• DNA repair mechanisms
• cancer stem cell
• chemotherapy resistance
• immunomodulation
• small molecule
• tumor microenvironment

• Humans
• Neoplasm Recurrence, Local
• Drug Delivery Systems
• Combined Modality Therapy

• BRCA1
• BRCA2
• Breast cancer
• gene
• hypermethylation

• Humans
• Female
• DNA Methylation
• Breast Neoplasms/genetics
• Breast Neoplasms/pathology
• Promoter Regions, Genetic
• Middle Aged
• Adult
• BRCA1 Protein/genetics
• BRCA2 Protein/genetics
• Aged
• Biomarkers, Tumor/genetics
• Case-Control Studies

• cancer genomics
• epigenetics
• chromatin

• Humans
• Chromatin/genetics
• Chromatin/metabolism
• Chromosome Aberrations
• Neoplasms/genetics
• Chromosomes, Human/genetics
• Genome, Human/genetics
• Chromosome Segregation/genetics
• Carcinogenesis/genetics
• Epigenesis, Genetic
• Disease Progression
• Transcription, Genetic
• Gene Expression Regulation, Neoplastic

• DNA damage repair inhibitors
• DNA damage response
• biomarkers
• drug resistance

• Algorithms
• Gene Regulatory Networks/genetics
• Humans
• Mutation/genetics
• Neoplasms/genetics
• Protein Interaction Maps/genetics

Lung cancer is one of the most invasive cancers affecting over a million of the population. Non-small cell lung cancer (NSCLC) constitutes up to 85% of all lung cancer cases, and therefore, it is essential to identify predictive biomarkers of NSCLC for therapeutic purposes. Here we use a network theoretical approach to investigate the complex behavior of the NSCLC gene-regulatory interactions. We have used eight NSCLC microarray datasets GSE19188, GSE118370, GSE10072, GSE101929, GSE7670, GSE33532, GSE31547, and GSE31210 and meta-analyzed them to find differentially expressed genes (DEGs) and further constructed a protein–protein interaction (PPI) network. We analyzed its topological properties and identified significant modules of the PPI network using cytoscape network analyzer and MCODE plug-in. From the PPI network, top ten genes of each of the six topological properties like closeness centrality, maximal clique centrality (MCC), Maximum Neighborhood Component (MNC), radiality, EPC (Edge Percolated Component) and bottleneck were considered for key regulator identification. We further compared them with top ten hub genes (those with the highest degrees) to find key regulator (KR) genes. We found that two genes, CDK1 and HSP90AA1, were common in the analysis suggesting a significant regulatory role of CDK1 and HSP90AA1 in non-small cell lung cancer. Our study using a network theoretical approach, as a summary, suggests CDK1 and HSP90AA1 as key regulator genes in complex NSCLC network.

• Boolean implication networks
• CRISPR-Cas9
• RNA interference
• chemotherapy
• drug reposition
• immune checkpoint inhibitor
• multi-omics
• non-small cell lung cancer
• prognostic gene signature
• radiotherapy

• MKL
• lung adenocarcinoma
• mRMR
• multi-omics data

• chromosomal instability (CIN)
• genomic instability
• homologous recombination (HR)
• microhomology-mediated end-joining (MMEJ)
• microsatellite instability (MSI)
• mismatch repair (MMR)
• non-homologous end-joining (NHEJ)
• nucleotide excision repair (NER)

• Animals
• BRCA1 Protein/genetics
• BRCA1 Protein/metabolism
• DNA Breaks, Double-Stranded
• DNA End-Joining Repair/genetics
• Genomic Instability
• Humans
• Neoplasms/genetics
• Neoplasms/metabolism
• Rad51 Recombinase/genetics
• Rad51 Recombinase/metabolism
• Risk Factors
• Tumor Suppressor p53-Binding Protein 1/genetics
• Tumor Suppressor p53-Binding Protein 1/metabolism

• N/A Uehara Memorial Foundation

In recent years, targeted therapy and immunotherapy have become important treatment strategies for patients with non-small cell lung cancer (NSCLC). However, the clinical evidence for successful off-label use of targeted drugs for patients with NSCLC following progression on multiple lines of treatment is still lacking.

