Gene Summary

Gene:WRN; Werner syndrome, RecQ helicase-like
Aliases: RECQ3, RECQL2, RECQL3
Summary:This gene encodes a member of the RecQ subfamily and the DEAH (Asp-Glu-Ala-His) subfamily of DNA and RNA helicases. DNA helicases are involved in many aspects of DNA metabolism, including transcription, replication, recombination, and repair. This protein contains a nuclear localization signal in the C-terminus and shows a predominant nucleolar localization. It possesses an intrinsic 3' to 5' DNA helicase activity, and is also a 3' to 5' exonuclease. Based on interactions between this protein and Ku70/80 heterodimer in DNA end processing, this protein may be involved in the repair of double strand DNA breaks. Defects in this gene are the cause of Werner syndrome, an autosomal recessive disorder characterized by premature aging. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:Werner syndrome ATP-dependent helicase
Source:NCBIAccessed: 08 August, 2015


What does this gene/protein do?
Show (45)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 08 August 2015 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.

  • DNA Replication
  • Self-Help Groups
  • Microsatellite Instability
  • Genomic Instability
  • Colorectal Cancer
  • Cancer DNA
  • Chromosome 8
  • Xeroderma Pigmentosum
  • Mutation
  • WRN
  • Werner Syndrome
  • DNA-Binding Proteins
  • Epigenetics
  • DNA Helicases
  • Adenocarcinoma
  • Exodeoxyribonucleases
  • p53 Protein
  • DNA Repair
  • Genotype
  • CpG Islands
  • Telomere
  • Risk Factors
  • Bloom Syndrome
  • Aging
  • RecQ Helicases
  • Phenotype
  • Biological Models
  • Genetic Predisposition
  • Aging, Premature
  • Cancer Gene Expression Regulation
  • Case-Control Studies
  • DNA Methylation
  • Nuclear Proteins
  • Bladder Cancer
  • Neoplastic Cell Transformation
  • Sequence Deletion
  • Stomach Cancer
  • Genetic Recombination
  • Breast Cancer
  • Single Nucleotide Polymorphism
  • DNA Damage
Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

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

Latest Publications: WRN (cancer-related)

Sokolenko AP, Preobrazhenskaya EV, Aleksakhina SN, et al.
Candidate gene analysis of BRCA1/2 mutation-negative high-risk Russian breast cancer patients.
Cancer Lett. 2015; 359(2):259-61 [PubMed] Related Publications
Twenty one DNA repair genes were analyzed in a group of 95 BC patients, who displayed clinical features of hereditary disease predisposition but turned out to be negative for mutations in BRCA1 and BRCA2 entire coding region as well as for founder disease-predisposing alleles in CHEK2, NBN/NBS1 and ATM genes. Full-length sequencing of CHEK2 and NBN/NBS1 failed to identify non-founder mutations. The analysis of TP53 revealed a woman carrying the R282W allele; further testing of additional 108 BC patients characterized by a very young age at onset (35 years or earlier) detected one more carrier of the TP53 germ-line defect. In addition, this study confirmed non-random occurrence of PALB2 truncating mutations in Russian hereditary BC patients. None of the studied cases carried germ-line defects in recently discovered hereditary BC genes, BRIP1, FANCC, MRE11A and RAD51C. The analysis of genes with yet unproven BC-predisposing significance (BARD1, BRD7, CHEK1, DDB2, ERCC1, EXO1, FANCG, PARP1, PARP2, RAD51, RNF8, WRN) identified single women carrying a protein-truncating allele, WRN R1406X. DNA sequencing of another set of 95 hereditary BC cases failed to reveal additional WRN heterozygous genotypes. Since WRN is functionally similar to the known BC-predisposing gene, BLM, it deserves to be analyzed in future hereditary BC studies. Furthermore, this investigation revealed a number of rare missense germ-line variants, which are classified as probably protein-damaging by online in silico tools and therefore may require further consideration.

Sun K, Gong A, Liang P
Predictive impact of genetic polymorphisms in DNA repair genes on susceptibility and therapeutic outcomes to colorectal cancer patients.
Tumour Biol. 2015; 36(3):1549-59 [PubMed] Related Publications
Several hereditary syndromes characterized by defective DNA repair are associated with high risk of colorectal cancer (CRC). To explore whether common polymorphisms in DNA repair genes affect risk and prognosis of CRC, we evaluated the association between single nucleotide polymorphisms (SNPs) in XPG, XPC, and WRN gene and susceptibility of CRC, and clinical outcomes in a population-based case-control study. A total of 890 CRC cases and 910 controls recruited into the study provided a biologic sample. Individuals with variant genotypes of XPC Ala499Val appeared to be associated with the increased risk of CRC. WRN Cys1367Arg variants carriers showed an increased susceptibility for CRC. More importantly, the risk of CRC increased further in a combined analysis of multiple polymorphisms. Furthermore, stratified analyses revealed that XPG Arg1104His polymorphism was associated with tumor differentiation of CRC patients (P = 0.043). Log-rank test and adjusted multivariate Cox regression analysis verified that XPG Arg1104His variants were associated with a longer disease-free survival (DFS) [CG genotype: adjusted HR (95% confidence interval (CI)) = 0.163 (0.107-0.248), P < 0.001; CC genotype: adjusted HR (95% CI) = 0.333 (0.235-0.470), P < 0.001; CG/CC genotype: adjusted HR (95% CI) = 0.333 (0.235-0.470)] in patients with oxaliplatin-based chemotherapy (N = 718). Moreover, XPC Ala499Val CT genotype showed a significant impact on DFS [CC genotype: adjusted HR (95% CI) = 0.691 (0.528-0.904), P = 0.007; CT/CC genotype: adjusted HR (95% CI) = 0.602 (0.389-0.934), P = 0.024]. However, no correlation was found between WRN Cys1367Arg polymorphism and prognosis in CRC patients. Our findings will add to the literature on the impact of genetic variation in DNA repair genes involved in susceptibility for CRC and therapeutic outcomes in response to oxaliplatin-based chemotherapy.

