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ATM; ATM serine/threonine kinase (11q22-q23)

Gene Summary

Gene:ATM; ATM serine/threonine kinase
Aliases: AT1, ATA, ATC, ATD, ATE, ATDC, TEL1, TELO1
Location:11q22-q23
Summary:The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:serine-protein kinase ATM
HPRD
Source:NCBI
Updated:14 December, 2014

Gene
Ontology:

What does this gene/protein do?
Show (50)

Pathways:

What pathways are this gene/protein implicaed in?
- Apoptotic Signaling in Response to DNA Damage BIOCARTA
- ATM Signaling Pathway BIOCARTA
- cdc25 and chk1 Regulatory Pathway in response to DNA damage BIOCARTA
- Cell Cycle BIOCARTA
- Cell Cycle BIOCARTA
- Hypoxia and p53 in the Cardiovascular system BIOCARTA
- p53 Signaling Pathway BIOCARTA
- RB Tumor Suppressor/Checkpoint Signaling in response to DNA damage BIOCARTA
- Regulation of cell cycle progression by Plk3 BIOCARTA
- Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility BIOCARTA
- Apoptosis KEGG
- Cell cycle KEGG
- Toll-like receptor signaling pathway KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Staging
  • Breast Cancer
  • Antineoplastic Agents
  • Proto-Oncogene Proteins
  • cdc25 Phosphatases
  • Protein-Serine-Threonine Kinases
  • Single Nucleotide Polymorphism
  • X-Rays
  • Eye Cancer
  • DNA Sequence Analysis
  • DNA Repair
  • Zinc Fingers
  • Cancer Gene Expression Regulation
  • Cell Proliferation
  • Ultraviolet Rays
  • Rectum
  • Histones
  • RNA Interference
  • TOR Serine-Threonine Kinases
  • Chronic Lymphocytic Leukemia
  • Zinostatin
  • Uveal Neoplasms
  • Chromosome 11
  • Thyroid Cancer
  • Promoter Regions
  • Telomere
  • DNA-Binding Proteins
  • Up-Regulation
  • Taiwan
  • Apoptosis
  • Toll-Like Receptor 2
  • Subcellular Fractions
  • Wnt1 Protein
  • DNA Damage
  • Cell Survival
  • Nuclear Proteins
  • Genetic Predisposition
  • p38 Mitogen-Activated Protein Kinases
  • Ataxia Telangiectasia Mutated Proteins
  • Double-Stranded DNA Breaks
  • Cell Cycle Proteins
Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (4)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerATM and Breast Cancer View Publications341
Chronic Lymphocytic LeukemiaATM and Chronic Lymphocytic Leukemia View Publications143
Thyroid CancerATM and Thyroid Cancer View Publications11
Eye CancerATM and Uveal Neoplasms View Publications1

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: ATM (cancer-related)

Zhang P, Wei Y, Wang L, et al.
ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1.
Nat Cell Biol. 2014; 16(9):864-75 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Epithelial-mesenchymal transition (EMT) is associated with characteristics of breast cancer stem cells, including chemoresistance and radioresistance. However, it is unclear whether EMT itself or specific EMT regulators play causal roles in these properties. Here we identify an EMT-inducing transcription factor, zinc finger E-box binding homeobox 1 (ZEB1), as a regulator of radiosensitivity and DNA damage response. Radioresistant subpopulations of breast cancer cells derived from ionizing radiation exhibit hyperactivation of the kinase ATM and upregulation of ZEB1, and the latter promotes tumour cell radioresistance in vitro and in vivo. Mechanistically, ATM phosphorylates and stabilizes ZEB1 in response to DNA damage, ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitylate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation. These findings identify ZEB1 as an ATM substrate linking ATM to CHK1 and the mechanism underlying the association between EMT and radioresistance.

Related: Breast Cancer TWIST1


Yan HQ, Huang XB, Ke SZ, et al.
Interleukin 6 augments lung cancer chemotherapeutic resistance via ataxia-telangiectasia mutated/NF-kappaB pathway activation.
Cancer Sci. 2014; 105(9):1220-7 [PubMed] Related Publications
Although it is known that ataxia-telangiectasia mutated (ATM) and interleukin 6 (IL-6) contribute to multiple drug resistance (MDR) in tumor chemotherapy, the exact role of ATM activation in MDR resulting from increased IL-6 expression is still unclear. In the present study, we demonstrate that the activation of the ATM-NF-kappaB pathway, resulting from increased IL-6 expression, plays a central role in augmented chemoresistance in lung cancer cell lines. This result was supported by the increased expressions of Bcl-2, Mcl-1, Bcl-xl, and the upregulation of MDR-associated protein ABCG2. The higher level of IL-6 reveals not only higher ATM/NF-kappaB activity but also increased expressions of ABCG2, Bcl-2, Mcl-1 and Bcl-xl. Most importantly, lung cancer cells themselves upregulated IL-6 secretion by activating the p38/NF-kappaB pathway through treatment with cisplatin and camptothecin. Taken together, these findings demonstrate that chemotherapeutic agents increase IL-6 expression, hence activating the ATM/NF-kappaB pathway, augmenting anti-apoptotic protein expression and contributing to MDR. This indicates that both IL-6 and ATM are potential targets for the treatment of chemotherapeutic resistance in lung cancer.

Related: Cisplatin Lung Cancer Risk Factors and Prevention of Lung Cancer ABCG2 MCL1


