• ATM
• ataxia-telangiectasia mutated
• chemotherapy
• homologous recombination repair
• immunotherapy
• lung cancer susceptibility
• radiotherapy
• targeted therapies

Background: The prognostic value of neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) in metastatic gastric cancer (mGC) treated with systemic chemotherapy is largely unknown, especially second-line chemotherapy. We retrospectively investigated the prognostic value of baseline NLR and MLR in the progression of mGC with systemic chemotherapy.

Methods: Patients with mGC diagnosed by pathology from January 2010 to December 2018 were identified. Baseline NLR and MLR were collected before treatment. The time to progression during or after first-line therapy from diagnosis (PFS1), and during or after second-line chemotherapy (PFS2) were primary endpoint. Overall survival (OS) was calculated from diagnosis to the date of death or final follow-up.

Results: 537 patients with first-line chemotherapy were included in the retrospective study. The cutoff values of NLR and MLR were 2.610 and 0.285, respectively. Pretreatment NLR and MLR were significantly independent prognostic factors for PFS1 (hazard ratio [HR]=1.597, 95% CI 1.261-2.022, P<0.001 and HR=1.574, 95% CI 1.239-1.999, P<0.001) and OS (HR=1.448, 95% CI 1.030-2.034, P=0.033 and HR=1.622, 95% CI 1.148-2.291, P=0.006). For 172 patients treated with second-line chemotherapy, the cutoff value of MLR was 0.355 and MLR maintained a significant association with PFS2 (HR=1.589, 95% CI 1.073-2.354, P=0.021) in multivariate analysis.

Conclusions: Elevated NLR and MLR were markedly related to the worse PFS1 and OS in mGC performed with first-line chemotherapy. In patients with second-line therapy, MLR was more closely connected to prognosis and was a significantly independent prognostic factor for PFS2.

• metastatic gastric cancer
• monocyte-to-lymphocyte ratio
• neutrophil-to-lymphocyte ratio
• progression-free survival
• systemic chemotherapy

• AJCC tumor category
• ATM
• BAP1
• Co-expression
• Immunohistochemistry
• Uveal Melanoma

• ATM protein
• Immunohistochemistry
• Prognosis
• Uveal melanoma

• DNA repair
• PARP
• anticancer therapy
• double strand breaks (DSB)
• radiotherapy
• synthetic lethality.

Gastric cancer remains one of the leading causes of cancer-related death worldwide, and most of the cases are associated with Helicobacter pylori infection. This bacterium promotes the production of reactive oxygen species (ROS), which cause DNA damage in gastric epithelial cells. In this study, we evaluated the expression of important genes involved in the recognition of DNA damage (ATM, ATR, and H2AX) and ROS-induced damage repair (APE1) and the expression of some miRNAs (miR-15a, miR-21, miR-24, miR-421 and miR-605) that target genes involved in the DNA damage response (DDR) in 31 fresh tissues of gastric cancer. Cytoscape v3.1.1 was used to construct the postulated miRNA:mRNA interaction network. Analysis performed by real-time quantitative PCR exhibited significantly increased levels of the APE1 (RQ = 2.55, p < 0.0001) and H2AX (RQ = 2.88, p = 0.0002) genes beyond the miR-421 and miR-605 in the gastric cancer samples. In addition, significantly elevated levels of miR-21, miR-24 and miR-421 were observed in diffuse-type gastric cancer. Correlation analysis reinforced some of the gene:gene (ATM/ATR/H2AX) and miRNA:mRNA relationships obtained also with the interaction network. Thus, our findings show that tumor cells from gastric cancer presents deregulation of genes and miRNAs that participate in the recognition and repair of DNA damage, which could confer an advantage to cell survival and proliferation in the tumor microenvironment.