We describe a 62-year-old male patient with a right lung adenocarcinoma who harbored an EGFR exon 19 deletion mutation. He received gefitinib combined with six cycles of vinorelbine, cisplatin, and recombinant human endostatin as the first-line therapy. Then gefitinib was administered in combination with recombinant human endostatin as maintenance therapy, resulting in a progression-free survival (PFS) of 14 mo. Chemoradiotherapy was added following progression (enlarged brain metastases) on maintenance treatment. Unfortunately, the brain lesions were highly refractory and progressed again after 15 mo, at which time next-generation sequencing (NGS) of 1021 cancer-related genes was performed using peripheral blood to identify potential actionable mutations. NGS revealed that the patient harbored a BRCA2 germline mutation, the EGFR exon 19 deletion mutation disappeared, and no additional targetable genetic variant was detected. Therefore, the patient received olaparib combined with gefitinib and recombinant human endostatin, with a rapid and long-lasting clinical response (PFS = 13.5 mo).

This is a rare case of lung adenocarcinoma in a patient with a BRCA2 germline mutation who had long-term benefit from olaparib combination treatment, suggesting that NGS-based genetic testing may render the possibility of long-term survival in NSCLC patients after disease progression.

• Non-small cell lung cancer
• Next-generation sequencing
• BRCA2 gene
• Poly (adenosine diphosphate-ribose) polymerase inhibitor
• Case report

BRCA2 is an essential genome stability gene that has various functions in cells, including roles in homologous recombination, G2 checkpoint control, protection of stalled replication forks, and promotion of cellular resistance to numerous types of DNA damage. Heterozygous mutation of BRCA2 is associated with an increased risk of developing cancers of the breast, ovaries, pancreas, and other sites, thus BRCA2 acts as a classic tumor suppressor gene. However, understanding BRCA2 function as a tumor suppressor is severely limited by the fact that ~70% of the encoded protein has not been tested or assigned a function in the cellular DNA damage response. Remarkably, even the specific role(s) of many known domains in BRCA2 are not well characterized, predominantly because stable expression of the very large BRCA2 protein in cells, for experimental purposes, is challenging. Here, we review what is known about these domains and the assay systems that are available to study the cellular roles of BRCA2 domains in DNA damage responses. We also list criteria for better testing systems because, ultimately, functional assays for assessing the impact of germline and acquired mutations identified in genetic screens are important for guiding cancer prevention measures and for tailored cancer treatments.

• BRCA2
• DNA binding
• DNA damage responses
• DNA repair
• G2 checkpoint
• homologous recombination
• tumor suppressor
• variants of uncertain significance

• BRCA2 Protein/genetics
• Binding Sites
• DNA Damage
• DNA Repair
• DNA Replication
• Fanconi Anemia Complementation Group N Protein
• Genes, Tumor Suppressor
• Genomic Instability
• Homologous Recombination
• Humans
• Protein Binding

• T32 ES007250 NIEHS NIH HHS

• biological mechanism
• circular rna
• clinicopathological characteristics
• lung cancer
• prognosis
• systematic review

• Biomarkers, Tumor/metabolism
• Disease Progression
• Humans
• Lung Neoplasms/diagnosis
• Lung Neoplasms/metabolism
• Lung Neoplasms/mortality
• Lung Neoplasms/pathology
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplasm Staging
• Prognosis
• RNA, Circular/metabolism

Lung malignancies comprise lethal and aggressive tumours that remain the leading cancer-related death cause worldwide. Regarding histological classification, lung squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD) account for the majority of cases. Surgical resection and various combinations of chemo- and radiation therapies are the golden standards in the treatment of lung cancers, although the five-year survival rate remains very poor. Notch, Hedgehog, Wnt and Erbb signalling are evolutionarily conserved pathways regulating pivotal cellular processes such as differentiation, proliferation, and angiogenesis during embryogenesis and post-natal life. However, to date, there is no study comprehensively revealing signalling networks of these four pathways in LUSC and LUAD. Therefore, the aim of the present study was the investigation profiles of downstream target genes of pathways that differ between LUSC and LUAD biology. Our results showed a few co-expression modules, identified through weighted gene co-expression network analysis (WGCNA), which significantly differentiated downstream signaling of Notch, ErbB, Hedgehog, and Wnt in LUSC and LUAD. Among co-expressed genes essential regulators of the cell cycle, DNA damage response, apoptosis, and proliferation have been found. Most of them were upregulated in LUSC compared to LUAD. In conclusion, identified downstream networks revealed distinct biological mechanisms underlying cancer development and progression in LUSC and LUAD that may diversify the clinical outcome of the disease.