Silva FC, Lisboa BC, Figueiredo MC, et al.
Hereditary breast and ovarian cancer: assessment of point mutations and copy number variations in Brazilian patients.
BMC Med Genet. 2014; 15:55 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: Germ line mutations in BRCA1 and BRCA2 (BRCA1/2) and other susceptibility genes have been identified as genetic causes of hereditary breast and ovarian cancer (HBOC). To identify the disease-causing mutations in a cohort of 120 Brazilian women fulfilling criteria for HBOC, we carried out a comprehensive screening of BRCA1/2, TP53 R337H, CHEK2 1100delC, followed by an analysis of copy number variations in 14 additional breast cancer susceptibility genes (PTEN, ATM, NBN, RAD50, RAD51, BRIP1, PALB2, MLH1, MSH2, MSH6, TP53, CDKN2A, CDH1 and CTNNB1).
METHODS: Capillary sequencing and multiplex ligation-dependent probe amplification (MLPA) were used for detecting point mutations and copy number variations (CNVs), respectively, for the BRCA1 and BRCA2 genes; capillary sequencing was used for point mutation for both variants TP53 R337H and CHEK2 1100delC, and finally array comparative genomic hybridization (array-CGH) was used for identifying CNVs in the 14 additional genes.
RESULTS: The positive detection rate in our series was 26%. BRCA1 pathogenic mutations were found in 20 cases, including two cases with CNVs, whereas BRCA2 mutations were found in 7 cases. We also found three patients with the TP53 R337H mutation and one patient with the CHEK2 1100delC mutation. Seven (25%) pathogenic mutations in BRCA1/2 were firstly described, including a splice-site BRCA1 mutation for which pathogenicity was confirmed by the presence of an aberrant transcript showing the loss of the last 62 bp of exon 7. Microdeletions of exon 4 in ATM and exon 2 in PTEN were identified in BRCA2-mutated and BRCA1/2-negative patients, respectively.
CONCLUSIONS: In summary, our results showed a high frequency of BRCA1/2 mutations and a higher prevalence of BRCA1 (64.5%) gene. Moreover, the detection of the TP53 R337H variant in our series and the fact that this variant has a founder effect in our population prompted us to suggest that all female breast cancer patients with clinical criteria for HBOC and negative for BRCA1/2 genes should be tested for the TP53 R337H variant. Furthermore, the presence of genomic structural rearrangement resulting in CNVs in other genes that predispose breast cancer in conjunction with BRCA2 point mutations demonstrated a highly complex genetic etiology in Brazilian breast cancer families.

Related: CHEK2 CGH BRCA1 BRCA2 TP53


Zhang JW, Zhang SS, Song JR, et al.
Autophagy inhibition switches low-dose camptothecin-induced premature senescence to apoptosis in human colorectal cancer cells.
Biochem Pharmacol. 2014; 90(3):265-75 [PubMed] Related Publications
Recently, several studies indicated that senescent tumor cells are resistant to apoptosis in chemotherapy. They may return to cell cycle, thus act as stumbling blocks in anticancer treatments. In the present study, we found that, in human colorectal cancer cells, low-dose camptothecin (CPT) simultaneously induced autophagy and premature senescence through AMPK-TSC2-mTOR pathway and ATM-Chk2-p53-p21 pathway respectively. What's important is the suppression of autophagy substantially increased apoptosis and greatly attenuated senescence possibly by blocking p53/p21 pathway, which suggests that autophagy plays an indispensable role in sustaining cell senescence caused by low-dose CPT. The combination of low-dose CPT and autophagy inhibitor, a way to lead senescent cells to die, would be potentially valuable in cancer therapy.

Related: Apoptosis Colorectal (Bowel) Cancer Signal Transduction TP53


Sasca D, Hähnel PS, Szybinski J, et al.
SIRT1 prevents genotoxic stress-induced p53 activation in acute myeloid leukemia.
Blood. 2014; 124(1):121-33 [PubMed] Related Publications
SIRT1 is an important regulator of cellular stress response and genomic integrity. Its role in tumorigenesis is controversial. Whereas sirtuin 1 (SIRT1) can act as a tumor suppressor in some solid tumors, increased expression has been demonstrated in many cancers, including hematologic malignancies. In chronic myeloid leukemia, SIRT1 promoted leukemia development, and targeting SIRT1 sensitized chronic myeloid leukemia progenitors to tyrosine kinase inhibitor treatment. In this study, we investigated the role of SIRT1 in acute myeloid leukemia (AML). We show that SIRT1 protein, but not RNA levels, is overexpressed in AML samples harboring activating mutations in signaling pathways. In FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)(+)-cells protein, expression of SIRT1 is regulated by FLT3 kinase activity. In addition, SIRT1 function is modulated via the ATM-DBC1-SIRT1 axis in a FLT3-ITD-dependent manner. In murine leukemia models driven by MLL-AF9 or AML1-ETO coexpressing FLT3-ITD, SIRT1 acts as a safeguard to counteract oncogene-induced stress, and leukemic blasts become dependent on SIRT1 activity. Pharmacologic targeting or RNAi-mediated knockdown of SIRT1 inhibited cell growth and sensitized AML cells to tyrosine kinase inhibitor treatment and chemotherapy. This effect was a result of the restoration of p53 activity. Our data suggest that targeting SIRT1 represents an attractive therapeutic strategy to overcome primary resistance in defined subsets of patients with AML.

Related: Acute Myeloid Leukemia (AML) Signal Transduction TP53


Oshrine BR, Olsen MN, Heneghan M, et al.
Acquired isochromosome 12p, somatic TP53 and PTEN mutations, and a germline ATM variant in an adolescent male with concurrent acute megakaryoblastic leukemia and mediastinal germ cell tumor.
Cancer Genet. 2014; 207(4):153-9 [PubMed] Related Publications
Previous reports have described an association between hematologic malignancies (HMs) and extragonadal germ cell tumor (GCT). Most patients have been adolescent males with mediastinal nonseminomatous GCT. Although a variety of HMs have been reported, there is a striking predilection toward acute megakaryoblastic leukemia (AMKL). Shared cytogenetic anomalies--particularly isochromosome 12p [i(12p)]--have suggested common clonal origins to the tumors. We report the case of a 17-year-old boy presenting with AMKL and a synchronous mediastinal GCT, with the characteristic i(12p) in both neoplasms. The common clonal origin of the AMKL and GCT was further confirmed with massively parallel sequencing, which identified somatic TP53 and PTEN mutations, as well as a rare germline ATM variant. Although these represent commonly mutated genes in cancer, this combination of mutations is not typically associated with either GCT or AMKL, suggesting that these tumors may represent unique biologic entities when they co-occur.