Lu L, Jin W, Liu H, Wang LL
RECQ DNA helicases and osteosarcoma.
Adv Exp Med Biol. 2014; 804:129-45 [PubMed] Related Publications
The RECQ family of DNA helicases is a conserved group of enzymes that are important for maintaining genomic integrity. In humans, there are five RECQ helicase genes, and mutations in three of them-BLM, WRN, and RECQL4-are associated with the genetic disorders Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome (RTS), respectively. Importantly all three diseases are cancer predisposition syndromes. Patients with RTS are highly and uniquely susceptible to developing osteosarcoma; thus, RTS provides a good model to study the pathogenesis of osteosarcoma. The "tumor suppressor" role of RECQL4 and the other RECQ helicases is an area of active investigation. This chapter reviews what is currently known about the cellular functions of RECQL4 and how these may relate to tumorigenesis, as well as ongoing efforts to understand RECQL4's functions in vivo using animal models. Understanding the RECQ pathways may provide insight into avenues for novel cancer therapies in the future.

Li B, Iglesias-Pedraz JM, Chen LY, et al.
Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells.
Aging Cell. 2014; 13(2):367-78 [PubMed] Free Access to Full Article Related Publications
The Werner syndrome protein (WRN) is a nuclear protein required for cell growth and proliferation. Loss-of-function mutations in the Werner syndrome gene are associated with the premature onset of age-related diseases. How loss of WRN limits cell proliferation and induces replicative senescence is poorly understood. Here, we show that WRN depletion leads to a striking metabolic shift that coordinately weakens the pathways that generate reducing equivalents for detoxification of reactive oxygen species and increases mitochondrial respiration. In cancer cells, this metabolic shift counteracts the Warburg effect, a defining characteristic of many malignant cells, resulting in altered redox balance and accumulation of oxidative DNA damage that inhibits cell proliferation and induces a senescence-like phenotype. Consistent with these findings, supplementation with antioxidant rescues at least in part cell proliferation and decreases senescence in WRN-knockdown cancer cells. These results demonstrate that WRN plays a critical role in cancer cell proliferation by contributing to the Warburg effect and preventing metabolic stress.

Kim HN, Kim NY, Yu L, et al.
Polymorphisms in DNA repair genes and MDR1 and the risk for non-Hodgkin lymphoma.
Int J Mol Sci. 2014; 15(4):6703-16 [PubMed] Free Access to Full Article Related Publications
The damage caused by oxidative stress and exposure to cigarette smoke and alcohol necessitate DNA damage repair and transport by multidrug resistance-1 (MDR1). To explore the association between polymorphisms in these genes and non-Hodgkin lymphoma risk, we analyzed 15 polymorphisms of 12 genes in a population-based study in Korea (694 cases and 1700 controls). Four genotypes of DNA repair pathway genes (XRCC1 399 GA, OGG1 326 GG, BRCA1 871 TT, and WRN 787 TT) were associated with a decreased risk for NHL [odds ratio (OR)XRCC1 GA=0.80, p=0.02; OROGG1 GG=0.70, p=0.008; ORBRCA1 TT=0.71, p=0.048; ORWRN TT=0.68, p=0.01]. Conversely, the MGMT 115 CT genotype was associated with an increased risk for NHL (OR=1.25, p=0.04). In the MDR1 gene, the 1236 CC genotype was associated with a decreased risk for NHL (OR=0.74, p=0.04), and the 3435 CT and TT genotypes were associated with an increased risk (OR3435CT=1.50, p<0.0001; OR3435TT=1.43, p=0.02). These results suggest that polymorphisms in the DNA repair genes XRCC1, OGG1, BRCA1, WRN1, and MGMT and in the MDR1 gene may affect the risk for NHL in Korean patients.

Wang L, Xie L, Wang J, et al.
Correlation between the methylation of SULF2 and WRN promoter and the irinotecan chemosensitivity in gastric cancer.
BMC Gastroenterol. 2013; 13:173 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: At present, no study has compared the correlation between SULF2, WRN promoter methylation and clinicopathological parameters of patients with gastric cancer and the sensitivity to irinotecan (CPT-11).
METHODS: We collected 102 fresh tumor tissues from pathologically diagnosed gastric carcinoma patients. Methylation specific PCR was used to detect the promoter methylation of SULF2 and WRN. The chemosensitivity of irinotecan to gastric tumor was tested by MTT. Then we compared the chemosensitivity difference of the methylated group with unmethylated group.
RESULTS: The rates of SULF2, WRN methylation were 28.3% (29/102) and 23.6% (24/102), separately. Patients with SULF2 methylation were more sensitive to CPT-11 than those without SULF2 methylation (P < 0.01). Patients with both SULF2 and WRN methylation were also more sensitive to CPT-11 than others (P < 0.05).
CONCLUSION: SULF2 and WRN promoter methylation detection indicates potential predictive biomarkers to identify and target the most sensitive gastric cancer subpopulation for personalized CPT-11 therapy.

Sugimoto M
A cascade leading to premature aging phenotypes including abnormal tumor profiles in Werner syndrome (review).
Int J Mol Med. 2014; 33(2):247-53 [PubMed] Related Publications
This perspective review focused on the Werner syndrome (WS) by addressing the issue of how a single mutation in a WRN gene encoding WRN DNA helicase induces a wide range of premature aging phenotypes accompanied by an abnormal pattern of tumors. The key event caused by WRN gene mutation is the dysfunction of telomeres. Studies on normal aging have identified a molecular circuit in which the dysfunction of telomeres caused by cellular aging activates the TP53 gene. The resultant p53 suppresses cell growth and induces a shorter cellular lifespan, and also compromises mitochondrial biogenesis leading to the overproduction of reactive oxygen species (ROS) causing multiple aging phenotypes. As an analogy of the mechanism in natural aging, we described a hypothetical mechanism of premature aging in WS: telomere dysfunction induced by WRN mutation causes multiple premature aging phenotypes of WS, including shortened cellular lifespan and inflammation induced by ROS, such as diabetes mellitus. This model also explains the relatively late onset of the disorder, at approximately age 20. Telomere dysfunction in WS is closely correlated with abnormality in tumorigenesis. Thus, the majority of wide and complex pathological phenotypes of WS may be explained in a unified manner by the cascade beginning with telomere dysfunction initiated by WRN gene mutation.