• DNA damage response
• DNA repair
• Gastric cancer
• Gene expression
• microRNA

• Adenoid cystic carcinoma
• ataxia telangiectasia mutated (ATM)
• p53
• prognostic marker
• salivary gland

• Adult
• Aged
• Ataxia Telangiectasia/metabolism
• Ataxia Telangiectasia Mutated Proteins/metabolism
• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/metabolism
• Carcinoma, Adenoid Cystic/metabolism
• Carcinoma, Adenoid Cystic/mortality
• Carcinoma, Mucoepidermoid/genetics
• Female
• Genes, p53
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neoplasm Recurrence, Local
• Phosphorylation/genetics
• Prognosis
• Republic of Korea
• Salivary Gland Neoplasms/metabolism
• Salivary Gland Neoplasms/mortality
• Salivary Gland Neoplasms/pathology
• Salivary Glands/pathology
• Survival Rate
• Tumor Suppressor Protein p53/metabolism

• Apoptosis
• Cell migration
• Gastric cancer
• ITGA2
• Integrin alpha-2
• Proliferation
• Therapeutic target

Ataxia-telangiectasia mutated (ATM) is critical in maintaining genomic integrity. In response to DNA double-strand breaks, ATM phosphorylates downstream proteins involved in cell-cycle checkpoint arrest, DNA repair, and apoptosis. Here we investigate the frequency, and influence of ATM deficiency on outcome, in early-resected non-small cell lung cancer (NSCLC). Tissue microarrays, containing 165 formalin-fixed, paraffin-embedded resected NSCLC tumours from patients diagnosed at the Tom Baker Cancer Centre, Calgary, Canada, between 2003 and 2006, were analyzed for ATM expression using quantitative fluorescence immunohistochemistry. Both malignant cell-specific ATM expression and the ratio of ATM expression within malignant tumour cells compared to that in the surrounding tumour stroma, defined as the ATM expression index (ATM-EI), were measured and correlated with clinical outcome. ATM loss was identified in 21.8% of patients, and was unaffected by clinical pathological variables. Patients with low ATM-EI tumours had worse survival outcomes compared to those with high ATM-EI (p < 0.01). This effect was pronounced in stage II/III patients, even after adjusting for other clinical co-variates (p < 0.001). Additionally, we provide evidence that ATM-deficient patients may derive greater benefit from guideline-recommended adjuvant chemotherapy following surgical resection. Taken together, these results indicate that ATM loss seems to be an early event in NSCLC carcinogenesis and is an independent prognostic factor associated with worse survival in stage II/III patients.

• ATM
• digital pathology
• early stage
• non-small cell lung cancer
• outcome

• BRCA1
• BRCA2
• Drug combinations
• PARP inhibitor

• Animals
• Drug Combinations
• Humans
• Immunotherapy
• Neoplasms/drug therapy
• Neoplasms/enzymology
• Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
• Poly(ADP-ribose) Polymerases/metabolism

• 14276 Cancer Research UK

• BRCAness
• DNA damage repair
• Gastric adenocarcinoma
• PARP inhibitor
• ataxia telangiectasia mutated (ATM)
• homologous recombination deficiency (HRD)
• synthetic lethality

• CagA
• CagA gene polymorphism
• Gastric carcinoma
• Gene methylation
• Haplotype
• Helicobacter pylori infection
• Human gene mutation
• Inflammatory cytokine

• ataxia-telangiectasia mutated
• interleukin 6
• lung cancer
• matrix metalloproteinases
• metastasis

• Animals
• Apoptosis/drug effects
• Ataxia Telangiectasia Mutated Proteins/genetics
• Ataxia Telangiectasia Mutated Proteins/metabolism
• Blotting, Western
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Immunoenzyme Techniques
• Interleukin-6/pharmacology
• Lung Neoplasms/drug therapy
• Lung Neoplasms/metabolism
• Lung Neoplasms/secondary
• Matrix Metalloproteinase 13/genetics
• Matrix Metalloproteinase 13/metabolism
• Matrix Metalloproteinase 3/genetics
• Matrix Metalloproteinase 3/metabolism
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Phosphorylation/drug effects
• RNA, Messenger/genetics
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays

For decades, radiotherapy and chemotherapy were the two only approaches exploiting DNA repair processes to fight against cancer. Nowadays, cancer therapeutics can be a major challenge when it comes to seeking personalized targeted medicine that is both effective and selective to the malignancy. Over the last decade, the discovery of new targeted therapies against DNA damage signalling and repair has offered the possibility of therapeutic improvements in oncology. In this review, we summarize the current knowledge of DNA damage signalling and repair inhibitors, their molecular and cellular effects, and future therapeutic use.

