The Polymorphism of EME1 Gene is Associated with an Increased Risk of Lung Cancer: A Case-Control Study from Chinese Population

Authors

  • Jianwei Zhao The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou 510182, China
  • Yongxiu Chen Department of gynecology, Guangdong Women and Children Hospital, Panyu xingnan Road, Guangzhou 511400, P.R., China
  • Xiaoxiao Lu School of Art and Science, Colby-Sawyer College, New London, NH 03257, USA
  • Di Wu The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou 510182, China
  • Jiansong Chen The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou 510182, China
  • Zhihuang Chen The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou 510182, China
  • Lin Liu The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou 510182, China
  • Lei Yang The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou 510182, China
  • Lan Zhang The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou 510182, China
  • Yifeng Zhou Department of gynecology, Guangdong Women and Children Hospital, Panyu xingnan Road, Guangzhou 511400, P.R., China
  • Jiachun Lu The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou 510182, China

DOI:

https://doi.org/10.6000/1929-2279.2014.03.04.1

Keywords:

Lung cancer, EME1, exonic variant, functional biomarker.

Abstract

 DNA double-strand breaks (DSBs) can lead to genomic instability and cancer susceptibility if unrepaired. EME1 is one of the key proteins that participate in the recognition and repair of DSBs in humans. We hypothesized that the exonic variants of EME1 are associated with lung cancer risk. In a two-stage case-control study of 1559 lung cancer patients and 1679 cancer-free controls, we genotyped two exonic variants of EME1(Glu69Asp: rs3760413T>G and Ile350Thr: rs12450550T>C) and analyzed their associations with risk of lung cancer. We found that the Asp variant genotypes conferred 1.35-folds risk of lung cancer compared to the Glu/Glu genotype (OR = 1.35, 95%CI = 1.18-1.56, P = 2.18 ƒ 10-5) in both stages. However, the SNP Ile350Thr was not confirmed to be associated with cancer risk in both stages. Moreover, by querying the gene expression database, we further found that the 69Asp variant genotypes confer a significantly lower mRNA expression of EME1 than the Glu/Glu genotype in 260 cases of lymphoblastoid cells (P=0.013). Our findings suggested that the SNP Glu69Asp of EME1 is associated with an increased risk of lung cancer, and may be a functional biomarker to predict lung cancer risk in Chinese. Validations in other ethnics are warranted.

References

Mollberg N, Surati M, Demchuk C, Fathi R, Salama AK, Husain AN, Hensing T, Salgia R. Mind-mapping for lung cancer: towards a personalized therapeutics approach. Adv Ther 2011; 28: 173-94. http://dx.doi.org/10.1007/s12325-010-0103-9

Cao KJ, Fan QY, Liu YL, Huang R, Yin CZ, Ma GS, Liu ZQ, Wan DS, Zeng YX. Cancer incidence and mortality in Guangzhou City from 2000 to 2002. Ai Zheng 2008; 27: 225-30.

Li Y, Dai M, Chen Y, Zhang S, Chen W, Dai Z, Zou X. Estimates of lung cancer mortality at the province level in China. Zhongguo Fei Ai Za Zhi 2011; 14: 120-26.

Chen W, Zhang S, Zou X. Estimation and projection of lung cancer incidence and mortality in China. Zhongguo Fei Ai Za Zhi 2010; 13: 488-93.

Yang Y, Wang JJ, Wang CX, Li Q, Yang GH. Awareness of tobacco-related health hazards among adults in China. Biomed Environ Sci 2010; 23: 437-44. http://dx.doi.org/10.1016/S0895-3988(11)60004-4

Li J, Zhang Y, Li Y, Yin G, Ning B, Guo J. [Descriptive study on the epidemiology of lung cancer in coal-producing area in eastern Yunnan, China]. Zhongguo Fei Ai Za Zhi 2011; 14: 107-19.

Robinson CF, Sullivan PA, Li J, Walker JT. Occupational lung cancer in US women, 1984-1998. Am J Ind Med 2011; 54: 102-17. http://dx.doi.org/10.1002/ajim.20905

Tokar EJ, Benbrahim-Tallaa L, Waalkes MP. Metal ions in human cancer development. Met Ions Life Sci 2011; 8: 375-401.