Lee H, Flaherty P, Ji HP
Systematic genomic identification of colorectal cancer genes delineating advanced from early clinical stage and metastasis.
BMC Med Genomics. 2013; 6:54 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colorectal cancer is the third leading cause of cancer deaths in the United States. The initial assessment of colorectal cancer involves clinical staging that takes into account the extent of primary tumor invasion, determining the number of lymph nodes with metastatic cancer and the identification of metastatic sites in other organs. Advanced clinical stage indicates metastatic cancer, either in regional lymph nodes or in distant organs. While the genomic and genetic basis of colorectal cancer has been elucidated to some degree, less is known about the identity of specific cancer genes that are associated with advanced clinical stage and metastasis.
METHODS: We compiled multiple genomic data types (mutations, copy number alterations, gene expression and methylation status) as well as clinical meta-data from The Cancer Genome Atlas (TCGA). We used an elastic-net regularized regression method on the combined genomic data to identify genetic aberrations and their associated cancer genes that are indicators of clinical stage. We ranked candidate genes by their regression coefficient and level of support from multiple assay modalities.
RESULTS: A fit of the elastic-net regularized regression to 197 samples and integrated analysis of four genomic platforms identified the set of top gene predictors of advanced clinical stage, including: WRN, SYK, DDX5 and ADRA2C. These genetic features were identified robustly in bootstrap resampling analysis.
CONCLUSIONS: We conducted an analysis integrating multiple genomic features including mutations, copy number alterations, gene expression and methylation. This integrated approach in which one considers all of these genomic features performs better than any individual genomic assay. We identified multiple genes that robustly delineate advanced clinical stage, suggesting their possible role in colorectal cancer metastatic progression.

Grohar PJ, Segars LE, Yeung C, et al.
Dual targeting of EWS-FLI1 activity and the associated DNA damage response with trabectedin and SN38 synergistically inhibits Ewing sarcoma cell growth.
Clin Cancer Res. 2014; 20(5):1190-203 [PubMed] Related Publications
PURPOSE: The goal of this study is to optimize the activity of trabectedin for Ewing sarcoma by developing a molecularly targeted combination therapy.
EXPERIMENTAL DESIGN: We have recently shown that trabectedin interferes with the activity of EWS-FLI1 in Ewing sarcoma cells. In this report, we build on this work to develop a trabectedin-based combination therapy with improved EWS-FLI1 suppression that also targets the drug-associated DNA damage to Ewing sarcoma cells.
RESULTS: We demonstrate by siRNA experiments that EWS-FLI1 drives the expression of the Werner syndrome protein (WRN) in Ewing sarcoma cells. Because WRN-deficient cells are known to be hypersensitive to camptothecins, we utilize trabectedin to block EWS-FLI1 activity, suppress WRN expression, and selectively sensitize Ewing sarcoma cells to the DNA-damaging effects of SN38. We show that trabectedin and SN38 are synergistic, demonstrate an increase in DNA double-strand breaks, an accumulation of cells in S-phase and a low picomolar IC50. In addition, SN38 cooperates with trabectedin to augment the suppression of EWS-FLI1 downstream targets, leading to an improved therapeutic index in vivo. These effects translate into the marked regression of two Ewing sarcoma xenografts at a fraction of the dose of camptothecin used in other xenograft studies.
CONCLUSIONS: These results provide the basis and rationale for translating this drug combination to the clinic. In addition, the study highlights an approach that utilizes a targeted agent to interfere with an oncogenic transcription factor and then exploits the resulting changes in gene expression to develop a molecularly targeted combination therapy.

Chen Y, Zheng T, Lan Q, et al.
Polymorphisms in DNA repair pathway genes, body mass index, and risk of non-Hodgkin lymphoma.
Am J Hematol. 2013; 88(7):606-11 [PubMed] Free Access to Full Article Related Publications
We conducted a population-based case-control study in Connecticut women to test the hypothesis that genetic variations in DNA repair pathway genes may modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL). Compared to those with BMI <25, women with BMI ≥25 had significantly increased risk of NHL among women who carried BRCA1 (rs799917) CT/TT, ERCC2 (rs13181) AA, XRCC1 (rs1799782) CC, and WRN (rs1801195) GG genotypes, but no increase in NHL risk among women who carried BRCA1 CC, ERCC2 AC/CC, XRCC1 CT/TT, and WRN GT/TT genotypes. A significant interaction with BMI was only observed for WRN (rs1801195; P = 0.004) for T-cell lymphoma and ERCC2 (rs13181; P = 0.002) for diffuse large B-cell lymphoma. The results suggest that common genetic variation in DNA repair pathway genes may modify the association between BMI and NHL risk.

Gaymes TJ, Mohamedali AM, Patterson M, et al.
Microsatellite instability induced mutations in DNA repair genes CtIP and MRE11 confer hypersensitivity to poly (ADP-ribose) polymerase inhibitors in myeloid malignancies.
Haematologica. 2013; 98(9):1397-406 [PubMed] Free Access to Full Article Related Publications
Inactivation of the DNA mismatch repair pathway manifests as microsatellite instability, an accumulation of mutations that drives carcinogenesis. Here, we determined whether microsatellite instability in acute myeloid leukemia and myelodysplastic syndrome correlated with chromosomal instability and poly (ADP-ribose) polymerase (PARP) inhibitor sensitivity through disruption of DNA repair function. Acute myeloid leukemia cell lines (n=12) and primary cell samples (n=18), and bone marrow mononuclear cells from high-risk myelodysplastic syndrome patients (n=63) were profiled for microsatellite instability using fluorescent fragment polymerase chain reaction. PARP inhibitor sensitivity was performed using cell survival, annexin V staining and cell cycle analysis. Homologous recombination was studied using immunocytochemical analysis. SNP karyotyping was used to study chromosomal instability. RNA silencing, Western blotting and gene expression analysis was used to study the functional consequences of mutations. Acute myeloid leukemia cell lines (4 of 12, 33%) and primary samples (2 of 18, 11%) exhibited microsatellite instability with mono-allelic mutations in CtIP and MRE11. These changes were associated with reduced expression of mismatch repair pathway components, MSH2, MSH6 and MLH1. Both microsatellite instability positive primary acute myeloid leukemia samples and cell lines demonstrated a downregulation of homologous recombination DNA repair conferring marked sensitivity to PARP inhibitors. Similarly, bone marrow mononuclear cells from 11 of 56 (20%) patients with de novo high-risk myelodysplastic syndrome exhibited microsatellite instability. Significantly, all 11 patients with microsatellite instability had cytogenetic abnormalities with 4 of them (36%) possessing a mono-allelic microsatellite mutation in CtIP. Furthermore, 50% reduction in CtIP expression by RNA silencing also down-regulated homologous recombination DNA repair responses conferring PARP inhibitor sensitivity, whilst CtIP differentially regulated the expression of homologous recombination modulating RecQ helicases, WRN and BLM. In conclusion, microsatellite instability dependent mutations in DNA repair genes, CtIP and MRE11 are detected in myeloid malignancies conferring hypersensitivity to PARP inhibitors. Microsatellite instability is significantly correlated with chromosomal instability in myeloid malignancies.