• ATM
• ATR
• CHK1
• CHK2
• DNA repair
• MRE11
• PARP
• RAD51
• inhibitors

• Irinotecan
• Metastatic gastric cancer
• Ramucirumab
• Second-line chemotherapy
• Targeted therapy
• Taxane

• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Biomarkers, Tumor/genetics
• Humans
• Neoplasm Metastasis
• Precision Medicine
• Retreatment
• Risk Factors
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/genetics
• Stomach Neoplasms/mortality
• Stomach Neoplasms/pathology
• Treatment Outcome

Our previous proteomic analysis revealed that mitogen-activated protein kinase activator with WD40 repeats (MAWD) and MAWD-binding protein (MAWBP) were downregulated in gastric cancer (GC) tissues. These proteins interacted and formed complexes in GC cells. To investigate the role of MAWD and MAWBP in GC differentiation, we analyzed the relationship between MAWD/MAWBP and clinicopathologic characteristics of GC tissues and examined the expression of E-cadherin and pepsinogen C (PGC)—used as gastric mucosa differentiation markers—in MAWD/MAWBP-overexpressing GC cells and xenografts.

We measured MAWD, MAWBP, transforming growth factor-beta (TGF-beta), E-cadherin, and PGC expression in 223 GC tissues and matched-adjacent normal tissues using tissue microarray and immunohistochemistry (IHC) analyses, and correlated these expression levels with clinicopathologic features. MAWD and MAWBP were overexpressed alone or together in SGC7901 cells and then E-cadherin, N-cadherin, PGC, Snail, and p-Smad2 levels were determined using western blotting, semiquantitative RT-PCR, and immunofluorescence analysis. Alkaline phosphatase (AKP) activity was measured to investigate the differentiation level of various transfected cells, and the transfected cells were used in tumorigenicity assays and for IHC analysis of protein expression in xenografts.

MAWD/MAWBP positive staining was significantly lower in GC tissues than in normal samples (P < 0.001), and the expression of these proteins was closely correlated with GC differentiation grade. Kaplan–Meier survival curves indicated that low MAWD and MAWBP expression was associated with poor patient survival (P < 0.05). The differentiation-related proteins E-cadherin and PGC were expressed in GC tissues at a lower level than in normal tissues (P < 0.001), but were upregulated in MAWD/MAWBP-overexpressing cells. N-cadherin and Snail expression was strongr in vector-expressing cells and comparatively weaker in MAWD/MAWBP co-overexpressing cells. MAWD/MAWBP co-overexpression inhibited Smad2 phosphorylation and nuclear translocation (P < 0.05), and AKP activity was lowest in MAWD/MAWBP coexpressing cells and highest in vector-expressing cells (P < 0.001). TGF-beta, E-cadherin, and PGC expression in xenograft tumors derived from MAWD/MAWBP coexpressing cells was higher than that in control.

MAWD and MAWBP were downregulated and associated with the differentiation grade in GC tissues. MAWD and MAWBP might induce the expression of differentiation-related proteins by modulating TGF-beta signaling in GC cells.

The online version of this article (doi:10.1186/s12885-015-1637-7) contains supplementary material, which is available to authorized users.