Related: Chromosome 12 FISH Germ Cell Tumors PTEN TP53


Liu X, Mody K, de Abreu FB, et al.
Molecular profiling of appendiceal epithelial tumors using massively parallel sequencing to identify somatic mutations.
Clin Chem. 2014; 60(7):1004-11 [PubMed] Related Publications
BACKGROUND: Some epithelial neoplasms of the appendix, including low-grade appendiceal mucinous neoplasm and adenocarcinoma, can result in pseudomyxoma peritonei (PMP). Little is known about the mutational spectra of these tumor types and whether mutations may be of clinical significance with respect to therapeutic selection. In this study, we identified somatic mutations using the Ion Torrent AmpliSeq Cancer Hotspot Panel v2.
METHODS: Specimens consisted of 3 nonneoplastic retention cysts/mucocele, 15 low-grade mucinous neoplasms (LAMNs), 8 low-grade/well-differentiated mucinous adenocarcinomas with pseudomyxoma peritonei, and 12 adenocarcinomas with/without goblet cell/signet ring cell features. Barcoded libraries were prepared from up to 10 ng of extracted DNA and multiplexed on single 318 chips for sequencing. Data analysis was performed using Golden Helix SVS. Variants that remained after the analysis pipeline were individually interrogated using the Integrative Genomics Viewer.
RESULTS: A single Janus kinase 3 (JAK3) mutation was detected in the mucocele group. Eight mutations were identified in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and GNAS complex locus (GNAS) genes among LAMN samples. Additional gene mutations were identified in the AKT1 (v-akt murine thymoma viral oncogene homolog 1), APC (adenomatous polyposis coli), JAK3, MET (met proto-oncogene), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), RB1 (retinoblastoma 1), STK11 (serine/threonine kinase 11), and tumor protein p53 (TP53) genes. Among the PMPs, 6 mutations were detected in the KRAS gene and also in the GNAS, TP53, and RB1 genes. Appendiceal cancers showed mutations in the APC, ATM (ataxia telangiectasia mutated), KRAS, IDH1 [isocitrate dehydrogenase 1 (NADP+)], NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog], PIK3CA, SMAD4 (SMAD family member 4), and TP53 genes.
CONCLUSIONS: Our results suggest molecular heterogeneity among epithelial tumors of the appendix. Next generation sequencing efforts have identified mutational spectra in several subtypes of these tumors that may suggest a phenotypic heterogeneity showing mutations that are relevant for targeted therapies.

Related: Appendix Cancers Gastrointestinal Carcinoid Tumours


Lee SH, Cheng H, Yuan Y, Wu S
Regulation of ionizing radiation-induced adhesion of breast cancer cells to fibronectin by alpha5beta1 integrin.
Radiat Res. 2014; 181(6):650-8 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Ionizing radiation (IR) is commonly used for cancer therapy, however, its potential influence on cancer metastatic potential remains controversial. In this study, we elucidated the role of integrins in regulation of IR-altered adhesion between breast cancer cells and extracellular matrix (ECM) proteins, which is a key step in the initial phase of metastasis. Our data suggest that the extent of effect that ionizing radiation had on cell adhesion depended on the genetic background of the breast cancer cells. Ionizing radiation was a better adhesion inducer for p53-mutated cells, such as MDA-MB-231 cells, than for p53 wild-type cells, such as MCF-7 cells. While IR-induced adhesions between MDA-MB-231 cells to fibronectin, laminin, collagen I and collagen IV, only blocking of the adhesion between α5β1 integrin and fibronectin using anti-α5β1 integrin antibody could completely inhibit the radiation-induced adhesion of the cells. A soluble Arg-Gly-Asp peptide, the binding motif for fibronectin binding integrins, could also reduce the adhesion of the cells to fibronectin with or without ionizing radiation exposure. The inhibition of the cell-fibronectin interaction also affected, but did not always correlate with, transwell migration of the cancer cells. In addition, our data showed that the total expression of α5 integrin and surface expression of α5β1 integrin were increased in the cells treated with ionizing radiation. The increased surface expression of α5β1 integrin, along with the adhesion between the cells and fibronectin, could be inhibited by both ataxia telangiectasia mutated (ATM) and Rad3-related (ATR) kinase inhibitors. These results suggested that ATM/ATR-mediated surface expression of α5β1 integrin might play a central role in regulation of ionizing radiation-altered adhesion.

Related: Breast Cancer


Kang J, Deng XZ, Fan YB, Wu B
Relationships of FOXE1 and ATM genetic polymorphisms with papillary thyroid carcinoma risk: a meta-analysis.
Tumour Biol. 2014; 35(7):7085-96 [PubMed] Related Publications
We conducted the meta-analysis of all relevant case-control studies aiming to evaluate the relationships of common polymorphisms in forkhead box E1 (FOXE1) and ataxia telangiectasia mutated (ATM) genes to the risk of papillary thyroid carcinoma (PTC). A range of electronic databases were searched without language restrictions: Web of Science (1945 ~ 2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966 ~ 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013). This meta-analysis was conducted using the STATA 12.0 software. Crude odds ratio (OR) with their 95 % confidence interval (CI) were calculated. Eight case-control studies with 2,085 PTC patients and 10,341 healthy controls were included. Fourteen common polymorphisms were evaluated, including rs3758249 A > G, rs907577 G > A, rs1867277 G > A, rs3021526 C > T, rs1443434 G > T, rs907580 G > A, rs965513 A > G, rs944289 C > T, and rs189037 G > A polymorphisms in the FOXE1 gene and rs373759 G > A, rs4988099 A > G, rs1801516 G > A, rs664677 T > C, and rs609429 G > C polymorphisms in the ATM gene. Our results demonstrated that the FOXE genetic polymorphisms might be closely related to an increased risk of developing PTC under five genetic models (all P < 0.005), especially for rs3758249, rs907577, rs1867277, rs3021526, rs1443434, rs907580, rs704839, rs894673, and rs10119760 polymorphisms. Nevertheless, no positive associations were found between the ATM genetic polymorphisms and the development of PTC (all P > 0.05). The current meta-analysis provided evidence that FOXE1 genetic polymorphisms may contribute to increased PTC risk, especially for rs3758249, rs907577, rs1867277, rs3021526, rs1443434, rs907580, rs704839, rs894673, and rs10119760 polymorphisms. However, the ATM genetic polymorphisms may not be important dominants of susceptibility to PTC.

Related: Thyroid Cancer


Kurian AW, Hare EE, Mills MA, et al.
Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment.
J Clin Oncol. 2014; 32(19):2001-9 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
PURPOSE: Multiple-gene sequencing is entering practice, but its clinical value is unknown. We evaluated the performance of a customized germline-DNA sequencing panel for cancer-risk assessment in a representative clinical sample.
METHODS: Patients referred for clinical BRCA1/2 testing from 2002 to 2012 were invited to donate a research blood sample. Samples were frozen at -80° C, and DNA was extracted from them after 1 to 10 years. The entire coding region, exon-intron boundaries, and all known pathogenic variants in other regions were sequenced for 42 genes that had cancer risk associations. Potentially actionable results were disclosed to participants.
RESULTS: In total, 198 women participated in the study: 174 had breast cancer and 57 carried germline BRCA1/2 mutations. BRCA1/2 analysis was fully concordant with prior testing. Sixteen pathogenic variants were identified in ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4 among 141 women without BRCA1/2 mutations. Fourteen participants carried 15 pathogenic variants, warranting a possible change in care; they were invited for targeted screening recommendations, enabling early detection and removal of a tubular adenoma by colonoscopy. Participants carried an average of 2.1 variants of uncertain significance among 42 genes.
CONCLUSION: Among women testing negative for BRCA1/2 mutations, multiple-gene sequencing identified 16 potentially pathogenic mutations in other genes (11.4%; 95% CI, 7.0% to 17.7%), of which 15 (10.6%; 95% CI, 6.5% to 16.9%) prompted consideration of a change in care, enabling early detection of a precancerous colon polyp. Additional studies are required to quantify the penetrance of identified mutations and determine clinical utility. However, these results suggest that multiple-gene sequencing may benefit appropriately selected patients.

