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Helicobacter pylori-Mediated Genetic Instability and Gastric Carcinogenesis

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Molecular Pathogenesis and Signal Transduction by Helicobacter pylori

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 400))

Abstract

Helicobacter pylori infection is the most important cause of human gastric cancer worldwide. Gastric cancer develops over a long time after H. pylori infection via stepwise accumulation of genetic alterations and positive selection of cells with growth advantages. H. pylori itself and the resultant chronic inflammation lead to the emergence of genetic alterations in gastric epithelial cells via increased susceptibility of these cells to DNA damage. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) in inflammatory and gastric epithelial cells, as well as the expression of cytidine deaminase in gastric epithelial cells, may link H. pylori-related inflammation and DNA damage. Recent comprehensive analyses of gastric cancer genomes provide clues for the possible molecular mechanisms of gastric carcinogenesis. In this chapter, we describe how genetic alterations emerge during gastric carcinogenesis related to H. pylori infection.

Disclosures: The authors have no conflicts of interest.

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References

  • Agrawal N, Jiao Y, Bettegowda C, Hutfless SM, Wang Y, David S, Cheng Y, Twaddell WS, Latt NL, Shin EJ, Wang LD, Wang L, Yang W, Velculescu VE, Vogelstein B, Papadopoulos N, Kinzler KW, Meltzer SJ (2012) Comparative genomic analysis of esophageal adenocarcinoma and squamous cell carcinoma. Cancer Discov 2(10):899–905. doi:10.1158/2159-8290.CD-12-0189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Børresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjörd JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jäger N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, López-Otín C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdés-Mas R, van Buuren MM, van ‘t Veer L, Vincent-Salomon A, Waddell N, Yates LR, Australian Pancreatic Cancer Genome Initiative, ICGC Breast Cancer Consortium, ICGC MMML-Seq Consortium, ICGC PedBrain, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR (2013) Signatures of mutational processes in human cancer. Nature 500(7463):415–421. doi:10.1038/nature12477

  • Backert S, Tegtmeyer N, Fischer W (2015) Composition, structure and function of the Helicobacter pylori cag pathogenicity island encoded type IV secretion system. Future Microbiol 10(6):955–965. doi:10.2217/fmb.15.32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3(5):421–429

    Article  CAS  PubMed  Google Scholar 

  • Beale RC, Petersen-Mahrt SK, Watt IN, Harris RS, Rada C, Neuberger MS (2004) Comparison of the differential context-dependence of DNA deamination by APOBEC enzymes: correlation with mutation spectra in vivo. J Mol Biol 337(3):585–596

    Article  CAS  PubMed  Google Scholar 

  • Beck B, Blanpain C (2013) Unravelling cancer stem cell potential. Nat Rev Cancer 13(10):727–738. doi:10.1038/nrc3597

    Article  CAS  PubMed  Google Scholar 

  • Bhutani N, Brady JJ, Damian M, Sacco A, Corbel SY, Blau HM (2010) Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 463(7284):1042–1047. doi:10.1038/nature08752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borrego S, Vazquez A, Dasí F, Cerdá C, Iradi A, Tormos C, Sánchez JM, Bagán L, Boix J, Zaragoza C, Camps J, Sáez G (2013) Oxidative stress and DNA damage in human gastric carcinoma: 8-oxo-7′8-dihydro-2′-deoxyguanosine (8-oxo-dG) as a possible tumor marker. Int J Mol Sci 14(2):3467–3486. doi:10.3390/ijms14023467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bruner SD, Norman DP, Verdine GL (2000) Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA. Nature 403(6772):859–866

    Article  CAS  PubMed  Google Scholar 

  • Brungs D, Aghmesheh M, Vine KL, Becker TM, Carolan MG, Ranson M (2016) Gastric cancer stem cells: evidence, potential markers, and clinical implications. J Gastroenterol 51(4):313–326. doi:10.1007/s00535-015-1125-5

    Article  CAS  PubMed  Google Scholar 

  • Burns MB, Lackey L, Carpenter MA, Rathore A, Land AM, Leonard B, Refsland EW, Kotandeniya D, Tretyakova N, Nikas JB, Yee D, Temiz NA, Donohue DE, McDougle RM, Brown WL, Law EK, Harris RS (2013a) APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 494(7437):366–370. doi:10.1038/nature11881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burns MB, Temiz NA, Harris RS (2013b) Evidence for APOBEC3B mutagenesis in multiple human cancers. Nat Genet 45(9):977–983. doi:10.1038/ng.2701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513(7517):202–209. doi:10.1038/nature13480

    Article  Google Scholar 

  • Cascalho M (2004) Advantages and disadvantages of cytidine deamination. J Immunol 172(11):6513–6518