DNA damage repair (DDR) pathways are essential to ensure the accurate transmission of genetic material. However, different endogenous and exogenous factors challenge genomic integrity. Mechanisms involved in the alterations of DDR pathways mainly include genetic inactivation and epigenetic mechanisms. The development and progression of carcinomas are closely associated with DDR pathway aberrations, including the epigenetic silencing of gene O6-alkylguanine-DNA methyltransferase (MGMT); deficiencies of mismatch repair (MMR) genes, including MutL homolog 1 (MLH1), MutS protein homologue (MSH)-2 (MSH2), MSH6, and PMS1 homolog 2; the mismatch repair system component (PMS2); and mutations of homologous recombination repair (HRR) genes, such as the breast cancer susceptibility gene 1/2 (BRCA1/2). Understanding the underlying mechanisms and the correlations between alterations to DDR pathways and cancer could improve the efficacy of antitumor therapies. Emerging evidence suggests that survival is higher in patients with DDR-deficient tumors than in those with DDR-proficient tumors. Thus, DDR alterations play a predictive and prognostic role in anticancer therapies. Theoretical studies on the co-administration of DDR inhibitors and other anticancer therapies, including chemotherapy, radiotherapy, immunotherapy, endocrine therapy, and epigenetic drugs, hold promise for cancer treatments. In this review, we focus on the basic mechanisms, characteristics, current applications, and combination strategies of DDR pathways in the anticancer field.

• Anticancer therapy
• DNA damage repair pathway (DDR pathway)
• DNA repair
• cancer
• immunotherapy

• Epstein–Barr virus
• John Cunningham virus
• Merkel cell polyomavirus
• human papillomavirus
• jaagsiekte sheep virus
• lung cancer
• oncogenic virus

Over the past decades, it is recognized that loss of DNA damage repair (DDR) pathways is an early and frequent event in tumorigenesis, occurring in 40-50% of many cancer types. The basis of synthetic lethality in cancer therapy is DDR deficient cancers dependent on backup DNA repair pathways. In cancer, the concept of synthetic lethality has been extended to pairs of genes, in which inactivation of one by deletion or mutation and pharmacological inhibition of the other leads to death of cancer cells whereas normal cells are spared the effect of the drug. The paradigm study is to induce cell death by inhibiting PARP in BRCA1/2 defective cells. Since the successful application of PARP inhibitor, a growing number of developed DDR inhibitors are ongoing in preclinical and clinical testing, including ATM, ATR, CHK1/2 and WEE1 inhibitors. Combination of PARP inhibitors and other DDR inhibitors, or combination of multiple components of the same pathway may have great potential synthetic lethality efficiency. As epigenetics joins Knudson’s two hit theory, silencing of DDR genes by aberrant epigenetic changes provide new opportunities for synthetic lethal therapy in cancer. Understanding the causative epigenetic changes of loss-of-function has led to the development of novel therapeutic agents in cancer. DDR and related genes were found frequently methylated in human cancers, including BRCA1/2, MGMT, WRN, MLH1, CHFR, P16 and APC. Both genetic and epigenetic alterations may serve as synthetic lethal therapeutic markers.

• BRCA1/2
• DNA damage repair
• Epigenetics
• PARP inhibitor
• Synthetic lethality

• BRCA1/2 compensatory effect
• DNA-repair pathway
• Hormonal asset
• Lung cancer risk
• Secondary unrelated cancer

Background/Aims: MicroRNAs (miRNAs) are short, non-coding RNA molecules that control gene expression trough negative translational regulation. MiR-623 is a tumor suppressor, and it’s function and mechanism in breast cancer has not been reported.