Related: Breast Cancer Breast Cancer Screening Cancer Screening and Early Detection


McFadden DG, Vernon A, Santiago PM, et al.
p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer.
Proc Natl Acad Sci U S A. 2014; 111(16):E1600-9 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Anaplastic thyroid carcinoma (ATC) has among the worst prognoses of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene homolog B (BRAF) and tumor protein p53 (TP53) mutations cooccur in a high proportion of ATCs, particularly those associated with a precursor papillary thyroid carcinoma (PTC). To develop an adult-onset model of BRAF-mutant ATC, we generated a thyroid-specific CreER transgenic mouse. We used a Cre-regulated Braf(V600E) mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from PTC to ATC. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis, and rapid lethality. We used small-animal ultrasound imaging to monitor autochthonous tumors and showed that treatment with the selective BRAF inhibitor PLX4720 improved survival but did not lead to tumor regression or suppress signaling through the MAPK pathway. The combination of PLX4720 and the mapk/Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small-molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma.

Related: BRAF gene Thyroid Cancer TP53


Nagarajan A, Dogra SK, Liu AY, et al.
PEA15 regulates the DNA damage-induced cell cycle checkpoint and oncogene-directed transformation.
Mol Cell Biol. 2014; 34(12):2264-82 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Regulation of the DNA damage response and cell cycle progression is critical for maintaining genome integrity. Here, we report that in response to DNA damage, COPS5 deubiquitinates and stabilizes PEA15 in an ATM kinase-dependent manner. PEA15 expression oscillates throughout the cell cycle, and the loss of PEA15 accelerates cell cycle progression by activating CDK6 expression via the c-JUN transcription factor. Cells lacking PEA15 exhibit a DNA damage-induced G2/M checkpoint defect due to increased CDC25C activity and, consequentially, higher cyclin-dependent kinase 1 (CDK1)/cyclin B activity, and accordingly they have an increased rate of spontaneous mutagenesis. We find that oncogenic RAS inhibits PEA15 expression and that ectopic PEA15 expression blocks RAS-mediated transformation, which can be partially rescued by ectopic expression of CDK6. Finally, we show that PEA15 expression is downregulated in colon, breast, and lung cancer samples. Collectively, our results demonstrate that tumor suppressor PEA15 is a regulator of genome integrity and is an integral component of the DNA damage response pathway that regulates cell cycle progression, the DNA-damage-induced G2/M checkpoint, and cellular transformation.

Related: CDK6 gene


Gutierrez A, Feng H, Stevenson K, et al.
Loss of function tp53 mutations do not accelerate the onset of myc-induced T-cell acute lymphoblastic leukaemia in the zebrafish.
Br J Haematol. 2014; 166(1):84-90 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
The TP53 tumour suppressor is activated in response to distinct stimuli, including an ARF-dependent response to oncogene stress and an ATM/ATR-dependent response to DNA damage. In human T-cell acute lymphoblastic leukaemia (T-ALL), TP53-dependent tumour suppression is typically disabled via biallelic ARF deletions. In murine models, loss of Arf (Cdkn2a) or Tp53 markedly accelerates the onset of Myc-induced lymphoblastic malignancies. In zebrafish, no ARF ortholog has been identified, but the sequence of ARF is very poorly conserved evolutionarily, making it difficult to exclude the presence of a zebrafish ARF ortholog without functional studies. Here we show that tp53 mutations have no significant influence on the onset of myc-induced T-ALL in zebrafish, consistent with the lack of additional effects of Tp53 loss on lymphomagenesis in Arf-deficient mice. By contrast, irradiation leads to complete T-ALL regression in tp53 wild-type but not homozygous mutant zebrafish, indicating that the tp53-dependent DNA damage response is intact. We conclude that tp53 inactivation has no impact on the onset of myc-induced T-ALL in the zebrafish, consistent with the lack of a functional ARF ortholog linking myc-induced oncogene stress to tp53-dependent tumour suppression. Thus, the zebrafish model is well suited to the study of ARF-independent pathways in T-ALL pathobiology.

Related: Apoptosis


Mackay C, Carroll E, Ibrahim AF, et al.
E3 ubiquitin ligase HOIP attenuates apoptotic cell death induced by cisplatin.
Cancer Res. 2014; 74(8):2246-57 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
The genotoxin cisplatin is commonly used in chemotherapy to treat solid tumors, yet our understanding of the mechanism underlying the drug response is limited. In a focused siRNA screen, using an siRNA library targeting genes involved in ubiquitin and ubiquitin-like signaling, we identified the E3 ubiquitin ligase HOIP as a key regulator of cisplatin-induced genotoxicity. HOIP forms, with SHARPIN and HOIL-1L, the linear ubiquitin assembly complex (LUBAC). We show that cells deficient in the HOIP ligase complex exhibit hypersensitivity to cisplatin. This is due to a dramatic increase in caspase-8/caspase-3-mediated apoptosis that is strictly dependent on ATM-, but not ATR-mediated DNA damage checkpoint activation. Moreover, basal and cisplatin-induced activity of the stress response kinase JNK is enhanced in HOIP-depleted cells and, conversely, JNK inhibition can increase cellular resistance to cisplatin and reverse the apoptotic hyperactivation in HOIP-depleted cells. Furthermore, we show that HOIP depletion sensitizes cancer cells, derived from carcinomas of various origins, through an enhanced apoptotic cell death response. We also provide evidence that ovarian cancer cells classified as cisplatin-resistant can regain sensitivity following HOIP downregulation. Cumulatively, our study identifies a HOIP-regulated antiapoptotic signaling pathway, and we envisage HOIP as a potential target for the development of combinatorial chemotherapies to potentiate the efficacy of platinum-based anticancer drugs.