UV radiation induced genomic instability is one of the leading causes for melanoma. Phosphorylation of Ataxia Telangiectasia Mutated (ATM) is one of the initial events that follow DNA damage. Phospho-ATM (p-ATM) plays a key role in the activation of DNA repair and several oncogenic pathways as well as in the maintenance of genomic integrity. The present study was therefore performed to understand the significance of p-ATM in melanoma progression and to correlate it with patient prognosis. Tissue microarray and immunohistochemical analysis were employed to study the expression of p-ATM in melanoma patients. A total of 366 melanoma patients (230 primary melanoma and 136 metastatic melanoma) were used for the study. Chi-square test, Kaplan-Meier, univariate and multivariate Cox regression analysis were used to elucidate the prognostic significance of p-ATM expression. Results revealed that both loss of, and gain in, p-ATM expression were associated with progression of melanoma from normal nevi to metastatic melanoma. Patients whose samples showed negative or strong p-ATM staining had significantly worse 5-year survival compared to patients who had weak to moderate expression. Loss of p-ATM expression was associated with relatively better 5-year survival, but the corresponding 10-year survival curve almost overlapped with that of strong p-ATM expression. p-ATM expression was found to be an independent prognostic factor for 5-year but not for 10-year patient survival. In conclusion our findings show that loss of p-ATM expression and gain-in p-ATM expression are indicators of worse melanoma patient survival.

• ataxia-telangiectasia mutated (ATM)
• nasopharyngeal carcinoma
• ribonucleotide reductase subunit M1 (RRM1)
• thymidylate synthetase (THMS)

• AKT2
• Gastric cancer
• Mutation
• PIK3CA

• Adult
• Aged
• Base Sequence
• Case-Control Studies
• Cell Line, Tumor
• Class I Phosphatidylinositol 3-Kinases
• Female
• Gene Frequency
• Genetic Predisposition to Disease
• Humans
• Male
• Middle Aged
• Mutation
• Phosphatidylinositol 3-Kinases/genetics
• Proto-Oncogene Proteins c-akt/genetics
• Stomach Neoplasms/epidemiology
• Stomach Neoplasms/genetics

• cancer progression
• gastric cancer
• microsatellite instability
• mutations

• ATM
• PARP-1 inhibitor
• gastric cancer
• olaparib
• p53

The interaction between ionizing radiation and substances in cells will induce the production of free radicals. These free radicals inflict damage to important biomolecules such as chromosomes, proteins and lipids which consequently trigger the expression of genes which are involved in protecting the cells or repair the oxidative damages. Honey has been known for its antioxidant properties and was used in medical and cosmetic products. Currently, research on honey is ongoing and diversifying. The aim of this study was to elucidate the role of Gelam honey as a radioprotector in human diploid fibroblast (HDFs) which were exposed to gamma-rays by determining the expression of genes and proteins involved in cell cycle regulation and cell death.

Six groups of HDFs were studied viz. untreated control, irradiated HDFs, Gelam honey-treated HDFs and HDF treated with Gelam honey pre-, during- and post-irradiation. HDFs were treated with 6 mg/ml of sterilized Gelam honey (w/v) for 24 h and exposed to 1 Gray (Gy) of gamma-rays at the dose rate of 0.25 Gy/min.

Our findings showed that, gamma-irradiation at 1 Gy up-regulated ATM, p53, p16^ink4a and cyclin D1 genes and subsequently initiated cell cycle arrest at G₀/G₁ phase and induced apoptosis (p < 0.05). Pre-treatment with Gelam honey however caused down regulation of these genes in irradiated HDFs while no significant changes was observed on the expression of GADD45 and PAK genes. The expression of ATM and p16 proteins was increased in irradiated HDFs but the p53 gene was translated into p73 protein which was also increased in irradiated HDFs. Gelam honey treatment however significantly decreased the expression of ATM, p73, and p16 proteins (p < 0.05) while the expression of cyclin D1 remained unchanged. Analysis on cell cycle profile showed that cells progressed to S phase with less percentage of cells in G₀/G₁ phase with Gelam honey treatment while apoptosis was inhibited.

Gelam honey acts a radioprotector against gamma-irradiation by attenuating radiation-induced cell death.