Takemoto M, Mori S, Kuzuya M, et al.
Diagnostic criteria for Werner syndrome based on Japanese nationwide epidemiological survey.
Geriatr Gerontol Int. 2013; 13(2):475-81 [PubMed] Related Publications
AIM: Werner syndrome (WS) is an autosomal recessive disorder of progeroid symptoms and signs. It is caused by mutations in the WRN gene, which encodes a RecQ DNA helicase. The aim of this study was to revise the diagnostic criteria for Japanese Werner syndrome.
METHODS: A nationwide epidemiological study was carried out from 2009 to 2011, involving 6921 surveys sent to hospitals with more than 200 beds to assess existing WS diagnostic criteria, as well as additional signs of high incidence on the basis of clinical experience with WS.
RESULTS: The existing diagnostic criteria were reviewed, and signs with >90% incidence were listed as cardinal signs. Several criteria were added, including genetic testing and calcification of the Achilles tendon, whereas criteria that are practically difficult to obtain, such as measurement of urinary hyaluronic acid, were omitted.
CONCLUSION: The 26-year-old diagnostic criteria for WS were revised on the basis of the results of a nationwide epidemiological study. The proposed revised criteria will facilitate simpler, faster and more robust diagnosis of WS in the Japanese population.

Masuda K, Banno K, Yanokura M, et al.
Association of epigenetic inactivation of the WRN gene with anticancer drug sensitivity in cervical cancer cells.
Oncol Rep. 2012; 28(4):1146-52 [PubMed] Free Access to Full Article Related Publications
The Werner (WRN) gene codes for a DNA helicase that contributes to genomic stability and has been identified as the gene responsible for progeria. Recent studies have shown reduced WRN expression due to aberrant DNA hypermethylation in cancer cells. Furthermore, WRN expression is thought to affect sensitivity to DNA topoisomerase I inhibitors in cancer therapy. In this study, we examined the relationship between aberrant DNA hypermethylation of WRN and the sensitivity of cervical cancer cells to anticancer drugs. DNA was extracted from samples from 22 patients with primary cervical cancer and 6 human cervical cancer-derived cell lines. Aberrant DNA hypermethylation was analyzed by methylation-specific PCR. WRN expression in cultured cells before and after addition of 5-aza-2-deoxycytidine, a demethylating agent, was examined using RT-PCR. The sensitivity of cells to anticancer drugs was determined using a collagen gel droplet embedded culture drug sensitivity test (CD-DST). siRNA against WRN was transfected into a cervical cancer-derived cell line with high WRN expression. Changes in drug sensitivity after silencing WRN were determined by CD-DST. Aberrant DNA hypermethylation and decreased expression of WRN were detected in 7/21 cases of primary cervical cancer and in two cervical cancer-derived cell lines. These two cell lines showed high sensitivity to CPT-11, a topoisomerase I inhibitor, but became resistant to CPT-11 after treatment with 5-aza-2-deoxycytidine. Transfection of siRNA against WRN increased the sensitivity of the cells to CPT-11. Aberrant DNA hypermethylation of WRN also increased the sensitivity of cervical cancer cells to CPT-11. Therefore, epigenetic inactivation of this gene may be a biomarker for selection of drugs for the treatment of cervical cancer. This is the first report to show a relationship between the methylation of the WRN gene and sensitivity to CPT-11 in gynecological cancers.

Nelson LD, Bender C, Mannsperger H, et al.
Triplex DNA-binding proteins are associated with clinical outcomes revealed by proteomic measurements in patients with colorectal cancer.
Mol Cancer. 2012; 11:38 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tri- and tetra-nucleotide repeats in mammalian genomes can induce formation of alternative non-B DNA structures such as triplexes and guanine (G)-quadruplexes. These structures can induce mutagenesis, chromosomal translocations and genomic instability. We wanted to determine if proteins that bind triplex DNA structures are quantitatively or qualitatively different between colorectal tumor and adjacent normal tissue and if this binding activity correlates with patient clinical characteristics.
METHODS: Extracts from 63 human colorectal tumor and adjacent normal tissues were examined by gel shifts (EMSA) for triplex DNA-binding proteins, which were correlated with clinicopathological tumor characteristics using the Mann-Whitney U, Spearman's rho, Kaplan-Meier and Mantel-Cox log-rank tests. Biotinylated triplex DNA and streptavidin agarose affinity binding were used to purify triplex-binding proteins in RKO cells. Western blotting and reverse-phase protein array were used to measure protein expression in tissue extracts.
RESULTS: Increased triplex DNA-binding activity in tumor extracts correlated significantly with lymphatic disease, metastasis, and reduced overall survival. We identified three multifunctional splicing factors with biotinylated triplex DNA affinity: U2AF65 in cytoplasmic extracts, and PSF and p54nrb in nuclear extracts. Super-shift EMSA with anti-U2AF65 antibodies produced a shifted band of the major EMSA H3 complex, identifying U2AF65 as the protein present in the major EMSA band. U2AF65 expression correlated significantly with EMSA H3 values in all extracts and was higher in extracts from Stage III/IV vs. Stage I/II colon tumors (p=0.024). EMSA H3 values and U2AF65 expression also correlated significantly with GSK3 beta, beta-catenin, and NF- B p65 expression, whereas p54nrb and PSF expression correlated with c-Myc, cyclin D1, and CDK4. EMSA values and expression of all three splicing factors correlated with ErbB1, mTOR, PTEN, and Stat5. Western blots confirmed that full-length and truncated beta-catenin expression correlated with U2AF65 expression in tumor extracts.
CONCLUSIONS: Increased triplex DNA-binding activity in vitro correlates with lymph node disease, metastasis, and reduced overall survival in colorectal cancer, and increased U2AF65 expression is associated with total and truncated beta-catenin expression in high-stage colorectal tumors.

