scholarly journals DNA Damage Repair Genes and Noncoding RNA in High-Grade Gliomas and Its Clinical Relevance

2021 ◽  
Author(s):  
Tanvi R. Parashar ◽  
Febina Ravindran ◽  
Bibha Choudhary
Keyword(s):  
Dna Damage ◽  
Noncoding Rna ◽  
Malignant Tumors ◽  
Dna Damage Repair ◽  
Noncoding Rnas ◽  
High Grade ◽  
Therapeutic Drugs ◽  
Damage Repair ◽  
Dna Repair Protein ◽  
High Grade Gliomas

Gliomas are the most common malignant tumors originating from the glial cells in the central nervous system. Grades III and IV, considered high-grade gliomas occur at a lower incidence (1.5%) but have higher mortality. Several genomic alterations like IDH mutation, MGMT mutation, 1p19q Codeletion, and p53 mutations have been attributed to its pathogenicity. Recently, several noncoding RNAs have also been identified to alter the expression of crucial genes. Current chemotherapeutic drugs include temozolomide targeting hypermethylated MGMT, a DNA repair protein; or bevacizumab, which targets VEGF. This book chapter delves deeper into the DNA damage repair pathway including its correlation with survival and the regulation of these genes by noncoding RNAs. Novel therapeutic drugs being developed are also highlighted.

scholarly journals Long noncoding RNA HCP5 participates in premature ovarian insufficiency by transcriptionally regulating MSH5 and DNA damage repair via YB1

2020 ◽  
Vol 48 (8) ◽  
pp. 4480-4491 ◽  
Author(s):  
Xiaoyan Wang ◽  
Xinyue Zhang ◽  
Yujie Dang ◽  
Duan Li ◽  
Gang Lu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Noncoding Rna ◽  
Dna Damage Repair ◽  
Noncoding Rnas ◽  
Epigenetic Mechanism ◽  
Premature Ovarian Insufficiency ◽  
Genetic Etiology ◽  
Ovarian Insufficiency ◽  
Damage Repair

Abstract The genetic etiology of premature ovarian insufficiency (POI) has been well established to date, however, the role of long noncoding RNAs (lncRNAs) in POI is largely unknown. In this study, we identified a down-expressed lncRNA HCP5 in granulosa cells (GCs) from biochemical POI (bPOI) patients, which impaired DNA damage repair and promoted apoptosis of GCs. Mechanistically, we discovered that HCP5 stabilized the interaction between YB1 and its partner ILF2, which could mediate YB1 transferring into the nucleus of GCs. HCP5 silencing affected the localization of YB1 into nucleus and reduced the binding of YB1 to the promoter of MSH5 gene, thereby diminishing MSH5 expression. Taken together, we identified that the decreased expression of HCP5 in bPOI contributed to dysfunctional GCs by regulating MSH5 transcription and DNA damage repair via the interaction with YB1, providing a novel epigenetic mechanism for POI pathogenesis.

scholarly journals HGG-34. A DNA DAMAGE REPAIR SIGNATURE IN PRIMARY AND RECURRENT PEDIATRIC HIGH-GRADE GLIOMAS: PROGNOSTIC AND THERAPEUTIC VALUE

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i24-i24
Author(s):  
Natacha Entz-Werle ◽  
Laetitia Poidevin ◽  
Petr Nazarov ◽  
Benoit Lhermitte ◽  
Marie Pierre Chenard ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Poor Responders ◽  
Stem Cell Markers ◽  
High Grade ◽  
Damage Repair ◽  
Transcriptomic Signature ◽  
High Grade Gliomas ◽  
Low Incidence ◽  
Diffuse Intrinsic Pontine Gliomas