Results: Exogenous overexpression of miR-623 suppressed cell proliferation, migration and invasion, meanwhile, but promoted cell apoptosis. MiR-623 knockdown displayed opposite results. Overexpression of miR-623 resulted in the downregulation of CDK4/6 as well as the inhibition of the phosphatidylinositol-3-kinase (PI3K)/Akt and Wnt/β-Catenin signaling pathways. MiR-623 knockdown displayed opposite results. Results of the reporter assay revealed that the luciferase activity was decreased in XRCC5-wt cells, suggesting that miR-623 could directly combine with 3’ UTR of XRCC5. MiR-623 significantly suppressed XRCC5 expression, which is critical for miR-623-induced proliferation and migration block in breast cancer cells.

Conclusion: miR-623 suppressed cell proliferation, migration and invasion through downregulation of cyclin dependent kinases and inhibition of the phosphatidylinositol-3-kinase (PI3K)/Akt and Wnt/β-Catenin pathways by targeting XRCC5.

Methods: miR-623 was either overexpressed in breast cancer cell lines through exogenous transfection or knocked down by specific siRNA. Cell proliferation, migration and invasion were examined using CCK-8, colony formation and transwell assay. The direct target of miR-623 was verified using luciferase reporter gene assay.

• XRCC5
• breast cancer
• microRNA
• migration
• proliferation

• Anticancer therapy
• DNA repair inhibition
• Synthetic lethality

• Animals
• Antineoplastic Agents/pharmacology
• DNA Damage/drug effects
• DNA Repair/drug effects
• Drug Discovery/methods
• Epigenesis, Genetic/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Genomic Instability/drug effects
• Humans
• Immunotherapy/methods
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/therapy
• Poly(ADP-ribose) Polymerase Inhibitors/pharmacology

• 732309 H2020 European Institute of Innovation and Technology
• 801347 H2020 Future and Emerging Technologies
• 472-EpiNotch Hellenic Foundation for Research and Innovation (GR)
• 16/1217 Worldwide Cancer Research

• epigenetic modifications
• extracellular vesicles
• melanoma
• miRNAs

• Animals
• DNA Methylation
• Disease Progression
• Epigenesis, Genetic
• Extracellular Vesicles/genetics
• Extracellular Vesicles/pathology
• Gene Expression Regulation, Neoplastic
• Humans
• Melanoma/genetics
• Melanoma/pathology
• MicroRNAs/genetics
• Skin Neoplasms/genetics
• Skin Neoplasms/pathology
• Melanoma, Cutaneous Malignant

• IG17536 Associazione Italiana per la Ricerca sul Cancro

Lung adenocarcinoma (LUAD) is one of the most common cancers and lethal diseases in the world. Recognition of the undetermined lung nodules at an early stage is useful for a favorable prognosis. However, there is no good method to identify the undetermined lung nodules and predict their clinical outcome. DNA methylation alteration is frequently observed in LUAD and may play important roles in carcinogenesis, diagnosis, and prediction. This study took advantage of publicly available methylation profiling resources and a machine learning method to investigate methylation differences between LUAD and adjacent non-malignant tissue. The prediction panel was first constructed using 338 tissue samples from LUAD patients including 149 non-malignant ones. This model was then validated with data from The Cancer Genome Atlas database and clinic samples. As a result, the methylation status of four CpG loci in homeobox A9 (HOXA9), keratin-associated protein 8-1 (KRTAP8-1), cyclin D1 (CCND1), and tubby-like protein 2 (TULP2) were highlighted as informative markers. A random forest classification model with an accuracy of 94.57% and kappa of 88.96% was obtained. To evaluate this panel for LUAD, the methylation levels of four CpG loci in HOXA9, KRTAP8-1, CCND1, and TULP2 of tumor samples and matched adjacent lung samples from 25 patients with LUAD were tested. In these LUAD patients, the methylation of HOXA9 was significantly upregulated, whereas the methylation of KRTAP8-1, CCND1, and TULP2 were downregulated obviously in tumor samples compared with adjacent tissues. Our study demonstrates that the methylation of HOXA9, KRTAP8-1, CCND1, and TULP2 has great potential for the early recognition of LUAD in the undetermined lung nodules. The findings also exhibit that the application of improved mathematic algorithms can yield accurate and particularly robust and widely applicable marker panels. This approach could greatly facilitate the discovery process of biomarkers in various fields.