You Z, Bailis JM: DNA damage and decisions. CtIP coordinates DNA repair and cell cycle checkpoints. Trends Cell Biol 2010; 20: 402-9. http://dx.doi.org/10.1016/j.tcb.2010.04.002

Gullotta F, De Marinis E, Ascenzi P, di Masi A. Targeting the DNA double strand breaks repair for cancer therapy. Curr Med Chem 2010; 17: 2017-48. http://dx.doi.org/10.2174/092986710791233698

Machella N, Terry MB, Zipprich J, Gurvich I, Liao Y, Senie RT, Kennedy DO, Santella RM. Double-strand breaks repair in lymphoblastoid cell lines from sisters discordant for breast cancer from the New York site of the BCFR. Carcinogenesis 2008; 29: 1367-72. http://dx.doi.org/10.1093/carcin/bgn140

Msiska Z, Pacurari M, Mishra A, Leonard SS, Castranova V, Vallyathan V. DNA double-strand breaks by asbestos, silica, and titanium dioxide: possible biomarker of carcinogenic potential? Am J Respir Cell Mol Biol 2010; 43: 210-9. http://dx.doi.org/10.1165/rcmb.2009-0062OC

Rassool FV, Tomkinson AE. Targeting abnormal DNA double strand break repair in cancer. Cell Mol Life Sci 2010; 67: 3699-710. http://dx.doi.org/10.1007/s00018-010-0493-5

Mao Z, Jiang Y, Liu X, Seluanov A, Gorbunova V. DNA repair by homologous recombination, but not by nonhomologous end joining, is elevated in breast cancer cells. Neoplasia 2009; 11: 683-91.

Inagaki A, Schoenmakers S, Baarends WM. DNA double strand break repair, chromosome synapsis and transcriptional silencing in meiosis. Epigenetics 2010; 5: 255-66. http://dx.doi.org/10.4161/epi.5.4.11518

Geuting V, Kobbe D, Hartung F, Durr J, Focke M, Puchta H. Two distinct MUS81-EME1 complexes from Arabidopsis process Holliday junctions. Plant Physiol 2009; 150: 1062-71. http://dx.doi.org/10.1104/pp.109.136846

Taylor ER, McGowan CH. Cleavage mechanism of human Mus81-Eme1 acting on Holliday-junction structures. Proc Natl Acad Sci U S A 2008; 105: 3757-62. http://dx.doi.org/10.1073/pnas.0710291105

Ehmsen KT, Heyer WD. A junction branch point adjacent to a DNA backbone nick directs substrate cleavage by Saccharomyces cerevisiae Mus81-Mms4. Nucleic Acids Res 2009; 37: 2026-36. http://dx.doi.org/10.1093/nar/gkp038

Chang JH, Kim JJ, Choi JM, Lee JH, Cho Y. Crystal structure of the Mus81-Eme1 complex. Genes Dev 2008; 22: 1093-106. http://dx.doi.org/10.1101/gad.1618708

Blais V, Gao H, Elwell CA, Boddy MN, Gaillard PH, Russell P, McGowan CH. RNA interference inhibition of Mus81 reduces mitotic recombination in human cells. Mol Biol Cell 2004; 15: 552-62. http://dx.doi.org/10.1091/mbc.E03-08-0580

Abraham J, Lemmers B, Hande MP, Moynahan ME, Chahwan C, Ciccia A, Essers J, Hanada K, Chahwan R, Khaw AK, McPherson P, Shehabeldin A, Laister R, Arrowsmith C, Kanaar R, West SC, Jasin M, Hakem R. Eme1 is involved in DNA damage processing and maintenance of genomic stability in mammalian cells. EMBO J 2003; 22: 6137-47. http://dx.doi.org/10.1093/emboj/cdg580

Hiyama T, Katsura M, Yoshihara T, Ishida M, Kinomura A, Tonda T, Asahara T, Miyagawa K. Haploinsufficiency of the Mus81-Eme1 endonuclease activates the intra-S-phase and G2/M checkpoints and promotes rereplication in human cells. Nucleic Acids Res 2006; 34: 880-92. http://dx.doi.org/10.1093/nar/gkj495

Yang L, Yang X, Ji W, Deng J, Qiu F, Yang R, Fang W, Zhang L, Huang D, Xie C, Zhang H, Zhong N, Ran P, Zhou Y, Lu J. Effects of a functional variant c.353T>C in snai1 on risk of two contextual diseases. Chronic obstructive pulmonary disease and lung cancer. American journal of respiratory and critical care medicine 2014; 189: 139-48.