Cheng WH, Wu RT, Wu M, et al.
Targeting Werner syndrome protein sensitizes U-2 OS osteosarcoma cells to selenium-induced DNA damage response and necrotic death.
Biochem Biophys Res Commun. 2012; 420(1):24-8 [PubMed] Related Publications
Mutations in the Werner syndrome protein (WRN), a caretaker of the genome, result in Werner syndrome, which is characterized by premature aging phenotypes and cancer predisposition. Methylseleninic acid (MSeA) can activate DNA damage responses and is a superior compound to suppress tumorigenesis in mouse models of cancer. To test the hypothesis that targeting WRN can potentiate selenium toxicity in cancer cells, isogenic WRN small hairpin RNA (shRNA) and control shRNA U-2 OS osteosarcoma cells were treated with MSeA for 2d, followed by recovery for up to 7d. WRN deficiency sensitized U-2 OS cells to MSeA-induced necrotic death. Co-treatment with the ataxia-telangiectasia mutated (ATM) kinase inhibitor KU55933 desensitized the control shRNA cells, but not WRN shRNA cells, to MSeA treatment. WRN did not affect MSeA-induced ATM phosphorylation on Ser-1981 or H2A.X phosphorylation on Ser-139, but promoted recovery from the MSeA-induced DNA damage. Taken together, WRN protects U-2 OS osteosarcoma cells against MSeA-induced cytotoxicity, suggesting that oxidative DNA repair pathway is a promising target for improving the efficacy of selenium on tumor suppression.

Li T, Suo Q, He D, et al.
Esophageal cancer risk is associated with polymorphisms of DNA repair genes MSH2 and WRN in Chinese population.
J Thorac Oncol. 2012; 7(2):448-52 [PubMed] Related Publications
INTRODUCTION: Normal function of DNA repair system is essential for the removal of damage induced by many kinds of internal and environmental agents. Genetic polymorphisms in DNA repair genes associated with modified repair capacity may be related to the risk of developing esophageal cancer (EC). This article dealt whether single-nucleotide polymorphisms of DNA repair genes MSH2, WRN, and Ku70 potentially contributed to EC susceptibility.
METHODS: A hospital-based case-control study with 117 EC cases and 132 controls in a Chinese population was conducted. We genotyped three single-nucleotide polymorphisms MSH2 c.2063T>G, WRN c.4330T>C, and Ku70 c.-1310 C>G using polymerase chain reaction-based restriction fragment length polymorphism and then performed statistical analysis by calculating the adjusted odds ratios (OR) and 95% confidence intervals (95% CI).
RESULTS: Carriers of the MSH2 c.2063 G allele were at a higher risk of developing EC with the TT genotype as reference (OR = 4.53, 95% CI = 1.92-10.64, 33p = 0.001). Also for WRN c.4330T>C, individuals with at least one C allele (T/C or C/C) had a 2.21-fold increased risk for EC development compared with those who bore the T/T wild-type genotype (OR = 2.21, 95% CI = 1.06-4.59, 33p = 0.035). Moreover, statistically significant variant genotypic interaction was suggested between MSH2 and WRN as a result of a much increased predisposition to EC (33p = 0.016). No obvious correlation was observed between Ku70 c.-1310 CG and esophageal carcinogenesis (33p > 0.05).
CONCLUSIONS: Our findings indicated that genetic variants in DNA repair pathways may be involved in esophageal tumorigenesis. MSH2 c.2063 G allele and WRN c.4330 C allele, not Ku70 c.-1310 CG, conferred risk for the process of developing EC.

Wang L, Kaku H, Huang P, et al.
Single nucleotide polymorphism WRN Leu1074Phe is associated with prostate cancer susceptibility in Chinese subjects.
Acta Med Okayama. 2011; 65(5):315-23 [PubMed] Related Publications
Deficiencies in the human DNA repair gene WRN are the cause of Werner syndrome, a rare autosomal recessive disorder characterized by premature aging and a predisposition to cancer. This study evaluated the association of WRN Leu1074Phe (rs1801195), a common missense single nucleotide polymorphism in WRN, with prostate cancer susceptibility in Chinese subjects. One hundred and forty-seven prostate cancer patients and 111 male cancer-free control subjects from 3 university hospitals in China were included. Blood samples were obtained from each subject, and the single nucleotide polymorphism WRN Leu1074Phe was genotyped by using a Snapshot assay. The results showed that WRN Leu1074Phe was associated with the risk of prostate cancer in Chinese men and that the TG/GG genotype displayed a decreased prevalence of prostate cancer compared with the TT genotype (OR=0.58, 95%CI:0.35-0.97, p=0.039). Through stratified analysis, more significant associations were revealed for the TG/GG genotype in the subgroup with diagnosis age ≤ 72 yr (OR=0.27, 95%CI:0.12-0.61, p=0.002) and in patients with localized diseases (OR=0.36, 95%CI:0.19-0.70, p=0.003). However, no statistically significant difference was found in the subgroup with age >72 yr or in patients with advanced diseases. We concluded that the genetic variant Leu1074Phe in the DNA repair gene WRN might play a role in the risk of prostate cancer in Chinese subjects.

Kim HN, Kim NY, Yu L, et al.
Association of GSTT1 polymorphism with acute myeloid leukemia risk is dependent on smoking status.
Leuk Lymphoma. 2012; 53(4):681-7 [PubMed] Related Publications
Genetic polymorphisms in drug-metabolizing, DNA repair and multidrug resistance genes affect the risks for many cancers. We analyzed 21 polymorphisms in 17 genes in these pathways to evaluate their association with the risk of acute myeloid leukemia (AML) and to examine whether smoking modifies these associations in a population-based study in Korea (415 cases, 1700 controls). We found marginal associations between the risk of AML and CYP1A1 1188, and XRCC1 194, ERCC1 IVS5 + 33 and WRN 787 polymorphisms. However, when we performed the analysis according to smoking exposure, we found a stronger association for ERCC1 only in the non-smoking population (odds ratio [OR] = 0.74; 95% confidence interval [CI] = 0.60-0.91, p = 0.004), while we found the GSTT1-null genotype to be associated with an increased risk of AML in ever-smokers (OR = 1.51; 95% CI = 1.06-2.15, p = 0.02). These results indicate that ERCC1 and GSTT1-null polymorphisms may have an effect on AML risk that is dependent on smoking exposure.