Abstract Pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine gliomas (DIPGs), despite their low incidence, are the leading cause of mortality in pediatric neuro-oncology. Frequently, pHGGs, harboring mainly histone mutations, are or become resistant to standard therapies like irradiation or chemotherapies. Recent insights showed in adult HGG the predominant role of DNA damage repair (DDR) as a way of prognostic classification. Given the recent evidence that transcription conflicts like in histone-mutated gliomas can induce replication stress and be linked to DDR abnormalities, this study is aiming to establish a DDR signature able to classify specifically pHGGs and to cluster among them poor responders to radiation. Transcriptomic analyses were performed to discriminate seven pHGGs comparatively to a cohort of 10 pilocytic astrocytomas with specific DDR deregulations. The specific transcriptomic signature obtained from this differential gene expression analysis was compared to the aHGG signature already established. To strengthen, refine and finalize the DDR signature able to classify and cluster the pHGGs, we explored both signatures and their common genes in already published transcriptomic analyses of DIPGs and sus-tentorial pHGGs. To check DDR protein expressions correlated to loss of trimethylation as well as histone and TP53 mutations, an immunohistochemical assessment of several DDR markers was performed on a collection of 21 pHGG diagnostic samples and 9 paired relapses. To validate the DDR functional inhibition, we used 3 patient-derived cell lines bearing H3.3K27M mutations. A finalized signature of 28 genes involved in DNA repair and cell cycle machineries was used to cluster in two groups the pHGG cohorts. The differential protein expression of PARP1, XRCC1, p53 and stem cell markers was linked significantly to the more resistant pHGGs and the rapid progressions after radiotherapy. Those DDR makers might be used as theranostic and therapeutic targets, which were screened in PDCLs with promising results.

Genomic characterization of brain metastases (BM) in high-grade serous ovarian cancer (HGSOC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13580-e13580
Author(s):  
Renata Duchnowska ◽  
Anna Maria Supernat ◽  
Rafał Pęksa ◽  
Marta Łukasiewicz ◽  
Tomasz Stokowy ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Somatic Mutations ◽  
Dna Damage Repair ◽  
Genetic Alterations ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Primary Tumors ◽  
Tp53 Mutations ◽  
Damage Repair

e13580 Background: BM are a rare occurrence in ovarian cancer (OC) and their molecular characteristics is virtually unknown. DNA damage repair (DDR) deficiency is prevalent in OC, and co-mutated TP53 and any DDR denotes high tumor mutation burden (TMB). We genetically characterized a unique series of high-grade serous ovarian cancer (HGSOC) patients who developed BM to identify alterations of potential clinical relevance. Methods: Whole-exome sequencing (2x150bp, SureSelectXT Library Prep Kit, Illumina’s NovaSeq platform) was performed in matched BM, primary tumors (PT) and normal tissue. DNA was extracted from FFPE samples using QIAamp DNA FFPE Tissue Kit (Qiagen, Germany). All mutations were checked with Catalogue of Somatic Mutations in Cancer (COSMIC) and Integrative Genomics Viewer (IGV). Results: Study group included 10 HGSOC patients (International Federation of Gynecology and Obstetrics classification (FIGO) II-IV, mean age at diagnosis 48 years, range 35-59). Median time from primary HGSOC diagnosis to BM was 38 months (range, 18 to 149). TP53 somatic mutations were found in both primary tumor (PT) and BM in 8 patients. The other 2 cases harbored TP53 mutations not reported in COSMIC catalogue: p.S60L and intronic TP53 mutation preceding p.I322 (IGV). In 9 cases TP53 mutations coexisted with germline or somatic DNA damage repair deficiency. Four cases contained BRCA1 mutations (all germline), and none harbored germline BRCA2 mutation. Other mutated genes included MLH1 (2 somatic, 2 germline), ATR (4 germline, 1 somatic), AMT (1 somatic), RAD50 (1 somatic), ERCC4 (1 somatic), FANCD2 (1 somatic) and RPA1 (1 germline). Three mutation signatures defined in the COSMIC database were indentified in BM: 6, 20 and 30. In 6 cases these mutations were shared in PT, and in another 4 their presence in PT could not be determined due to technical reasons. Median survival from BM was 31 months (range, 5 to 184). Conclusions: Genomic analysis of BM provides an opportunity to identify potentially clinically informative alterations. Mutational profiles in PT are generally reflected in BM. Detected genetic alterations suggest their potential sensitivity to PARP inhibitors and immunotherapy.