    Article  CAS  PubMed  Google Scholar 

  • Chan K, Roberts SA, Klimczak LJ, Sterling JF, Saini N, Malc EP, Kim J, Kwiatkowski DJ, Fargo DC, Mieczkowski PA, Getz G, Gordenin DA (2015) An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers. Nat Genet 47(9):1067–1072. doi:10.1038/ng.3378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaturvedi R, Cheng Y, Asim M, Bussière FI, Xu H, Gobert AP, Hacker A, Casero RA Jr, Wilson KT (2004) Induction of polyamine oxidase 1 by Helicobacter pylori causes macrophage apoptosis by hydrogen peroxide release and mitochondrial membrane depolarization. J Biol Chem 279(38):40161–40173

    Article  CAS  PubMed  Google Scholar 

  • Chaturvedi R, Asim M, Romero-Gallo J, Barry DP, Hoge S, de Sablet T, Delgado AG, Wroblewski LE, Piazuelo MB, Yan F, Israel DA, Casero RA Jr, Correa P, Gobert AP, Polk DB, Peek RM Jr, Wilson KT (2011) Spermine oxidase mediates the gastric cancer risk associated with Helicobacter pylori CagA. Gastroenterology. 141(5):1696–1708. e1–2. doi:10.1053/j.gastro.2011.07.045

  • Choi E, Hendley AM, Bailey JM, Leach SD, Goldenring JR (2016) Expression of activated ras in gastric chief cells of mice leads to the full spectrum of metaplastic lineage transitions. Gastroenterology 150(4):918–930. e13. doi:10.1053/j.gastro.2015.11.049

  • Correa P (1988) A human model of gastric carcinogenesis. Cancer Res 48(13):3554–3560

    CAS  PubMed  Google Scholar 

  • Cover TL, Blanke SR (2005) Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nat Rev Microbiol 3(4):320–332

    Article  CAS  PubMed  Google Scholar 

  • Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, Liu J, Yue YG, Wang J, Yu K, Ye XS, Do IG, Liu S, Gong L, Fu J, Jin JG, Choi MG, Sohn TS, Lee JH, Bae JM, Kim ST, Park SH, Sohn I, Jung SH, Tan P, Chen R, Hardwick J, Kang WK, Ayers M, Hongyue D, Reinhard C, Loboda A, Kim S, Aggarwal A (2015) Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med 21(5):449–456. doi:10.1038/nm.3850

    Article  CAS  PubMed  Google Scholar 

  • Davies GR, Simmonds NJ, Stevens TR, Sheaff MT, Banatvala N, Laurenson IF, Blake DR, Rampton DS (1994) Helicobacter pylori stimulates antral mucosal reactive oxygen metabolite production in vivo. Gut 35(2):179–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dulak AM, Stojanov P, Peng S, Lawrence MS, Fox C, Stewart C, Bandla S, Imamura Y, Schumacher SE, Shefler E, McKenna A, Carter SL, Cibulskis K, Sivachenko A, Saksena G, Voet D, Ramos AH, Auclair D, Thompson K, Sougnez C, Onofrio RC, Guiducci C, Beroukhim R, Zhou Z, Lin L, Lin J, Reddy R, Chang A, Landrenau R, Pennathur A, Ogino S, Luketich JD, Golub TR, Gabriel SB, Lander ES, Beer DG, Godfrey TE, Getz G, Bass AJ (2013) Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat Genet 45(5):478–486. doi:10.1038/ng.2591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Esashi F, Christ N, Gannon J, Liu Y, Hunt T, Jasin M, West SC (2005) CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 434(7033):598–604

    Article  CAS  PubMed  Google Scholar 

  • Eso Y, Takai A, Matsumoto T, Inuzuka T, Horie T, Ono K, Uemoto S, Lee K, Edelmann W, Chiba T, Marusawa H (2015) MSH2 dysregulation is triggered by proinflammatory cytokine stimulation and is associated with liver cancer development. Cancer Res 76(15):1–11. doi:10.1158/0008-5472.CAN-15-2926

    Google Scholar 

  • Gao YB, Chen ZL, Li JG, Hu XD, Shi XJ, Sun ZM, Zhang F, Zhao ZR, Li ZT, Liu ZY, Zhao YD, Sun J, Zhou CC, Yao R, Wang SY, Wang P, Sun N, Zhang BH, Dong JS, Yu Y, Luo M, Feng XL, Shi SS, Zhou F, Tan FW, Qiu B, Li N, Shao K, Zhang LJ, Zhang LJ, Xue Q, Gao SG, He J (2014) Genetic landscape of esophageal squamous cell carcinoma. Nat Genet 46(10):1097–1102. doi:10.1038/ng.3076

    Article  CAS  PubMed  Google Scholar 

  • Gobert AP, Wilson KT (2016) The immune battle against Helicobacter pylori infection: no offense. Trends Microbiol 24(5):366–376. doi:10.1016/j.tim.2016.02.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goldenring JR, Nam KT, Wang TC, Mills JC, Wright NA (2010) Spasmolytic polypeptide-expressing metaplasia and intestinal metaplasia: time for reevaluation of metaplasias and the origins of gastric cancer. Gastroenterology 138(7):2207–2210, 2210. e1. doi:10.1053/j.gastro.2010.04.023