• CCND1
• DNA methylation
• HOXA9
• KRTAP8-1
• TULP2
• biomarker
• lung adenocarcinoma
• random forest

• BRCA
• Cancer predisposition genes
• DNA repair
• EGFR T790 M
• EGFR mutation
• Family history of cancer
• Inherited susceptibility
• Lung cancer
• Lung cancer aetiology
• TP53

• Adenocarcinoma/ethnology
• Adenocarcinoma/genetics
• Adult
• Aged
• Asian People/genetics
• ErbB Receptors/genetics
• Female
• Genetic Predisposition to Disease
• Germ-Line Mutation
• Humans
• Lung Neoplasms/ethnology
• Lung Neoplasms/genetics
• Male
• Middle Aged
• Retrospective Studies
• Self Report
• Smoking
• Young Adult

• CSC201706240094 China Scholarship Council
• ZYJC18001 1.3.5 Project for Disciplines of Excellence, West China Hospital. Sichuan University
• 2016CZYD0001 Transformation Projects of Sci-Tech Achievements of Sichuan Province
• 2017YFC0910004 National Key Development Plan for Precision Medicine Research
• West China-Liverpool Clinician-Scientist Leadership Scholarship
• Roy Castle Lung Cancer Foundation
• National Key Development Plan for Precision Medicine Research

Phenotypic and functional heterogeneity is one of the hallmarks of human cancers. Tumor genotype variations among tumors within different patients are known as interpatient heterogeneity, and variability among multiple tumors of the same type arising in the same patient is referred to as intra-patient heterogeneity. Subpopulations of cancer cells with distinct phenotypic and molecular features within a tumor are called intratumor heterogeneity (ITH). Since Nowell proposed the clonal evolution of tumor cell populations in 1976, tumor heterogeneity, especially ITH, was actively studied. Research has focused on the genetic basis of cancer, particularly mutational activation of oncogenes or inactivation of tumor-suppressor genes (TSGs). The phenomenon of ITH is commonly explained by Darwinian-like clonal evolution of a single tumor. Despite the monoclonal origin of most cancers, new clones arise during tumor progression due to the continuous acquisition of mutations. It is clear that disruption of the "epigenetic machinery" plays an important role in cancer development. Aberrant epigenetic changes occur more frequently than gene mutations in human cancers. The epigenome is at the intersection of the environment and genome. Epigenetic dysregulation occurs in the earliest stage of cancer. The current trend of epigenetic therapy is to use epigenetic drugs to reverse and/or delay future resistance to cancer therapies. A majority of cancer therapies fail to achieve durable responses, which is often attributed to ITH. Epigenetic therapy may reverse drug resistance in heterogeneous cancer. Complete understanding of genetic and epigenetic heterogeneity may assist in designing combinations of targeted therapies based on molecular information extracted from individual tumors.

• Epigenetic intratumor heterogeneity
• Epigenetic machinery
• Epigenetics
• Intratumor heterogeneity
• Microenvironment

• Cancer
• Carcinoma
• DNA repair
• Health span
• Mutagenesis
• Mutation
• Tumor

• Cigarette smoke
• Emphysema
• Mutations
• Nucleotide excision repair
• Oxidative stress

Recently, many potential prognostic biomarkers for gastric cancer (GC) have been identified, but the prognosis of advanced GC patients remains poor. Chloride channels are promising cancer biomarkers, and their family member chloride channel-3 (CLC-3) is involved in multiple biological behaviors. However, whether CLC-3 is a prognostic biomarker for GC patients is rarely reported. The molecular mechanisms by which CLC-3 is regulated in GC are unclear.

The expression of CLC-3 and XRCC5 in human specimens was analyzed using immunohistochemistry. The primary biological functions and pathways related to CLC-3 were enriched by RNA sequencing. A 5′-biotin-labeled DNA probe with a promoter region between − 248 and + 226 was synthesized to pull down CLC-3 promoter-binding proteins. Functional studies were detected by MTS, clone formation, wound scratch, transwell, and xenograft mice model. Mechanistic studies were investigated by streptavidin-agarose-mediated DNA pull-down, mass spectrometry, ChIP, dual-luciferase reporter assay system, Co-IP, and immunofluorescence.