scholarly journals Proteogenomic analysis of Inhibitor of Differentiation 4 (ID4) in basal-like breast cancer

2020 ◽  
Author(s):  
Laura A. Baker ◽  
Holly Holliday ◽  
Daniel Roden ◽  
Christoph Krisp ◽  
Sunny Z. Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Chemotherapy Resistance ◽  
Clinical Samples ◽  
High Grade ◽  
Data Link ◽  
Helix Loop Helix ◽  
Damage Repair ◽  
Basal Like Breast Cancer

Abstract Background Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of Differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC, through unknown mechanisms. Methods Here, we have defined unique molecular insights into the function of ID4 in BLBC and the related disease high-grade serous ovarian cancer (HGSOC), by combining RIME proteomic analysis, ChIP-seq mapping of genomic binding sites and RNA-seq. Results These studies reveal novel interactions with DNA damage response proteins, in particular, mediator of DNA damage checkpoint protein 1 (MDC1). Through MDC1, ID4 interacts with other DNA repair proteins (γH2AX and BRCA1) at fragile chromatin sites. ID4 does not affect transcription at these sites, instead binding to chromatin following DNA damage. Analysis of clinical samples demonstrates that ID4 is amplified and overexpressed at a higher frequency in BRCA1 -mutant BLBC compared with sporadic BLBC, providing genetic evidence for an interaction between ID4 and DNA damage repair deficiency. Conclusions These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOC.

Long noncoding RNA SNHG12 integrates a DNA-PK–mediated DNA damage response and vascular senescence

2020 ◽  
Vol 12 (531) ◽  
pp. eaaw1868 ◽  
Author(s):  
Stefan Haemmig ◽  
Dafeng Yang ◽  
Xinghui Sun ◽  
Debapria Das ◽  
Siavash Ghaffari ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Vascular Endothelium ◽  
Vessel Wall ◽  
Noncoding Rna ◽  
Dna Damage Repair ◽  
Atherosclerotic Lesion ◽  
High Cholesterol Diet ◽  
Damage Repair ◽  
Damage Response

Long noncoding RNAs (lncRNAs) are emerging regulators of biological processes in the vessel wall; however, their role in atherosclerosis remains poorly defined. We used RNA sequencing to profile lncRNAs derived specifically from the aortic intima of Ldlr−/− mice on a high-cholesterol diet during lesion progression and regression phases. We found that the evolutionarily conserved lncRNA small nucleolar host gene-12 (SNHG12) is highly expressed in the vascular endothelium and decreases during lesion progression. SNHG12 knockdown accelerated atherosclerotic lesion formation by 2.4-fold in Ldlr−/− mice by increased DNA damage and senescence in the vascular endothelium, independent of effects on lipid profile or vessel wall inflammation. Conversely, intravenous delivery of SNHG12 protected the tunica intima from DNA damage and atherosclerosis. LncRNA pulldown in combination with liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis showed that SNHG12 interacted with DNA-dependent protein kinase (DNA-PK), an important regulator of the DNA damage response. The absence of SNHG12 reduced the DNA-PK interaction with its binding partners Ku70 and Ku80, abrogating DNA damage repair. Moreover, the anti-DNA damage agent nicotinamide riboside (NR), a clinical-grade small-molecule activator of NAD+, fully rescued the increases in lesional DNA damage, senescence, and atherosclerosis mediated by SNHG12 knockdown. SNHG12 expression was also reduced in pig and human atherosclerotic specimens and correlated inversely with DNA damage and senescent markers. These findings reveal a role for this lncRNA in regulating DNA damage repair in the vessel wall and may have implications for chronic vascular disease states and aging.