Arai A, Chano T, Futami K, et al.
RECQL1 and WRN proteins are potential therapeutic targets in head and neck squamous cell carcinoma.
Cancer Res. 2011; 71(13):4598-607 [PubMed] Related Publications
RECQL1 and WRN proteins are RecQ DNA helicases that participate in suppression of DNA hyper-recombination and repair. In this study, we report evidence supporting their candidacy as cancer therapeutic targets. In hypopharyngeal carcinomas, which have the worst prognosis among head and neck squamous cell carcinomas (HNSCC) that are rapidly rising in incidence, we found that RECQL1 and WRN proteins are highly expressed and that siRNA-mediated silencing of either gene suppressed carcinoma cell growth in vitro. Similarly, siRNA administration in a murine xenograft model of hypopharyngeal carcinoma markedly inhibited tumor growth. Moreover, combining either siRNA with cis-platinum (II) diammine dichloride significantly augmented the in vivo anticancer effects of this drug that is used commonly in HNSCC treatment. Notably, we observed no recurrence of some tumors following siRNA treatment in this model. Our findings offer a preclinical proof of concept for RECQL1 and WRN proteins as novel therapeutic targets to treat aggressive HNSCC and perhaps other cancers.

Salagovič J, Klimčáková L, Ilenčíková D, Kafková A
Association of follicular lymphoma risk with BRCA2 N372H polymorphism in Slovak population.
Med Oncol. 2012; 29(2):1173-8 [PubMed] Related Publications
Follicular lymphoma (FL) is one of the most common Non-Hodgkin lymphoma (NHL) subtype. Only small number of studies concerning NHL and DNA reparation gene polymorphisms has been performed so far. Hence, we have assessed the effect of 4 selected polymorphisms with possible influence on risk of FL development in a case-control study in Slovak population. We have genotyped polymorphisms in the RAG1 (K820R), LIG4 (T9I), BRCA2 (N372H), and WRN (V114I) genes in 108 patients with histologically proven FL diagnosis and 127 healthy controls. For discrimination between the allelic variants, we have established the genotyping by real-time melting analysis of an unlabeled probe. The most notable finding was related to polymorphism N372H in the BRCA2 gene. Compared with the wild-type genotype (NN), the homozygous variant genotype (HH) was associated with an increased FL risk (OR = 2.91, 95% CI: 0.96-8.81), although on the borderline of statistical significance (P = 0.050). However, after stratification by gender and age, the FL risk was significantly increased in men with variant-containing genotypes (OR = 2.79, 95% CI: 1.20-6.45) and even severalfold significantly increased among men with homozygous variant BRCA2 genotype (OR = 21.18, 95% CI: 2.46-182.2). No significant associations with FL risk were identified for other polymorphisms.

Lachapelle S, Oesterreich S, Lebel M
The Werner syndrome helicase protein is required for cell proliferation, immortalization, and tumorigenesis in Scaffold attachment factor B1 deficient mice.
Aging (Albany NY). 2011; 3(3):277-90 [PubMed] Free Access to Full Article Related Publications
Werner syndrome (WS) is a rare disorder characterized by the premature onset of several pathologies associated with aging. The gene responsible for WS codes for a RecQ-type DNA helicase and is believed to be involved in different aspects of DNA repair, replication, and transcription. We recently identified the Scaffold attachment factor B1 (SAFB1) as a potential interactants in human cells. SAFB1 is a multifunctional protein that binds both nucleic acids and is involved in the attachment of chromatin to the nuclear matrix, transcription, and stress response. Mice lacking SAFB1 exhibit developmental abnormalities in their lungs, high incidence of perinatal lethality, and adults develop different types of tumors. Mouse embryonic fibroblasts from Safb1-null animals are immortalized in culture. In this study, mice with a mutation in the helicase domain of the Wrn gene were crossed to Safb1-null mice. Double homozygous mutant mice exhibited increased apoptosis, a lower cell proliferation rate in their lungs and a higher incidence of perinatal death compared to Safb1-null mice. Few double homozygous mutants survived weaning and died before the age of six months. Finally, mouse embryonic fibroblasts lacking a functional Wrn helicase inhibited the immortalization of Safb1-null cells. These results indicate that an intact Wrn protein is required for immortalization and tumorigenesis in Safb1-null mice.

Goh WW, Lee YH, Zubaidah RM, et al.
Network-based pipeline for analyzing MS data: an application toward liver cancer.
J Proteome Res. 2011; 10(5):2261-72 [PubMed] Free Access to Full Article Related Publications
Current limitations in proteome analysis by high-throughput mass spectrometry (MS) approaches have sometimes led to incomplete (or inconclusive) data sets being published or unpublished. In this work, we used an iTRAQ reference data on hepatocellular carcinoma (HCC) to design a two-stage functional analysis pipeline to widen and improve the proteome coverage and, subsequently, to unveil the molecular changes that occur during HCC progression in human tumorous tissue. The first involved functional cluster analysis by incorporating an expansion step on a cleaned integrated network. The second used an in-house developed pathway database where recovery of shared neighbors was followed by pathway enrichment analysis. In the original MS data set, over 500 proteins were detected from the tumors of 12 male patients, but in this paper we reported an additional 1000 proteins after application of our bioinformatics pipeline. Through an integrative effort of network cleaning, community finding methods, and network analysis, we also uncovered several biologically interesting clusters implicated in HCC. We established that HCC transition from a moderate to poor stage involved densely connected clusters that comprised of PCNA, XRCC5, XRCC6, PARP1, PRKDC, and WRN. From our pathway enrichment analyses, it appeared that the HCC moderate stage, unlike the poor stage, is enriched in proteins involved in immune responses, thus suggesting the acquisition of immuno-evasion. Our strategy illustrates how an original oncoproteome could be expanded to one of a larger dynamic range where current technology limitations prevent/limit comprehensive proteome characterization.