The results showed that CLC-3 was overexpressed in human GC tissues and that overexpression of CLC-3 was a poor prognostic biomarker for GC patients (P = 0.012). Furthermore, higher expression of CLC-3 was correlated with deeper tumor invasion (P = 0.006) and increased lymph node metastasis (P = 0.016), and knockdown of CLC-3 inhibited cell proliferation and migration in vitro. In addition, X-ray repair cross-complementing 5 (XRCC5) was identified as a CLC-3 promoter-binding protein, and both CLC-3 (HR 1.671; 95% CI 1.012–2.758; P = 0.045) and XRCC5 (HR 1.795; 95% CI 1.076–2.994; P = 0.025) were prognostic factors of overall survival in GC patients. The in vitro and in vivo results showed that the expression and function of CLC-3 were inhibited after XRCC5 knockdown, and the inhibition effects were rescued by CLC-3 overexpression. Meanwhile, the expression and function of CLC-3 were promoted after XRCC5 overexpression, and the promotion effects were reversed by the CLC-3 knockdown. The mechanistic study revealed that knockdown of XRCC5 suppressed the binding of XRCC5 to the CLC-3 promoter and subsequent promoter activity, thus regulating CLC-3 expression at the transcriptional level by interacting with PARP1.

Our findings indicate that overexpression of CLC-3 is regulated by XRCC5 and is a poor prognostic biomarker for gastric cancer. Double targeting CLC-3 and XRCC5 may provide the promising therapeutic potential for GC treatment.

The online version of this article (10.1186/s13045-018-0660-y) contains supplementary material, which is available to authorized users.

• Biomarker
• CLC-3
• Gastric cancer
• Prognosis
• XRCC5

Lung cancer had been leading mounts of deaths worldwide. Advances in genes microarray had helped human further understand genes and identify novel circular RNAs. This study aimed at investigating the biological functions and molecular mechanisms of hsa_circ_0046264 in lung cancer which may be helpful in lung cancer early diagnosis and clinical treatment.

Gene microarray data screened the differential gene of hsa_circ_0046264 and its downstream genes were found by bioinformatics analysis and verified by luciferase reporter assay. QRT-PCR and Western blot was used to detect the RNA and protein levels respectively. RNase R digestion confirmed the existences of circular RNA. Cell viability, invasion and apoptosis were determined by MTT assay, flow cytometry and DNA damage assay. Tumor formation in nude mice and immunohistochemistry proved the functions of hsa_circ_0046264 in vivo.

Hsa_circ_0046264 and BRCA2 were down-regulated in lung cancer tissues while miR-1245 was up-regulated. Hsa_circ_0046264 induced apoptosis but inhibited proliferation and invasion of lung cancer cells through targeting miR-1245 to up-regulate BRCA2. Hsa_circ_0046264 inhibited the tumor growth in vivo.

Hsa_circ_0046264 was a tumor suppressor in lung cancer. Overexpression of hsa_circ_0046264 could up-regulate BRCA2 expression through down-regulating of miR-1245.

The online version of this article (10.1186/s12931-018-0819-7) contains supplementary material, which is available to authorized users.

• BRCA2
• Hsa-miR-1245
• Lung cancer
• hsa_circ_0046264

The stability and integrity of the human genome are maintained by the DNA damage repair (DDR) system. Unrepaired DNA damage is a major source of potentially mutagenic lesions that drive carcinogenesis. In addition to gene mutation, DNA methylation occurs more frequently in DDR genes in human cancer. Thus, DNA methylation may play more important roles in DNA damage repair genes to drive carcinogenesis. Aberrant methylation patterns in DNA damage repair genes may serve as predictive, diagnostic, prognostic and chemosensitive markers of human cancer. MGMT methylation is a marker for poor prognosis in human glioma, while, MGMT methylation is a sensitive marker of glioma cells to alkylating agents. Aberrant epigenetic changes in DNA damage repair genes may serve as therapeutic targets. Treatment of MLH1-methylated colon cancer cell lines with the demethylating agent 5′-aza-2′-deoxycytidine induces the expression of MLH1 and sensitizes cancer cells to 5-fluorouracil. Synthetic lethality is a more exciting approach in patients with DDR defects. PARP inhibitors are the most effective anticancer reagents in BRCA-deficient cancer cells.