Related: Apoptosis Cisplatin MAP2K4 gene Ovarian Cancer Signal Transduction


Zhang J, Jima D, Moffitt AB, et al.
The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells.
Blood. 2014; 123(19):2988-96 [PubMed] Article available free on PMC after 08/05/2015 Related Publications
In this study, we define the genetic landscape of mantle cell lymphoma (MCL) through exome sequencing of 56 cases of MCL. We identified recurrent mutations in ATM, CCND1, MLL2, and TP53. We further identified a number of novel genes recurrently mutated in patients with MCL including RB1, WHSC1, POT1, and SMARCA4. We noted that MCLs have a distinct mutational profile compared with lymphomas from other B-cell stages. The ENCODE project has defined the chromatin structure of many cell types. However, a similar characterization of primary human mature B cells has been lacking. We defined, for the first time, the chromatin structure of primary human naïve, germinal center, and memory B cells through chromatin immunoprecipitation and sequencing for H3K4me1, H3K4me3, H3Ac, H3K36me3, H3K27me3, and PolII. We found that somatic mutations that occur more frequently in either MCLs or Burkitt lymphomas were associated with open chromatin in their respective B cells of origin, naïve B cells, and germinal center B cells. Our work thus elucidates the landscape of gene-coding mutations in MCL and the critical interplay between epigenetic alterations associated with B-cell differentiation and the acquisition of somatic mutations in cancer.

Related: Mantle Cell Lymphoma RB1 TP53 MLL2 gene POT1


Hornhardt S, Rößler U, Sauter W, et al.
Genetic factors in individual radiation sensitivity.
DNA Repair (Amst). 2014; 16:54-65 [PubMed] Related Publications
Cancer risk and radiation sensitivity are often associated with alterations in DNA repair, cell cycle, or apoptotic pathways. Interindividual variability in mutagen or radiation sensitivity and in cancer susceptibility may also be traced back to polymorphisms of genes affecting e.g. DNA repair capacity. We studied possible associations between 70 polymorphisms of 12 DNA repair genes with basal and initial DNA damage and with repair thereof. We investigated DNA damage induced by ionizing radiation in lymphocytes isolated from 177 young lung cancer patients and 169 cancer-free controls. We also sought replication of our findings in an independent sample of 175 families (in total 798 individuals). DNA damage was assessed by the Olive tail moment (OTM) of the comet assay. DNA repair capacity (DRC) was determined for 10, 30 and, 60min of repair. Genes involved in the single-strand-repair pathway (SSR; like XRCC1 and MSH2) as well as genes involved in the double-strand-repair pathway (DSR; like RAD50, XRCC4, MRE11 and ATM) were found to be associated with DNA damage. The most significant association was observed for marker rs3213334 (p=0.005) of XRCC1 with basal DNA damage (B), in both cases and controls. A clear additive effect on the logarithm of OTM was identified for the marker rs1001581 of the same LD-block (p=0.039): BCC=-1.06 (95%-CI: -1.16 to -0.96), BCT=-1.02 (95%-CI: -1.11 to -0.93) and BTT=-0.85 (95%-CI: -1.01 to -0.68). In both cases and controls, we observed significantly higher DNA basal damage (p=0.007) for carriers of the genotype AA of marker rs2237060 of RAD50 (involved in DSR). However, this could not be replicated in the sample of families (p=0.781). An alteration to DRC after 30min of repair with respect to cases was observed as borderline significant for marker rs611646 of ATM (involved in DSR; p=0.055), but was the most significant finding in the sample of families (p=0.009). Our data indicate that gene variation impacts measurably on DNA damage and repair, suggesting at least a partial contribution to radiation sensitivity and lung cancer susceptibility.

Related: Lung Cancer


Alkema NG, Tomar T, van der Zee AG, et al.
Checkpoint kinase 2 (Chk2) supports sensitivity to platinum-based treatment in high grade serous ovarian cancer.
Gynecol Oncol. 2014; 133(3):591-8 [PubMed] Related Publications
OBJECTIVE: Platinum-based chemotherapy is the standard treatment in advanced stage high grade serous ovarian cancer (HGSOC), but the majority of patients will relapse with drug-resistant disease. Platinum induces double-strand DNA breaks and subsequently activation of the DNA damage response (DDR). Drugs targeting DDR pathway components have gained major interest to be combined with chemotherapy as they could increase the therapeutic window. In the present study, we investigated the activation status of the Ataxia Telangiectasia Mutated (ATM) signaling axis within the DDR in a large, well-defined cohort of advanced stage HGSOC patients.
METHODS: Pre-therapy activation status of the ATM signaling axis of the DDR was determined by immunohistochemistry in 125 chemo-naive advanced stage HGSOC patients. Ovarian cancer cell lines with stable checkpoint kinase 2 (Chk2) knock down were used to study cell cycle distribution and survival in long-term clonogenic survival assays.
RESULTS: All ATM signaling axis components showed high expression levels. In two well-defined groups with the largest contrast in treatment response, high expression of Chk2 was related to good response (OR=0.132; P=0.014). Chk2 depletion abrogated the cisplatin-induced S-phase cell cycle arrest and caused increased resistance to cisplatin in long-term clonogenic survival assays.
CONCLUSIONS: Chk2 is related to good response to platinum-based chemotherapy in advanced stage HGSOC patients. Chk2-depleted ovarian cancer cell lines have diminished platinum sensitivity, suggesting that Chk2 should not be considered a therapeutic target along with platinum-based treatment in HGSOC patients.

Related: CHEK2 Cisplatin Ovarian Cancer Signal Transduction


Usmani N, Leong N, Martell K, et al.
Single-nucleotide polymorphisms studied for associations with urinary toxicity from (125)I prostate brachytherapy implants.
Brachytherapy. 2014 May-Jun; 13(3):285-91 [PubMed] Related Publications
PURPOSE: To identify clinical, dosimetric, and genetic factors that are associated with late urinary toxicity after a (125)I prostate brachytherapy implant.
METHODS AND MATERIALS: Genomic DNA from 296 men treated with (125)I prostate brachytherapy monotherapy was extracted from saliva samples for this study. A retrospective database was compiled including clinical, dosimetric, and toxicity data for this cohort of patients. Fourteen candidate single-nucleotide polymorphism (SNPs) from 13 genes (TP53, ERCC2, GSTP1, NOS, TGFβ1, MSH6, RAD51, ATM, LIG4, XRCC1, XRCC3, GSTA1, and SOD2) were tested in this cohort for correlations with toxicity.
RESULTS: This study identified 217 men with at least 2 years of followup. Of these, 39 patients developed Grade ≥2 late urinary complications with a transurethral resection of prostate, urethral stricture, gross hematuria, or a sustained increase in their International Prostate Symptom Score. The only clinical or dosimetric factor that was associated with late urinary toxicity was age (p = 0.02). None of the 14 SNPs tested in this study were associated with late urinary toxicity in the univariate analysis.
CONCLUSIONS: This study identified age as the only variable being associated with late urinary toxicity. However, the small sample size and the candidate gene approach used in this study mean that further investigations are essential. Genome-wide association studies are emerging as the preferred approach for future radiogenomic studies to overcome the limitations from a candidate gene approach.

