DNA damage response and repair in ovarian cancer: Potential targets for therapeutic strategies
TL;DR: The complexity of the DDR process in ovarian cancer and how this process works in metastatic conditions is comprehensively reviewed and the components of this system including DDR sensors, DDR transducers, DDR mediators, and DDR effectors are discussed.
About: This article is published in DNA Repair.The article was published on 2019-08-01. It has received 29 citations till now.
Citations
More filters
TL;DR: The intricate crosstalks between DNA damage and cell cycle checkpoints activation are highlighted and the DNA damage mediated regulation of autophagy and mitophagy is also reviewed in detail.
49 citations
TL;DR: In this paper, the authors present the exceptional biochemical environment implicated in ovarian cancer and highlights mechanisms of chemoresistance, along with innovative molecules and new therapeutic opportunities, and currently available therapies and ongoing clinical trials.
31 citations
TL;DR: The most important genes of the DNA repair system are emphasized and their targeting in ovarian cancer will deserve further attention, and lack of knowledge particularly in non-homologous end joining repair pathway and the interplay between DNA repair pathways needs to be confronted.
Abstract: 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, highpenetrance 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 (eg, 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
24 citations
Cites background from "DNA damage response and repair in o..."
...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....
[...]
01 Jan 2015
TL;DR: In this paper, immunohistochemical detection of BRCA1 and PARP expression in epithelial ovarian cancer (EOC) and their possible prognostic relevance was investigated.
Abstract: BRCA1/2 mutation status in epithelial ovarian cancer (EOC) presently relies on genetic testing which is resource consuming. Immunohistochemistry is cheap, fairly reproducible, and may identify gene product alterations due to both germline and somatic mutations and other defects along the BRCA gene pathway (BRCAness phenomenon), which is important when treatment with poly (adenosine-diphosphate-ribose) polymerase (PARP) inhibitors is considered. The aim of this study was to investigate immunohistochemical detection of BRCA1 and PARP expression in EOC and their possible prognostic relevance. Tumor tissue from 170 patients with EOC was stained immunohistochemically with BRCA1 and PARP antibodies. Semiquantitative analyses were performed to determine loss of, equivocal, and retained BRCA1 and high versus low PARP protein expression. These parameters were analyzed for relation with patient and clinicopathologic characteristics and overall survival. BRCA1 expression was reduced in 21.2 % of the tumors and 36.5% showed high PARP expression. No correlation between the 2 parameters or between PARP and clinicopathologic features was found. Overall survival was significantly increased in the BRCA1-reduced and equivocal groups [median survival 2.4 y (95% CI, 1.6–6.6) and 4.9 y (95 % CI, 2.3–6.7) vs. 1.5 y (95% CI, 1.3–1.9); P=0.0002]. Multivariate analysis confirmed these findings; hazard ratio=0.53 (95% CI, 0.34–0.81; P=0.0037; loss of BRCA1 expression). In conclusion, immunohistochemical BRCA1 expression in EOC holds considerable prognostic information, whereas PARP expression did not influence the outcome. The results call for validation in prospective trials.
22 citations
TL;DR: This work reviews 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.
Abstract: 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.
18 citations
Cites background from "DNA damage response and repair in o..."
...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]....
[...]
...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]....
[...]
...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]....
[...]
References
More filters
TL;DR: The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptoses in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptotic proteins.
Abstract: The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.
10,744 citations
TL;DR: The authors' improving understanding of DNA-damage responses is providing new avenues for disease management, and these responses are biologically significant because they prevent diverse human diseases.
Abstract: The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management.
4,871 citations
University of Cambridge1, University of Toronto2, Yale University3, University of Iceland4, University of Melbourne5, Lund University6, National Institutes of Health7, Princess Anne Hospital8, The Chinese University of Hong Kong9, University of California, Irvine10, Pomeranian Medical University11, Helsinki University Central Hospital12, Institute of Cancer Research13, University of London14, St Mary's Hospital15
TL;DR: Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age and for variation in risk by mutation position for both genes, and some evidence for a reduction in risk in women from earlier birth cohorts is found.
Abstract: Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.
3,384 citations
TL;DR: The abundance of literature suggests that targeting apoptosis in cancer is feasible, however, many troubling questions arise with the use of new drugs or treatment strategies that are designed to enhance apoptosis and critical tests must be passed before they can be used safely in human subjects.
Abstract: Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. It is also one of the most studied topics among cell biologists. An understanding of the underlying mechanism of apoptosis is important as it plays a pivotal role in the pathogenesis of many diseases. In some, the problem is due to too much apoptosis, such as in the case of degenerative diseases while in others, too little apoptosis is the culprit. Cancer is one of the scenarios where too little apoptosis occurs, resulting in malignant cells that will not die. The mechanism of apoptosis is complex and involves many pathways. Defects can occur at any point along these pathways, leading to malignant transformation of the affected cells, tumour metastasis and resistance to anticancer drugs. Despite being the cause of problem, apoptosis plays an important role in the treatment of cancer as it is a popular target of many treatment strategies. The abundance of literature suggests that targeting apoptosis in cancer is feasible. However, many troubling questions arise with the use of new drugs or treatment strategies that are designed to enhance apoptosis and critical tests must be passed before they can be used safely in human subjects.
2,029 citations
TL;DR: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate.
Abstract: BackgroundProstate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibition with olaparib. MethodsWe conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor...
1,694 citations