• DNA damage repair
• DNA methylation
• MGMT
• PARP inhibitor
• synthetic lethality

• gene-gene interactions
• penalized selection
• tensor regression

• Cancer therapy
• DNA repair
• Epigenetic silencing
• GADD45
• Genotoxic stress
• MGMT
• Promoter methylation
• TET
• p53
• tumor formation

• Animals
• CpG Islands/genetics
• DNA Methylation/genetics
• DNA Repair/genetics
• Epigenesis, Genetic/genetics
• Humans
• Neoplasms/genetics

• Breast/ovarian cancer
• Cancer in other sites
• Hereditary syndrome
• Hereditary/non hereditary branch

• DNA methylation
• Epigenetics
• Lung cancer
• Methylated DNA immunoprecipitation
• Polycyclic aromatic hydrocarbon
• Transplacental

• Animals
• Carcinogens/toxicity
• DNA Methylation/drug effects
• Female
• Humans
• Lung/drug effects
• Lung/metabolism
• Male
• Mice
• Polycyclic Aromatic Hydrocarbons/toxicity
• Uterus/drug effects
• Uterus/metabolism

• R03 ES018919 NIEHS NIH HHS

• Cancer
• Epigenetics
• Oncogenes
• Therapy
• Tumor suppressor genes

• Akt
• GSK-3
• Hedgehog
• Notch
• PI3K
• Targeted therapy
• Therapy resistance
• Wnt/beta-catenin
• mTOR

• B[a]P
• DNA repair
• HPV
• environmental exposure
• promoter hypermethylation

• Benzo(a)pyrene/poisoning
• Cell Transformation, Neoplastic/drug effects
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/metabolism
• DNA Adducts/drug effects
• DNA Adducts/genetics
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/metabolism
• Environmental Exposure/adverse effects
• ErbB Receptors/genetics
• ErbB Receptors/metabolism
• Gene Expression Regulation/drug effects
• Humans
• Immunohistochemistry
• Ku Autoantigen/genetics
• Ku Autoantigen/metabolism
• Lung/drug effects
• Lung/pathology
• Lung/virology
• Lung Neoplasms/etiology
• Lung Neoplasms/genetics
• Lung Neoplasms/virology
• Mutation/drug effects
• Oncogene Proteins, Viral/genetics
• Oncogene Proteins, Viral/metabolism
• Papillomavirus Infections/complications
• Papillomavirus Infections/genetics
• Papillomavirus Infections/metabolism
• Repressor Proteins/genetics
• Repressor Proteins/metabolism
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

Breast cancer stem cells (BCSCs) are considered the cause of tumor growth, multidrug resistance, metastasis, and recurrence. Therefore, differentiation therapy to reduce self-renewal of BCSCs is a promising approach. We have examined the effects of 5-aza-2′-deoxycytidine (DAC) on BCSC differentiation.

BCSCs were treated with a range of DAC concentrations from 0.625 to 100 µM. The differentiation status of DAC-treated BCSCs was graded by changes in cell proliferation, CD44⁺CD24⁻ phenotype, expression of tumor suppressor genes, including BRCA1, BRCA2, p15, p16, p53, and PTEN, and antitumor drug resistance.

DAC treatment caused significant BCSC differentiation. BCSCs showed a 15%–23% reduction in proliferation capacity, 3.0%–21.3% decrease in the expression of BCSC marker CD44⁺/CD24⁻, activation of p53 expression, and increased p15, p16, BRCA1, and BRCA2 expression. Concentrations of DAC ranging from 0.625 to 40 µM efficiently induce cell cycle arrest in S-phase. ABCG2, highly expressed in BCSCs, also decreased with DAC exposure. Of particular note, drug-sensitivity of BCSCs to doxorubicin, verapamil, and tamoxifen also increased 1.5-, 2.0-, and 3.7-fold, respectively, after pretreatment with DAC.