Related: Brachytherapy Prostate Cancer


Ma CQ, Yang Y, Wang JM, et al.
The aPKCι blocking agent ATM negatively regulates EMT and invasion of hepatocellular carcinoma.
Cell Death Dis. 2014; 5:e1129 [PubMed] Article available free on PMC after 08/05/2015 Related Publications
Epithelial-to-mesenchymal transition (EMT) has an important role in invasion and metastasis of hepatocellular carcinoma (HCC). To explore the regulatory mechanism of atypical protein kinase C ι (aPKCι) signaling pathways to HCC development, and find an agent for targeted therapy for HCC, immortalized murine hepatocytes were employed to establish an EMT cell model of HCC, MMH-RT cells. Our study showed that EMT took place in MMH-R cells under the effect of transforming growth factor-β1 (TGF-β1) overexpressing aPKCι. Furthermore, we showed that the aPKCι blocking agent aurothiomalate (ATM) inhibited EMT and decreased invasion of hepatocytes. Moreover, ATM selectively inhibited proliferation of mesenchymal cells and HepG2 cells and induced apoptosis. However, ATM increased proliferation of epithelial cells and had little effect on apoptosis and invasion of epithelial cells. In conclusion, our result suggested that aPKCι could be an important bio-marker of tumor EMT, and used as an indicator of invasion and malignancy. ATM might be a promising agent for targeted treatment of HCC.

Related: Apoptosis Liver Cancer Signal Transduction TGFB1


Morrison JA, Pike LA, Sams SB, et al.
Thioredoxin interacting protein (TXNIP) is a novel tumor suppressor in thyroid cancer.
Mol Cancer. 2014; 13:62 [PubMed] Article available free on PMC after 08/05/2015 Related Publications
BACKGROUND: Thyroid cancer is the most common endocrine malignancy, and many patients with metastatic differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC) fail to respond to conventional therapies, resulting in morbidity and mortality. Additional therapeutic targets and treatment options are needed for these patients. We recently reported that peroxisome proliferator-activated receptor gamma (PPARγ) is highly expressed in ATC and confers an aggressive phenotype when overexpressed in DTC cells.
METHODS: Microarray analysis was used to identify downstream targets of PPARγ in ATC cells. Western blot analysis and immunohistochemistry (IHC) were used to assess thioredoxin interacting protein (TXNIP) expression in thyroid cancer cell lines and primary tumor specimens. Retroviral transduction was used to generate ATC cell lines that overexpress TXNIP, and assays that assess glucose uptake, viable cell proliferation, and invasion were used to characterize the in vitro properties of these cells. An orthotopic thyroid cancer mouse model was used to assess the effect of TXNIP overexpression in ATC cell lines in vivo.
RESULTS: Using microarray analysis, we show that TXNIP is highly upregulated when PPARγ is depleted from ATC cells. Using Western blot analysis and IHC, we show that DTC and ATC cells exhibit differential TXNIP expression patterns. DTC cell lines and patient tumors have high TXNIP expression in contrast to low or absent expression in ATC cell lines and tumors. Overexpression of TXNIP decreases the growth of HTh74 cells compared to vector controls and inhibits glucose uptake in the ATC cell lines HTh74 and T238. Importantly, TXNIP overexpression in T238 cells results in attenuated tumor growth and decreased metastasis in an orthotopic thyroid cancer mouse model.
CONCLUSIONS: Our findings indicate that TXNIP functions as a tumor suppressor in thyroid cells, and its downregulation is likely important in the transition from differentiated to advanced thyroid cancer. These studies underscore the potential of TXNIP as a novel therapeutic target and prognostic indicator in advanced thyroid cancer.

Related: Thyroid Cancer TXNIP


Ramdzan ZM, Vadnais C, Pal R, et al.
RAS transformation requires CUX1-dependent repair of oxidative DNA damage.
PLoS Biol. 2014; 12(3):e1001807 [PubMed] Article available free on PMC after 08/05/2015 Related Publications
The Cut homeobox 1 (CUX1) gene is a target of loss-of-heterozygosity in many cancers, yet elevated CUX1 expression is frequently observed and is associated with shorter disease-free survival. The dual role of CUX1 in cancer is illustrated by the fact that most cell lines with CUX1 LOH display amplification of the remaining allele, suggesting that decreased CUX1 expression facilitates tumor development while increased CUX1 expression is needed in tumorigenic cells. Indeed, CUX1 was found in a genome-wide RNAi screen to identify synthetic lethal interactions with oncogenic RAS. Here we show that CUX1 functions in base excision repair as an ancillary factor for the 8-oxoG-DNA glycosylase, OGG1. Single cell gel electrophoresis (comet assay) reveals that Cux1⁺/⁻ MEFs are haploinsufficient for the repair of oxidative DNA damage, whereas elevated CUX1 levels accelerate DNA repair. In vitro base excision repair assays with purified components demonstrate that CUX1 directly stimulates OGG1's enzymatic activity. Elevated reactive oxygen species (ROS) levels in cells with sustained RAS pathway activation can cause cellular senescence. We show that elevated expression of either CUX1 or OGG1 prevents RAS-induced senescence in primary cells, and that CUX1 knockdown is synthetic lethal with oncogenic RAS in human cancer cells. Elevated CUX1 expression in a transgenic mouse model enables the emergence of mammary tumors with spontaneous activating Kras mutations. We confirmed cooperation between Kras(G12V) and CUX1 in a lung tumor model. Cancer cells can overcome the antiproliferative effects of excessive DNA damage by inactivating a DNA damage response pathway such as ATM or p53 signaling. Our findings reveal an alternate mechanism to allow sustained proliferation in RAS-transformed cells through increased DNA base excision repair capability. The heightened dependency of RAS-transformed cells on base excision repair may provide a therapeutic window that could be exploited with drugs that specifically target this pathway.

Related: CUX1


Wójcicka A, Czetwertyńska M, Świerniak M, et al.
Variants in the ATM-CHEK2-BRCA1 axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma.
Genes Chromosomes Cancer. 2014; 53(6):516-23 [PubMed] Article available free on PMC after 08/05/2015 Related Publications
The risk of developing papillary thyroid carcinoma (PTC), the most frequent form of thyroid malignancy, is elevated up to 8.6-fold in first-degree relatives of PTC patients. The familial risk could be explained by high-penetrance mutations in yet unidentified genes, or polygenic action of low-penetrance alleles. Since the DNA-damaging exposure to ionizing radiation is a known risk factor for thyroid cancer, polymorphisms in DNA repair genes are likely to affect this risk. In a search for low-penetrance susceptibility alleles we employed Sequenom technology to genotype deleterious polymorphisms in ATM, CHEK2, and BRCA1 in 1,781 PTC patients and 2,081 healthy controls. As a result of the study, we identified CHEK2 rs17879961 (OR = 2.2, P = 2.37e-10) and BRCA1 rs16941 (odds ratio [OR] = 1.16, P = 0.005) as risk alleles for PTC. The ATM rs1801516 variant modifies the risk associated with the BRCA1 variant by 0.78 (P = 0.02). Both the ATM and BRCA1 variants modify the impact of male gender on clinical variables: T status (P = 0.007), N status (P = 0.05), and stage (P = 0.035). Our findings implicate an important role of variants in the ATM- CHEK2- BRCA1 axis in modification of the genetic predisposition to PTC and its clinical manifestations.