DNA repair capacity and tumor recurrence in patients with non-muscle-invasive bladder cancer (NMIBC).

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 305-305
Author(s):  
Timothy F. Donahue ◽  
S. Machele Donat ◽  
Himali Patel ◽  
Joanne F. Chou ◽  
Sharon Bayuga ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Tumor Recurrence ◽  
Dna Damage Repair ◽  
Intravesical Therapy ◽  
High Grade ◽  
Repair Capacity ◽  
Dna Repair Capacity ◽  
Time To Recurrence ◽  
Damage Repair

305 Background: NMIBC requires lifelong surveillance to monitor for recurrence. Identifying patients at greatest risk and altering surveillance accordingly could impact health care cost. Inadequate DNA repair may increase the risk for developing subsequent tumors. This prospective study evaluated the association between DNA damage/repair capacity and tumor recurrence with the goal of finding new prognostic markers. Methods: Patients newly diagnosed with NMIBC (n=100) who received standard care provided blood samples and completed risk surveys and were followed for a median of 78 mos. DNA damage in peripheral blood lymphocytes measured with the Comet Assay revealed constitutive damage, sensitivity to carcinogens after exposing cells to the tobacco-derived carcinogen BPDE, and repair capacity after allowing cells to repair post BPDE induced damage. DNA damage was expressed as log-transformed Tail Intensity. Median time to recurrence and cumulative incidence of recurrence at 4 mos were estimated by Kaplan-Meier methods and compared by log-rank test. Hazard ratios for recurrence in association with patient characteristics and DNA damage/repair variables were estimated with Cox proportional hazard models. Associations of DNA damage/repair variables between patients’ characteristics were tested with Wilcoxon Rank-Sum. Results: This NMIBC cohort included patients with mean age 64 yrs and 71% males. Tumors were high grade in 74% and multifocal in 34%. Median time to recurrence was 6 months and 42/69 recurrences occurred <4 mos. Patients with higher grade/stage, multifocality, and intravesical therapy had higher cumulative incidence of recurrence at 4 mos (p<0.01). Those with higher stage/grade compared to low stage/grade tumors showed significant reduction in DNA repair capacity after exposure to BPDE (p<0.03). Conclusions: In univariate analysis, DNA damage is associated with higher stage and higher grade tumors; however host DNA damage/repair capacity does not predict recurrence in NMIBC. Traditional disease characteristics including multifocality, high-grade, increasing stage, and intravesical therapy remained predictors of recurrence.

Abstract A04: Profiling DNA damage repair and immunophenotypes in BRCA1/2 mutated high-grade serous ovarian cancers

2018 ◽  
Author(s):  
Anniina Farkkila ◽  
Bose Kochupurakkal ◽  
Brooke E. Howitt ◽  
Kyle C. Strickland ◽  
Dipanjan Chowdhury ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
High Grade ◽  
Ovarian Cancers ◽  
Damage Repair

Overcoming miR-106a induced radioresistance in prostate cancer: Targeting senescence with KU-55933.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 77-77
Author(s):  
Christianne Hoey ◽  
Jessica Ray ◽  
Xiaoyong Huang ◽  
Jouhyun Jeon ◽  
Paul Christopher Boutros ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Clonogenic Survival ◽  
High Grade ◽  
Prostate Tumors ◽  
Normal Prostate ◽  
Damage Repair