Many tumors contain mutations that confer defects in the DNA-damage response and genome stability. DNA-damaging agents are powerful therapeutic tools that can differentially kill cells with an impaired DNA-damage response. The response to DNA damage is complex and composed of a network of coordinated pathways, often with a degree of redundancy. Tumor-specific somatic mutations in DNA-damage response genes could be exploited by inhibiting the function of a second gene product to increase the sensitivity of tumor cells to a sublethal concentration of a DNA-damaging therapeutic agent, resulting in a class of conditional synthetic lethality we call synthetic cytotoxicity. We used the Saccharomyces cerevisiae nonessential gene-deletion collection to screen for synthetic cytotoxic interactions with camptothecin, a topoisomerase I inhibitor, and a null mutation in TEL1, the S. cerevisiae ortholog of the mammalian tumor-suppressor gene, ATM. We found and validated 14 synthetic cytotoxic interactions that define at least five epistasis groups. One class of synthetic cytotoxic interaction was due to telomere defects. We also found that at least one synthetic cytotoxic interaction was conserved in Caenorhabditis elegans. We have demonstrated that synthetic cytotoxicity could be a useful strategy for expanding the sensitivity of certain tumors to DNA-damaging therapeutics.

• DNA damage response
• DNA-damaging agents
• conditional synthetic lethality
• genetic interaction
• synthetic cytotoxicity

• Apoptosis/genetics
• Ataxia Telangiectasia Mutated Proteins/genetics
• Cell Line
• Cell Line, Tumor
• Cell Movement/genetics
• Cell Proliferation/genetics
• Computational Biology/methods
• Down-Regulation/genetics
• Gene Expression Regulation, Neoplastic/genetics
• Genes, Tumor Suppressor/physiology
• HEK293 Cells
• Humans
• MicroRNAs/genetics
• Neoplasm Invasiveness/genetics
• RNA, Messenger/genetics
• Stomach Neoplasms/genetics
• Transfection/methods

• DNA repair
• MUS81/EME1
• esophageal adenocarcinoma

• adjuvant
• ataxia-telangiectasia-mutated
• gastric cancer
• microsatellite instability
• prognosis

• Adenocarcinoma/genetics
• Adenocarcinoma/metabolism
• Adenocarcinoma/mortality
• Adult
• Aged
• Aged, 80 and over
• Ataxia Telangiectasia Mutated Proteins/biosynthesis
• Ataxia Telangiectasia Mutated Proteins/genetics
• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Disease-Free Survival
• Female
• Humans
• Immunohistochemistry
• Male
• Microsatellite Instability
• Middle Aged
• Polymerase Chain Reaction
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/mortality

• ATM
• DNA damage response
• TPD52
• cancer
• protein-protein interaction

AIM: To investigate the association of p42.3 expression with clinicopathological characteristics and the biological function of p42.3 in human hepatocellular carcinoma (HCC).

METHODS: We used reverse transcription-polymerase chain reaction (RT-PCR), quantitative real-time RT-PCR and western blotting to detect p42.3 mRNA and protein expression in hepatic cell lines. We examined primary HCC samples and matched adjacent normal tissue by immunohistochemistry to investigate the correlation between p42.3 expression and clinicopathological features. HepG2 cells were transfected with a pIRES2-EGFP-p42.3 expression vector to examine the function of the p42.3 gene. Transfected cells were analyzed for their viability and malignant transformation abilities by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay, and tumorigenicity assay in nude mice.

RESULTS: p42.3 is differentially expressed in primary HCC tumors and cell lines. Approximately 69.6% (96/138) of cells were p42.3-positive in hepatic tumor tissues, while 30.7% (35/114) were p42.3-positive in tumor-adjacent normal tissues. Clinicopathological characteristics of the HCC specimens revealed a significant correlation between p42.3 expression and tumor differentiation (P = 0.031). However, p42.3 positivity was not related to tumor tumor-node-metastasis classification, hepatitis B virus status, or hepatoma type. Regarding p42.3 overexpression in stably transfected HepG2 cells, we discovered significant enhancement of cancer cell growth and colony formation in vitro, and significantly enhanced tumorigenicity in nude mice. Western blot analysis of cell cycle proteins revealed that enhanced p42.3 levels promote upregulation of proliferating cell nuclear antigen, cyclin B1 and mitotic arrest deficient 2.

