and pathways specifically involved in tumor growth and metastasis. To date, loss-of-function screenings are extensively applied to identify key drug targets in cancer, seeking for more effective, disease-tailored treatments to overcome lack of response or resistance to current therapies. We review here the information relative to essential genes and functional pathways recently discovered in OC, often strictly interconnected with each other and representing promising biomarkers and molecular targets to treat these malignancies.

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“…Defects in DDR are associated with increased mutational load and genome instability, leading to a neoplastic transformation and proliferation (Minchom et al, 2018). The DNA repair gene (DRG) alterations were common in cancers, including ovarian cancer, breast cancer, and prostate cancer (Ali et al, 2017;Mateo et al, 2017;Mirza-Aghazadeh-Attari et al, 2019). Due to the DDR defects, cancer cells are more reliant on other repair pathways for survival, which makes DDR targeting an attractive therapeutic strategy.…”

Section: Introductionmentioning

confidence: 99%

Identification of a DNA Repair Gene Signature and Establishment of a Prognostic Nomogram Predicting Biochemical-Recurrence-Free Survival of Prostate Cancer

Long

Ouyang

Zhang

et al. 2021

Front. Mol. Biosci.

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Background: The incidence of prostate cancer (PCa) is high and increasing worldwide. The prognosis of PCa is relatively good, but it is important to identify the patients with a high risk of biochemical recurrence (BCR) so that additional treatment could be applied.Method: Level 3 mRNA expression and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) to serve as training data. The GSE84042 dataset was used as a validation set. Univariate Cox, lasso Cox, and stepwise multivariate Cox regression were applied to identify a DNA repair gene (DRG) signature. The performance of the DRG signature was assessed based on Kaplan–Meier curve, receiver operating characteristic (ROC), and Harrell’s concordance index (C-index). Furtherly, a prognostic nomogram was established and evaluated likewise.Results: A novel four DRG signature was established to predict BCR of PCa, which included POLM, NUDT15, AEN, and HELQ. The ROC and C index presented good performance in both training dataset and validation dataset. The patients were stratified by the signature into high- and low-risk groups with distinct BCR survival. Multivariate Cox analysis revealed that the DRG signature is an independent prognostic factor for PCa. Also, the DRG signature high-risk was related to a higher homologous recombination deficiency (HRD) score. The nomogram, incorporating the DRG signature and clinicopathological parameters, was able to predict the BCR with high efficiency and showed superior performance compared to models that consisted of only clinicopathological parameters.Conclusion: Our study identified a DRG signature and established a prognostic nomogram, which were reliable in predicting the BCR of PCa. This model could help with individualized treatment and medical decision making.

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DNA damage response and repair in ovarian cancer: Potential targets for therapeutic strategies

Cited by 41 publications

References 338 publications

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

An Overview of Candidate Therapeutic Target Genes in Ovarian Cancer

Identification of a DNA Repair Gene Signature and Establishment of a Prognostic Nomogram Predicting Biochemical-Recurrence-Free Survival of Prostate Cancer

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