Bacolla A, Wang G, Jain A, et al.
Non-B DNA-forming sequences and WRN deficiency independently increase the frequency of base substitution in human cells.
J Biol Chem. 2011; 286(12):10017-26 [PubMed] Free Access to Full Article Related Publications
Although alternative DNA secondary structures (non-B DNA) can induce genomic rearrangements, their associated mutational spectra remain largely unknown. The helicase activity of WRN, which is absent in the human progeroid Werner syndrome, is thought to counteract this genomic instability. We determined non-B DNA-induced mutation frequencies and spectra in human U2OS osteosarcoma cells and assessed the role of WRN in isogenic knockdown (WRN-KD) cells using a supF gene mutation reporter system flanked by triplex- or Z-DNA-forming sequences. Although both non-B DNA and WRN-KD served to increase the mutation frequency, the increase afforded by WRN-KD was independent of DNA structure despite the fact that purified WRN helicase was found to resolve these structures in vitro. In U2OS cells, ∼70% of mutations comprised single-base substitutions, mostly at G·C base-pairs, with the remaining ∼30% being microdeletions. The number of mutations at G·C base-pairs in the context of NGNN/NNCN sequences correlated well with predicted free energies of base stacking and ionization potentials, suggesting a possible origin via oxidation reactions involving electron loss and subsequent electron transfer (hole migration) between neighboring bases. A set of ∼40,000 somatic mutations at G·C base pairs identified in a lung cancer genome exhibited similar correlations, implying that hole migration may also be involved. We conclude that alternative DNA conformations, WRN deficiency and lung tumorigenesis may all serve to increase the mutation rate by promoting, through diverse pathways, oxidation reactions that perturb the electron orbitals of neighboring bases. It follows that such "hole migration" is likely to play a much more widespread role in mutagenesis than previously anticipated.

Uchiumi F, Watanabe T, Hasegawa S, et al.
The effect of resveratrol on the Werner syndrome RecQ helicase gene and telomerase activity.
Curr Aging Sci. 2011; 4(1):1-7 [PubMed] Related Publications
Various protein factors, including telomerase and WRN helicase, are involved in telomere maintenance. Resveratrol (Rsv), a polyphenol that extends the lifespan of diverse species is an activator of SIRT1, a NAD(+) dependent deacetylating enzyme in mammalian cells. Here, we examined the changes in gene expressions and promoter activities of WRN helicase and telomerase after Rsv treatment. This treatment increased the amount of WRN transcript and protein product by activating its promoter and telomerase promoter activity and gene expression. However cell proliferation was not changed. This suggests that Rsv induces telomere maintenance factors like WRN helicase without affecting cell proliferation.

Job B, Bernheim A, Beau-Faller M, et al.
Genomic aberrations in lung adenocarcinoma in never smokers.
PLoS One. 2010; 5(12):e15145 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lung cancer in never smokers would rank as the seventh most common cause of cancer death worldwide.
METHODS AND FINDINGS: We performed high-resolution array comparative genomic hybridization analysis of lung adenocarcinoma in sixty never smokers and identified fourteen new minimal common regions (MCR) of gain or loss, of which five contained a single gene (MOCS2, NSUN3, KHDRBS2, SNTG1 and ST18). One larger MCR of gain contained NSD1. One focal amplification and nine gains contained FUS. NSD1 and FUS are oncogenes hitherto not known to be associated with lung cancer. FISH showed that the amplicon containing FUS was joined to the next telomeric amplicon at 16p11.2. FUS was over-expressed in 10 tumors with gain of 16p11.2 compared to 30 tumors without that gain. Other cancer genes present in aberrations included ARNT, BCL9, CDK4, CDKN2B, EGFR, ERBB2, MDM2, MDM4, MET, MYC and KRAS. Unsupervised hierarchical clustering with adjustment for false-discovery rate revealed clusters differing by the level and pattern of aberrations and displaying particular tumor characteristics. One cluster was strongly associated with gain of MYC. Another cluster was characterized by extensive losses containing tumor suppressor genes of which RB1 and WRN. Tumors in that cluster frequently harbored a central scar-like fibrosis. A third cluster was associated with gains on 7p and 7q, containing ETV1 and BRAF, and displayed the highest rate of EGFR mutations. SNP array analysis validated copy-number aberrations and revealed that RB1 and WRN were altered by recurrent copy-neutral loss of heterozygosity.
CONCLUSIONS: The present study has uncovered new aberrations containing cancer genes. The oncogene FUS is a candidate gene in the 16p region that is frequently gained in never smokers. Multiple genetic pathways defined by gains of MYC, deletions of RB1 and WRN or gains on 7p and 7q are involved in lung adenocarcinoma in never smokers.

Blagoev KB, Goodwin EH, Bailey SM
Telomere sister chromatid exchange and the process of aging.
Aging (Albany NY). 2010; 2(10):727-30 [PubMed] Free Access to Full Article Related Publications
Telomeres are a hotspot for sister chromatid exchange (T-SCE). Any biological consequence of this form of instability remained obscure until quantitative modeling revealed a link between elevated T-SCE rates and accelerated cellular replicative senescence. This work strongly suggests that progressive telomere erosion is not the only determinant of replicative capacity; instead, T-SCE need to be considered as an independent factor controlling colony growth and senescence. Additionally high T-SCE rates have been observed in cells with deficiencies in WRN and BLM, the genes that are defective in Werner's and Bloom's syndromes, implying a connection to premature aging. In this Research Perspective we will explore some of the implications this recent work has for human health.

Toyota M, Suzuki H
Epigenetic drivers of genetic alterations.
Adv Genet. 2010; 70:309-23 [PubMed] Related Publications
DNA methylation plays a key role in the silencing of cancer-related genes, thereby affecting numerous cellular processes, including the cell cycle checkpoint, apoptosis, signal transduction, cell adhesion, and angiogenesis. DNA methylation also affects the expression of genes involved in maintaining the integrity of the genome through DNA repair and detoxification of reactive oxygen species. Here, we discuss how epigenetic changes lead to genetic alterations, including microsatellite instability and nucleotide and chromosomal alterations. Epigenetic inactivation of hMLH1 is a major cause of microsatellite instability in sporadic colorectal cancers, and germline epimutation of hMLH1 and hMSH2 is a cause of hereditary nonpolyposis colorectal cancers, which do not show mutation of mismatch repair genes. Epigenetic inactivation of MGMT is often associated with G:C-to-A:T mutations in K-ras and p53, while epigenetic inactivation of BRCA1, WRN, FANCF, and CHFR impairs the machinery involved in maintaining genomic integrity. Epigenetic alteration of the genes involved in the induction of senescence is often associated with cancers showing mutations in the Ras signaling pathway. In addition to regional hypermethylation, global hypomethylation is also a common feature of tumors. Hypomethylation of short and long interspersed repetitive elements has been reported, and hypomethylation affecting the integrity of the genome has been observed in ICF syndrome and various cancers. Dissection of the epigenetic drivers of genetic instability may be important for the development of novel approaches to the treatment of cancer.