CONCLUSION: p42.3 promotes tumorigenicity and tumor growth in HCC and may be a potential target for future clinical cancer therapeutics.

• p42.3
• Hepatocellular carcinoma
• HepG2
• Overexpression
• Tumorigenicity

AIM: To investigate the expression deficiency of key molecular markers in the homologous recombination pathway.

METHODS: Expression loss of breast cancer type 1 susceptibility protein (BRCA1), ataxia telangiectasia mutated (ATM), ATM-Rad3-related (ATR), mediator of DNA damage checkpoint protein 1 (MDC1) and meiotic recombination 11 (Mre11) were correlated with their clinicopathological parameters in gastric cancer (GC). One hundred and twenty treatment-naive GC samples were formalin-fixed and paraffin-embedded into tissue blocks. Two representative cores from each block were extracted and constructed into tissue microarrays. Expression levels of BRCA1, ATM, ATR, MDC1 and Mre11 were determined using immunohistochemical analysis, and correlated with clinical parameters, including age, gender, Lauren subtype, tumor grades, clinical stage and overall survival.

RESULTS: Expression loss of BRCA1, ATM, ATR, MDC1, and Mre11 was found in 21.4%, 20.2%, 21.0%, 11.1% and 4.6%, respectively, of interpretable cases. BRCA1 loss was significantly associated with patients of diffused subtype (intestinal vs diffused, 8.2% vs 31.7%, P = 0.001), higher tumor grade (I/II vs III, 10.7% vs 20.5; I/II vs IV, 10.7% vs 54.5%, P = 0.047) and advanced clinical stage (I/II vs III, 12.9% vs 16.9%; I/II vs IV, 12.9% vs 45.5%, P = 0.006). MDC1 loss was significantly associated with patients of diffused subtype (intestinal vs diffused, 0% vs 19.7%, P = 0.001) and higher tumor grade (I/II vs III, 0% vs 12%; I/II vs IV, 0% vs 30.8%, P = 0.012). In addition, the survival time of the patients with expression loss of BRCA1 was significantly shorter than those with positive expression of BRCA1 (2-year survival rate, 32.4% vs 62.8%, P = 0.015). No correlations were found between clinicopathological parameters and expression loss of ATM, ATR and Mre11.

CONCLUSION: Our results support the hypothesis that homologous recombination deficiency plays an important role in the progression of gastric carcinoma. Loss of expression of BRCA1 and MDC1 may serve as predictive factors in tumor development or progression in GC patients.

• Homologous recombination deficiency
• Gastric cancer
• Breast cancer type 1 susceptibility protein
• Mediator of DNA damage checkpoint protein 1
• Ataxia telangiectasia mutated
• Ataxia telangiectasia mutated-Rad3-related

• Adaptor Proteins, Signal Transducing
• Adenocarcinoma/genetics
• Adenocarcinoma/metabolism
• Adenocarcinoma/mortality
• Adenocarcinoma/pathology
• Adult
• Aged
• Aged, 80 and over
• Ataxia Telangiectasia Mutated Proteins/metabolism
• BRCA1 Protein/metabolism
• Biomarkers, Tumor/metabolism
• Cell Cycle Proteins
• China/epidemiology
• DNA-Binding Proteins/metabolism
• Female
• Genes, BRCA1
• Homologous Recombination
• Humans
• MRE11 Homologue Protein
• Male
• Middle Aged
• Nuclear Proteins/metabolism
• Stomach/pathology
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/mortality
• Stomach Neoplasms/pathology
• Trans-Activators/metabolism
• Young Adult