Related: CHEK2 Thyroid Cancer


Alshareeda AT, Negm OH, Green AR, et al.
SUMOylation proteins in breast cancer.
Breast Cancer Res Treat. 2014; 144(3):519-30 [PubMed] Related Publications
Small Ubiquitin-like Modifier proteins (or SUMO) modify the function of protein substrates involved in various cellular processes including DNA damage response (DDR). It is becoming apparent that dysregulated SUMO contribute to carcinogenesis by affecting post-transcriptional modification of key proteins. It is hypothesised that SUMO contributes to the aggressive nature of breast cancer particularly those associated with features similar to breast carcinoma arising in patients with BRCA1 germline mutations. This study aims to assess the clinical and biological significance of three members of SUMO in a well-characterised annotated series of BC with emphasis on DDR. The study cohort comprised primary operable invasive BC including tumours from patients with known BRCA1 germline mutations. SUMO proteins PIAS1, PIAS4 and UBC9 were assessed using immunohistochemistry utilising tissue microarray technology. Additionally, their expression was assessed using reverse phase protein microarray utilising different cell lines. PIAS1 and UBC9 showed cytoplasmic and/or nuclear expression while PIAS4 was detected only in the nuclei. There was a correlation between subcellular localisation and expression of the nuclear transport protein KPNA2. Tumours showing positive nuclear/negative cytoplasmic expression of SUMO featured good prognostic characteristics including lower histologic grade and had a good outcome. Strong correlation with DDR-related proteins including BRCA1, Rad51, ATM, CHK1, DNA-PK and KU70/KU80 was observed. Correlation with ER and BRCA1 was confirmed using RPPA on cell lines. SUMO proteins seem to play important role in BC. Not only expression but also subcellular location is associated with BC phenotype.

Related: Breast Cancer


Lin SJ, Lee SO, Lee YF, et al.
TR4 nuclear receptor functions as a tumor suppressor for prostate tumorigenesis via modulation of DNA damage/repair system.
Carcinogenesis. 2014; 35(6):1399-406 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Testicular nuclear receptor 4 (TR4), a member of the nuclear receptor superfamily, plays important roles in metabolism, fertility and aging. The linkage of TR4 functions in cancer progression, however, remains unclear. Using three different mouse models, we found TR4 could prevent or delay prostate cancer (PCa)/prostatic intraepithelial neoplasia development. Knocking down TR4 in human RWPE1 and mouse mPrE normal prostate cells promoted tumorigenesis under carcinogen challenge, suggesting TR4 may play a suppressor role in PCa initiation. Mechanism dissection in both in vitro cell lines and in vivo mice studies found that knocking down TR4 led to increased DNA damage with altered DNA repair system that involved the modulation of ATM expression at the transcriptional level, and addition of ATM partially interrupted the TR4 small interfering RNA-induced tumorigenesis in cell transformation assays. Immunohistochemical staining in human PCa tissue microarrays revealed ATM expression is highly correlated with TR4 expression. Together, these results suggest TR4 may function as a tumor suppressor to prevent or delay prostate tumorigenesis via regulating ATM expression at the transcriptional level.

Related: PTEN Prostate Cancer


Watanabe Y, Maeda I, Oikawa R, et al.
Aberrant DNA methylation status of DNA repair genes in breast cancer treated with neoadjuvant chemotherapy.
Genes Cells. 2013; 18(12):1120-30 [PubMed] Related Publications
Dysregulation of homologous recombination (HR) DNA repair has been implicated in breast carcinogenesis and chemosensitivity. Here, we investigated the methylation status of sixteen HR genes and analyzed their association with tumor subtypes and responses to neoadjuvant chemotherapy. Core specimens were obtained before neoadjuvant chemotherapy from sixty cases of primary breast cancer of the following four subgroups: luminal breast cancer (LBC) with pathological complete response (pCR), LBC with stable disease, triple-negative breast cancer (TNBC) with pCR and TNBC with poor response. The aberrant DNA methylation status of the following HR related-genes was analyzed using bisulfite-pyrosequencing: BRCA1, BRCA2, BARD1, MDC1, RNF8, RNF168, UBC13, ABRA1, PALB2, RAD50, RAD51, RAD51C, MRE11, NBS1, CtIP and ATM. Among the genes analyzed, only the incidence of BRCA1 and RNF8 methylation was significantly higher in TNBC than that in LBC. Whereas the incidence of BRCA1 methylation was tended to be higher in pCR cases than in poor-response cases in TNBC, that of RNF8 was significantly lower in pCR cases than in poor-response cases. Our results indicate that the methylation status of HR genes was not generally associated with TNBC subtype or chemosensitivity although hypermethylation of BRCA1 is associated with TNBC subtype and may impact chemosensitivity.

Related: Breast Cancer Cyclophosphamide Fluorouracil Methotrexate Docetaxel


Do H, Wong NC, Murone C, et al.
A critical re-assessment of DNA repair gene promoter methylation in non-small cell lung carcinoma.
Sci Rep. 2014; 4:4186 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
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.

Related: Non-Small Cell Lung Cancer Lung Cancer


Schweighofer N, Lerchbaum E, Trummer O, et al.
Metformin resistance alleles in polycystic ovary syndrome: pattern and association with glucose metabolism.
Pharmacogenomics. 2014; 15(3):305-17 [PubMed] Related Publications
Insulin-sensitizer treatment with metformin is common in polycystic ovary syndrome (PCOS). OCT alleles were investigated in PCOS patients to identify genetic 'bad responders' and 'nonresponders' to metformin including their possible effects on glucose metabolism without treatment. We genotyped eight SNPs in OCT1, OCT2 and ATM genes in 676 women with PCOS and 90 control women, we also measured oral glucose tolerance tests prior to treatment. Nonfunctional alleles were present in 29.8% and low-functional alleles in 57.9% of our PCOS cohort. OCT variants were significantly associated with elevated baseline and glucose-induced C-peptide levels in PCOS. Metformin bad responders or nonresponders based on OCT genotypes might be relevant in clinical practice - their modulation of metformin pharmacokinetics and pharmacodynamics and metformin-independent glucose effects remain to be elucidated.