DAC reduced breast cancer cell survival and induced differentiation through reexpression of tumor suppressor genes. These results indicate the potential of DAC in targeting specific chemotherapy-resistant cells within a tumor.

• 5-aza-2′-deoxycytidine
• breast cancer
• breast cancer stem cells
• differentiation
• epigenetics

Although thousands of DNA damaging events occur in each cell every day, efficient DNA repair pathways have evolved to counteract them. The DNA repair machinery plays a key role in maintaining genomic stability by avoiding the maintenance of mutations. The DNA repair enzymes continuously monitor the chromosomes to correct any damage that is caused by exogenous and endogenous mutagens. If DNA damage in proliferating cells is not repaired because of an inadequate expression of DNA repair genes, it might increase the risk of cancer. In addition to mutations, which can be either inherited or somatically acquired, epigenetic silencing of DNA repair genes has been associated with carcinogenesis. Gastric cancer represents the second highest cause of cancer mortality worldwide. The disease develops from the accumulation of several genetic and epigenetic changes during the lifetime. Among the risk factors, Helicobacter pylori (H. pylori) infection is considered the main driving factor to gastric cancer development. Thus, in this review, we summarize the current knowledge of the role of H. pylori infection on the epigenetic regulation of DNA repair machinery in gastric carcinogenesis.

• Helicobacter pylori
• DNA repair
• Epigenetic
• DNA methylation
• Gastric cancer
• Histone modification

• Animals
• Cell Transformation, Neoplastic/genetics
• DNA Damage
• DNA Methylation
• DNA Repair
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Helicobacter Infections/complications
• Helicobacter Infections/microbiology
• Helicobacter pylori/genetics
• Helicobacter pylori/pathogenicity
• Host-Pathogen Interactions
• Humans
• Risk Factors
• Stomach Neoplasms/genetics
• Stomach Neoplasms/microbiology
• Virulence/genetics

• cancer
• oncogene
• therapeutic targeting
• tumor suppressor gene

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• DNA Repair
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Genetic Therapy
• Humans
• Immunotherapy
• Molecular Targeted Therapy
• Neoplasms/genetics
• Neoplasms/therapy
• Tumor Suppressor Protein p53/antagonists & inhibitors
• Tumor Suppressor Protein p53/genetics

• K08 DE024774 NIDCR NIH HHS

• Cisplatin
• DNA repair
• Lung cancer
• Resistance

• Antineoplastic Agents/therapeutic use
• BRCA1 Protein/genetics
• BRCA2 Protein/genetics
• Cisplatin/pharmacology
• Cisplatin/therapeutic use
• DNA Damage
• DNA Repair/drug effects
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/metabolism
• Drug Resistance, Neoplasm/drug effects
• Drug Resistance, Neoplasm/genetics
• Endonucleases/genetics
• Endonucleases/metabolism
• Homologous Recombination
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Poly(ADP-ribose) Polymerases/genetics
• Poly(ADP-ribose) Polymerases/metabolism

• DNA repair capacity
• Multiplex assays
• Personalized disease prevention and treatment

• BRCA mutation
• BRCA-like
• DNA damage repair pathway
• poly(ADP-ribose) polymerase inhibitors
• solid tumors

DNA repair genes that have been inactivated by promoter methylation offer potential therapeutic targets either by targeting the specific repair deficiency, or by synthetic lethal approaches. This study evaluated promoter methylation status for eight selected DNA repair genes (ATM, BRCA1, ERCC1, MGMT, MLH1, NEIL1, RAD23B and XPC) in 56 non-small cell lung cancer (NSCLC) tumours and 11 lung cell lines using the methylation-sensitive high resolution melting (MS-HRM) methodology. Frequent methylation in NEIL1 (42%) and infrequent methylation in ERCC1 (2%) and RAD23B (2%) are reported for the first time in NSCLC. MGMT methylation was detected in 13% of the NSCLCs. Contrary to previous studies, methylation was not detected in ATM, BRCA1, MLH1 and XPC. Data from The Cancer Genome Atlas (TCGA) was consistent with these findings. The study emphasises the importance of using appropriate methodology for accurate assessment of promoter methylation.

• DNA damage signalling and repair
• cancer
• synthetic lethality