• Adenocarcinoma/metabolism
• Adenocarcinoma/secondary
• Ataxia Telangiectasia Mutated Proteins
• Biomarkers, Tumor/analysis
• Biopsy
• Cell Cycle Proteins/analysis
• Cell Cycle Proteins/biosynthesis
• DNA-Binding Proteins/analysis
• DNA-Binding Proteins/biosynthesis
• Female
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• Protein Serine-Threonine Kinases/analysis
• Protein Serine-Threonine Kinases/biosynthesis
• Sensitivity and Specificity
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Tissue Array Analysis
• Tumor Suppressor Proteins/analysis
• Tumor Suppressor Proteins/biosynthesis

• Adult
• Aged
• Ataxia Telangiectasia Mutated Proteins
• Biomarkers, Tumor/metabolism
• Cell Cycle Proteins/metabolism
• Cyclin B1/metabolism
• DNA-Binding Proteins/metabolism
• Female
• Humans
• Male
• Middle Aged
• Neoplasm Staging
• Neuroendocrine Tumors/metabolism
• Neuroendocrine Tumors/mortality
• Neuroendocrine Tumors/pathology
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/mortality
• Pancreatic Neoplasms/pathology
• Prognosis
• Protein Serine-Threonine Kinases/metabolism
• Tumor Suppressor Proteins/metabolism

• Adenocarcinoma/genetics
• Adenocarcinoma/microbiology
• Adenocarcinoma/pathology
• Chromosomal Instability
• Chromosome Segregation
• Chromosomes, Human/genetics
• DNA Damage
• DNA Repair
• Environment
• Epigenesis, Genetic
• Gene-Environment Interaction
• Genome, Human
• Helicobacter Infections/microbiology
• Humans
• Microsatellite Instability
• Signal Transduction
• Stomach Neoplasms/genetics
• Stomach Neoplasms/microbiology
• Stomach Neoplasms/pathology

Poly-ADP ribose polymerase (PARP) inhibitors have shown promise in the treatment of human malignancies characterized by deficiencies in the DNA damage repair proteins BRCA1 and BRCA2 and preclinical studies have demonstrated the potential effectiveness of PARP inhibitors in targeting ataxia-telangiectasia mutated (ATM)-deficient tumours. Here, we show that mantle cell lymphoma (MCL) cells deficient in both ATM and p53 are more sensitive to the PARP inhibitor olaparib than cells lacking ATM function alone. In ATM-deficient MCL cells, olaparib induced DNA-PK-dependent phosphorylation and stabilization of p53 as well as expression of p53-responsive cell cycle checkpoint regulators, and inhibition of DNA-PK reduced the toxicity of olaparib in ATM-deficient MCL cells. Thus, both DNA-PK and p53 regulate the response of ATM-deficient MCL cells to olaparib. In addition, small molecule inhibition of both ATM and PARP was cytotoxic in normal human fibroblasts with disruption of p53, implying that the combination of ATM and PARP inhibitors may have utility in targeting p53-deficient malignancies.

Ataxia-Telangiectasia syndrome is characterized by progressive cerebellar dysfunction, conjuctival and cutaneous telangiectasias, severe immune deficiencies, premature aging and predisposition to cancer. Clinical and radiographic evaluation for malignancy in ataxia-telangiectasia patients is usually atypical, leading to delays in diagnosis.

We report the case of a 20 year old ataxia-telangiectasia patient with gastric adenocarcinoma that presented as complete gastric outlet obstruction.

A literature search of adenocarcinoma associated with ataxia-telangiectasia revealed 6 cases. All patients presented with non-specific gastrointestinal complaints suggestive of ulcer disease. Although there was no correlation between immunoglobulin levels and development of gastric adenocarcinoma, the presence of chronic gastritis and intestinal metaplasia seem to lead to the development of gastric adenocarcinoma. One should consider adenocarcinoma in any patient with ataxia-telangiectasia who presents with non-specific gastrointestinal complaints, since this can lead to earlier diagnosis.

• Anesthesia, Conduction/adverse effects
• Humans
• Ophthalmologic Surgical Procedures/adverse effects
• Ophthalmologic Surgical Procedures/methods
• Orbit/surgery
• Postoperative Complications/etiology
• Postoperative Complications/prevention & control