Cai MY, Liang H, Li M, et al.
Lamin C protein deficiency in the primary fibroblasts from a new laminopathy case with ovarian cystadenoma.
Chin Med J (Engl). 2010; 123(16):2237-43 [PubMed] Related Publications
BACKGROUND: Laminopathies are a group of rare genetic disorders characterized by multiple-tissue degeneration. We describe a new laminopathy with ovarian cystadenoma and explore its molecular etiology.
METHODS: The case is a 15-year-old girl who presents the prominent progeroid disorders, multiple system degeneration and early-onset cystadenoma of the ovary. Candidate genes including LMNA, ZMPSTE24, PPAR G, INSR and WRN were sequenced to screen for DNA variants. The mRNA and protein expression levels of LMNA were examined in primary fibroblasts. The pathophysiological events such as morphologic alterations, cell senescence, cell proliferation, apoptosis and pRb as well as p53 protein expressions were also investigated in primary fibroblasts.
RESULTS: No mutation was identified in the candidate genes screened. Nuclear abnormalities including nuclear blebs, mislocalization of lamin A/C were evident in the patient fibroblasts. Ultrastructurally, nucleus exhibited nuclear herniation and almost complete loss of peripheral heterochromatin. In addition, lamin C protein expression was markedly reduced whereas lamin A protein level was normal and no prelamin A was detected in the primary fibroblasts. Although the senescence-associated beta-galactosidase staining of patient' cells was negative, cells in S phase increased in accompany with a decrease in pRb protein expression. Furthermore, increases in apoptotic cell death and p53 expression were observed.
CONCLUSIONS: Our data suggest that selective deficiency of lamin C protein is associated with a case of laminopathy with ovarian cystadenoma. The abnormalities in nuclear structure and alterations in gene expression such as the decrease in pRb and increase in p53 may be responsible for the multiple tissue degeneration.

Mao FJ, Sidorova JM, Lauper JM, et al.
The human WRN and BLM RecQ helicases differentially regulate cell proliferation and survival after chemotherapeutic DNA damage.
Cancer Res. 2010; 70(16):6548-55 [PubMed] Free Access to Full Article Related Publications
Loss-of-function mutations in the human RecQ helicase genes WRN and BLM respectively cause the genetic instability/cancer predisposition syndromes Werner syndrome and Bloom syndrome. To identify common and unique functions of WRN and BLM, we systematically analyzed cell proliferation, cell survival, and genomic damage in isogenic cell lines depleted of WRN, BLM, or both proteins. Cell proliferation and survival were assessed before and after treatment with camptothecin, cis-diamminedichloroplatinum(II), hydroxyurea, or 5-fluorouracil. Genomic damage was assessed, before and after replication arrest, by gamma-H2AX staining, which was quantified at the single-cell level by flow cytometry. Cell proliferation was affected strongly by the extent of WRN and/or BLM depletion, and more strongly by BLM than by WRN depletion (P = 0.005). The proliferation of WRN/BLM-codepleted cells, in contrast, did not differ from BLM-depleted cells (P = 0.34). BLM-depleted and WRN/BLM-codepleted cells had comparably impaired survival after DNA damage, whereas WRN-depleted cells displayed a distinct pattern of sensitivity to DNA damage. BLM-depleted and WRN/BLM-codepleted cells had similar, significantly higher gamma-H2AX induction levels than did WRN-depleted cells. Our results provide new information on the role of WRN and BLM in determining cell proliferation, cell survival, and genomic damage after chemotherapeutic DNA damage or replication arrest. We also provide new information on functional redundancy between WRN and BLM. These results provide a strong rationale for further developing WRN and BLM as biomarkers of tumor chemotherapeutic responsiveness.

Chun SG, Yee NS
Werner syndrome as a hereditary risk factor for exocrine pancreatic cancer: potential role of WRN in pancreatic tumorigenesis and patient-tailored therapy.
Cancer Biol Ther. 2010; 10(5):430-7 [PubMed] Free Access to Full Article Related Publications
Advanced age is considered a risk factor for pancreatic cancer, but this relationship at the molecular and genetic level remains unclear. We present a clinical case series focusing on an association between pancreatic adenocarcinoma and Werner syndrome (WS) that is an autosomal recessive genetic disorder characterized by accelerated aging and cancer predisposition, and is caused by loss-of-function mutations in the WS RecQ helicase gene (WRN). Although pancreatic adenocarcinoma mostly occurs in a sporadic fashion, a minority of cases occurs in the context of susceptible individuals with hereditary syndromes. While WS has not been previously recognized as a risk factor for developing malignant tumors of the exocrine pancreas, the clinicopathologic features of three reported patients suggest a contributory role of WRN deficiency in pancreatic carcinogenesis. Molecular genetic analyses support the role of WRN as a tumor suppressor gene, although recent evidence reveals that WRN can alternatively promote oncogenicity depending on the molecular context. Based upon the clinico-pathologic features of these patients and the role of WRN in experimental models, we propose that its loss-of-function predisposes the development of pancreatic adenocarcinoma through epigenetic silencing or loss-of-heterozygosity of WRN. To test this hypothesis, we are investigating the mechanistic role of WRN in pancreatic cancer models including a pancreatic adenocarcinoma cell line generated from a human with WS. These studies are expected to provide new insight into the relationship between aging and pancreatic tumorigenesis, and facilitate development of novel strategies for patient-tailored interventions in this deadly malignancy.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. WRN, Cancer Genetics Web: http://www.cancer-genetics.org/WRN.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 08 August, 2015     Cancer Genetics Web, Established 1999