Yang L, Liu B, Huang B, Deng J, Li H, Yu B, Qiu F, Cheng M, Wang H, Yang R, Yang X, Zhou Y, Lu J. A functional copy number variation in the WWOX gene is associated with lung cancer risk in Chinese. Human molecular genetics 2013; 22: 1886-94. http://dx.doi.org/10.1093/hmg/ddt019

Liu B, Yang L, Huang B, Cheng M, Wang H, Li Y, Huang D, Zheng J, Li Q, Zhang X, Ji W, Zhou Y, Lu J. A functional copy-number variation in MAPKAPK2 predicts risk and prognosis of lung cancer. American journal of human genetics 2012; 91: 384-90. http://dx.doi.org/10.1016/j.ajhg.2012.07.003

Yang L, Li Y, Cheng M, Huang D, Zheng J, Liu B, Ling X, Li Q, Zhang X, Ji W, Zhou Y, Lu J. A functional polymorphism at microRNA-629-binding site in the 3'-untranslated region of NBS1 gene confers an increased risk of lung cancer in Southern and Eastern Chinese population. Carcinogenesis 2012; 33: 338-47. http://dx.doi.org/10.1093/carcin/bgr272

Wei Y, Wang L, Lan P, Zhao H, Pan Z, Huang J, Lu J, Wang J. The association between -1304T>G polymorphism in the promoter of MKK4 gene and the risk of sporadic colorectal cancer in southern Chinese population. Int J Cancer 2009; 125: 1876-83. http://dx.doi.org/10.1002/ijc.24575

Lu J, Yang L, Zhao H, Liu B, Li Y, Wu H, Li Q, Zeng B, Wang Y, Ji W, Zhou Y. The polymorphism and haplotypes of PIN1 gene are associated with the risk of lung cancer in Southern and Eastern Chinese populations. Human mutation 2011; 32: 1299-308. http://dx.doi.org/10.1002/humu.21574

Zhao J, Liu L, Zhang A, Chen Q, Fang W, Zeng L, Lu J. Effect of EME1 exon variant Ile350Thr on risk and early onset of breast cancer in southern Chinese women. Journal of biomedical research 2013; 27: 193-201. http://dx.doi.org/10.7555/JBR.27.20130013

Chang JS, Yeh RF, Wiencke JK, Wiemels JL, Smirnov I, Pico AR, Tihan T, Patoka J, Miike R, Sison JD, Rice T, Wrensch MR. Pathway analysis of single-nucleotide polymorphisms potentially associated with glioblastoma multiforme susceptibility using random forests. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2008; 17: 1368-73. http://dx.doi.org/10.1158/1055-9965.EPI-07-2830

Farah JA, Cromie GA, Smith GR. Ctp1 and Exonuclease 1, alternative nucleases regulated by the MRN complex, are required for efficient meiotic recombination. Proceedings of the National Academy of Sciences of the United States of America 2009; 106: 9356-61. http://dx.doi.org/10.1073/pnas.0902793106

Sarbajna S, Davies D, West SC. Roles of SLX1-SLX4, MUS81-EME1, and GEN1 in avoiding genome instability and mitotic catastrophe. Genes & development 2014; 28: 1124-36. http://dx.doi.org/10.1101/gad.238303.114

Weinandy A, Piroth MD, Goswami A, Nolte K, Sellhaus B, Gerardo-Nava J, Eble M, Weinandy S, Cornelissen C, Clusmann H, Lüscher B, Weis J. Cetuximab induces eme1-mediated DNA repair: a novel mechanism for cetuximab resistance. Neoplasia 2014; 16: 207-2. http://dx.doi.org/10.1016/j.neo.2014.03.004

Downloads

Published

2014-12-29

How to Cite

Jianwei Zhao, Yongxiu Chen, Xiaoxiao Lu, Di Wu, Jiansong Chen, Zhihuang Chen, Lin Liu, Lei Yang, Lan Zhang, Yifeng Zhou, & Jiachun Lu. (2014). The Polymorphism of EME1 Gene is Associated with an Increased Risk of Lung Cancer: A Case-Control Study from Chinese Population. Journal of Cancer Research Updates, 3(4),  174–181. https://doi.org/10.6000/1929-2279.2014.03.04.1

Issue

Section

Articles