Xie Q, Bai Q, Zou LY, et al.
Genistein inhibits DNA methylation and increases expression of tumor suppressor genes in human breast cancer cells.
Genes Chromosomes Cancer. 2014; 53(5):422-31 [PubMed] Related Publications
It has been previously demonstrated that genistein exhibits anticancer activity against breast cancer. However, the precise mechanisms underlying the anticancer effect of genistein, in particular the epigenetic basis, remain unclear. In this study, we investigated whether genistein could modulate the DNA methylation status and expression of cancer-related genes in breast cancer cells. We treated MCF-7 and MDA-MB-231 human breast cancer cells with genistein in vitro. We found that genistein decreased the levels of global DNA methylation, DNA methyltransferase (DNMT) activity and expression of DNMT1. Yet, the expression of DNMT3A and DNMT3B showed no significant change. Using molecular modeling, we observed that genistein might directly interact with the catalytic domain of DNMT1, thus competitively inhibiting the binding of hemimethylated DNA to the catalytic domain of DNMT1. Furthermore, genistein decreased DNA methylation in the promoter region of multiple tumor suppressor genes (TSGs) such as ataxia telangiectasia mutated (ATM), adenomatous polyposis coli (APC), phosphatase and tensin homolog (PTEN), mammary serpin peptidase inhibitor (SERPINB5), and increased the mRNA expression of these genes. However, we detected no significant changes in the DNA methylation status or mRNA expression of stratifin (SFN). These results suggest that the anticancer effect of genistein on breast cancer may be partly due to its ability to demethylate and reactivate methylation-silenced TSGs through direct interaction with the DNMT1 catalytic domain and inhibition of DNMT1 expression.

Related: Breast Cancer


Gala MK, Mizukami Y, Le LP, et al.
Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas.
Gastroenterology. 2014; 146(2):520-9 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
BACKGROUND & AIMS: Little is known about the genetic factors that contribute to the development of sessile serrated adenomas (SSAs). SSAs contain somatic mutations in BRAF or KRAS early in development. However, evidence from humans and mouse models indicates that these mutations result in oncogene-induced senescence (OIS) of intestinal crypt cells. Progression to serrated neoplasia requires cells to escape OIS via inactivation of tumor suppressor pathways. We investigated whether subjects with multiple SSAs carry germline loss-of function mutations (nonsense and splice site) in genes that regulate OIS: the p16-Rb and ATM-ATR DNA damage response pathways.
METHODS: Through a bioinformatic analysis of the literature, we identified a set of genes that function at the main nodes of the p16-Rb and ATM-ATR DNA damage response pathways. We performed whole-exome sequencing of 20 unrelated subjects with multiple SSAs; most had features of serrated polyposis. We compared sequences with those from 4300 subjects matched for ethnicity (controls). We also used an integrative genomics approach to identify additional genes involved in senescence mechanisms.
RESULTS: We identified mutations in genes that regulate senescence (ATM, PIF1, TELO2,XAF1, and RBL1) in 5 of 20 subjects with multiple SSAs (odds ratio, 3.0; 95% confidence interval, 0.9–8.9; P =.04). In 2 subjects,we found nonsense mutations in RNF43, indicating that it is also associated with multiple serrated polyps (odds ratio, 460; 95% confidence interval, 23.1–16,384; P = 6.8 x 10(-5)). In knockdown experiments with pancreatic duct cells exposed to UV light, RNF43 appeared to function as a regulator of ATMATRDNA damage response.
CONCLUSIONS: We associated germline loss-of-function variants in genes that regulate senescence pathways with the development of multiple SSAs.We identified RNF43 as a regulator of the DNA damage response and associated nonsense variants in this gene with a high risk of developing SSAs.

Related: BRAF gene RBL1 retinoblastoma-like 1 (p107) KRAS gene


Son CH, Keum JH, Yang K, et al.
Synergistic enhancement of NK cell-mediated cytotoxicity by combination of histone deacetylase inhibitor and ionizing radiation.
Radiat Oncol. 2014; 9:49 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
BACKGROUND: The overexpression of histone deacetylase (HDAC) and a subsequent decrease in the acetylation levels of nuclear histones are frequently observed in cancer cells. Generally it was accepted that the deacetylation of histones suppressed expression of the attached genes. Therefore, it has been suggested that HDAC might contribute to the survival of cancer cells by altering the NKG2D ligands transcripts. By the way, the translational regulation of NKG2D ligands remains unclear in cancer cells. It appears the modulation of this unclear mechanism could enhance NKG2D ligand expressions and the susceptibility of cancer cells to NK cells. Previously, it was reported that irradiation can increase the surface expressions of NKG2D ligands on several cancer cell types without increasing the levels of NKG2D ligand transcripts via ataxia telangiectasia mutated and ataxia telangiectasia and Rad3 related (ATM-ATR) pathway, and suggested that radiation therapy might be used to increase the translation of NKG2D ligands.
METHODS: Two NSCLC cell lines, that is, A549 and NCI-H23 cells, were used to investigate the combined effects of ionizing radiation and HDAC inhibitors on the expressions of five NKG2D ligands. The mRNA expressions of the NKG2D ligands were quantitated by multiplex reverse transcription-PCR. Surface protein expressions were measured by flow cytometry, and the susceptibilities of cancer cells to NK cells were assayed by time-resolved fluorometry using the DELFIA® EuTDA cytotoxicity kit and by flow cytometry.
RESULTS: The expressions of NKG2D ligands were found to be regulated at the transcription and translation levels. Ionizing radiation and HDAC inhibitors in combination synergistically increased the expressions of NKG2D ligands. Furthermore, treatment with ATM-ATR inhibitors efficiently blocked the increased translations of NKG2D ligands induced by ionizing radiation but did not block the increased ligand translations induced by HDAC inhibitors. The study confirms that increased NKG2D ligand levels by ionizing radiation and HDAC inhibitors could synergistically enhance the susceptibilities of cancer cells to NK-92 cells.
CONCLUSIONS: This study suggests that the expressions of NKG2D ligands are regulated in a complex manner at the multilevel of gene expression, and that their expressions can be induced by combinatorial treatments in lung cancer cells.

Related: Non-Small Cell Lung Cancer Lung Cancer


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Cite this page: Cotterill SJ. ATM, Cancer Genetics Web: http://www.cancerindex.org/geneweb/ATM.htm Accessed: date

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