77 Background: Prostate cancer is a leading cause of cancer related death in men worldwide, with recurrence being a major clinical problem after radiotherapy. There is an unmet need to better characterize radioresistant tumors and identify biomarkers to improve patient outcomes. Methods: We identified that miR-106a was overexpressed in radiation resistant cell lines compared to parental cells. We analyzed The Cancer Genome Atlas dataset to assess miR-106a expression in normal prostate, and low- to high-grade prostate tumors. To assess the functional role of miR-106a, we performed in vitro and in vivo assays for radiation response, including clonogenic survival, proliferation, senescence, and tumor xenograft growth after radiation. We performed gene array and pathway analyses to identify downstream effectors of miR-106a. Results: MiR-106a expression was significantly higher in prostate tumors with Gleason score > 7 compared to Gleason ≤ 7, suggesting miR-106a is involved in high grade disease. MiR-106a overexpression confers radioresistance in vitro and in vivo, by targeting LITAF. We now extend miR-106a’s effects to upregulation of ATM at the promoter level, thereby increasing ATM transcript and protein in the cell. Unexpectedly, we found that miR-106a’s mechanism of radioresistance through ATM upregulation does not alter DNA damage repair. ATM upregulation affects clonogenic survival through reduced senescence. KU-55933, a specific ATM kinase inhibitor, resensitizes miR-106a overexpressing cells to radiation by inducing senescence, a predominant mode of cell death in prostate cancer. Conclusions: Our research challenges the current paradigm of ATM and DNA damage repair by outlining another mechanism of radioresistance through alteration of senescence. Our findings suggest that miR-106a may be a promising biomarker for high-grade disease and radioresistant prostate cancer. In addition, we have identified a therapeutic intervention for miR-106a induced radioresistance. Improvements in bioavailability of KU-55933 may lead to its clinical use in combination with radiation therapy to radiosensitize miR-106a induced radioresistant prostate cancer.

scholarly journals Clinical Impact of Somatic Variants in Homologous Recombination Repair-Related Genes in Ovarian High-Grade Serous Carcinoma

2020 ◽  
Vol 52 (2) ◽  
pp. 634-644 ◽  
Author(s):  
Min Chul Choi ◽  
Sohyun Hwang ◽  
Sewha Kim ◽  
Sang Geun Jung ◽  
Hyun Park ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Disease Free Survival ◽  
Serous Carcinoma ◽  
High Grade ◽  
Repair Gene ◽  
Damage Repair ◽  
Repair Genes

PurposeIn this study, we investigated the frequencies of mutations in DNA damage repair genes including <i>BRCA1</i>, <i>BRCA2</i>, homologous recombination genes and <i>TP53</i> gene in ovarian high-grade serous carcinoma, alongside those of germline and somatic <i>BRCA</i> mutations, with the aim of improving the identification of patients suitable for treatment with poly(ADP-ribose) polymerase inhibitors.Materials and MethodsTissue samples from 77 Korean patients with ovarian high-grade serous carcinoma were subjected to next-generation sequencing. Pathogenic alterations of 38 DNA damage repair genes and <i>TP53</i> gene and their relationships with patient survival were examined. Additionally, we analyzed <i>BRCA</i> germline variants in blood samples from 47 of the patients for comparison.Results<i>BRCA1</i>, <i>BRCA2</i>, and <i>TP53</i> mutations were detected in 28.6%, 5.2%, and 80.5% of the 77 patients, respectively. Alterations in <i>RAD50, ATR, MSH6, MSH2</i>, and <i>FANCA</i> were also identified. At least one mutation in a DNA damage repair gene was detected in 40.3% of patients (31/77). Germline and somatic <i>BRCA</i> mutations were found in 20 of 47 patients (42.6%), and four patients had only somatic mutations without germline mutations (8.5%, 4/47). Patients with DNA damage repair gene alterations with or without <i>TP53</i>mutation, exhibited better disease-free survival than those with <i>TP53</i> mutation alone.ConclusionDNA damage repair genes were mutated in 40.3% of patients with high-grade serous carcinoma, with somatic <i>BRCA</i> mutations in the absence of germline mutation in 8.5%. Somatic variant examination, along with germline testing of DNA damage repair genes, has potential to detect additional candidates for PARP inhibitor treatment.

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