  • Hanada K, Uchida T, Tsukamoto Y, Watada M, Yamaguchi N, Yamamoto K, Shiota S, Moriyama M, Graham DY, Yamaoka Y (2014) Helicobacter pylori infection introduces DNA double-strand breaks in host cells. Infect Immun 82(10):4182–4189. doi:10.1128/IAI.02368-14

    Article  PubMed  PubMed Central  Google Scholar 

  • Handa O, Naito Y, Yoshikawa T (2011) Redox biology and gastric carcinogenesis: the role of Helicobacter pylori. Redox Rep 16(1):1–7. doi:10.1179/174329211X12968219310756

    Article  CAS  PubMed  Google Scholar 

  • Hardbower DM, Peek RM Jr, Wilson KT (2014) At the bench: Helicobacter pylori, dysregulated host responses, DNA damage, and gastric cancer. J Leukoc Biol 96(2):201–212. doi:10.1189/jlb.4BT0214-099R

    Article  PubMed  PubMed Central  Google Scholar 

  • Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, Watt IN, Neuberger MS, Malim MH (2003) DNA deamination mediates innate immunity to retroviral infection. Cell 113(6):803–809

    Article  CAS  PubMed  Google Scholar 

  • Hartung ML, Gruber DC, Koch KN, Grüter L, Rehrauer H, Tegtmeyer N, Backert S, Müller A (2015) H. pylori-Induced DNA strand breaks are introduced by nucleotide excision repair endonucleases and promote NF-κB target gene expression. Cell Rep 13(1):70–79. doi:10.1016/j.celrep.2015.08.074

  • Hayakawa Y, Fox JG, Gonda T, Worthley DL, Muthupalani S, Wang TC (2013) Mouse models of gastric cancer. Cancers (Basel) 5(1):92–130. doi:10.3390/cancers5010092

    Article  PubMed Central  Google Scholar 

  • Heitzer E, Tomlinson I (2014) Replicative DNA polymerase mutations in cancer. Curr Opin Genet Dev 24:107–113. doi:10.1016/j.gde.2013.12.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Helleday T, Eshtad S, Nik-Zainal S (2014) Mechanisms underlying mutational signatures in human cancers. Nat Rev Genet 15(9):585–598. doi:10.1038/nrg3729

    Article  CAS  PubMed  Google Scholar 

  • Hussain SP, Hofseth LJ, Harris CC (2003) Radical causes of cancer. Nat Rev Cancer 3(4):276–285

    Article  CAS  PubMed  Google Scholar 

  • Imai K, Yamamoto H (2008) Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics. Carcinogenesis 29(4):673–680

    Article  CAS  PubMed  Google Scholar 

  • Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H, Oshima M, Ikeda T, Asaba R, Yagi H, Masuko T, Shimizu T, Ishikawa T, Kai K, Takahashi E, Imamura Y, Baba Y, Ohmura M, Suematsu M, Baba H, Saya H (2011) CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth. Cancer Cell 19(3):387–400. doi:10.1016/j.ccr.2011.01.038

    Article  CAS  PubMed  Google Scholar 

  • Jayaraman SS, Rayhan DJ, Hazany S, Kolodney MS (2014) Mutational landscape of basal cell carcinomas by whole-exome sequencing. J Invest Dermatol 134(1):213–220. doi:10.1038/jid.2013.276

    Article  CAS  PubMed  Google Scholar 

  • Kakiuchi M, Nishizawa T, Ueda H, Gotoh K, Tanaka A, Hayashi A, Yamamoto S, Tatsuno K, Katoh H, Watanabe Y, Ichimura T, Ushiku T, Funahashi S, Tateishi K, Wada I, Shimizu N, Nomura S, Koike K, Seto Y, Fukayama M, Aburatani H, Ishikawa S (2014) Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet 46(6):583–587. doi:10.1038/ng.2984

    Article  CAS  PubMed  Google Scholar 

  • Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, Leiserson MD, Miller CA, Welch JS, Walter MJ, Wendl MC, Ley TJ, Wilson RK, Raphael BJ, Ding L (2013) Mutational landscape and significance across 12 major cancer types. Nature 502(7471):333–339. doi:10.1038/nature12634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim JJ, Tao H, Carloni E, Leung WK, Graham DY, Sepulveda AR (2002) Helicobacter pylori impairs DNA mismatch repair in gastric epithelial cells. Gastroenterology 123(2):542–553

    Article  CAS  PubMed  Google Scholar 

  • Kim H, An JY, Noh SH, Shin SK, Lee YC, Kim H (2011) High microsatellite instability predicts good prognosis in intestinal-type gastric cancers. J Gastroenterol Hepatol 26(3):585–592. doi:10.1111/j.1440-1746.2010.06487.x

    Article  CAS  PubMed  Google Scholar 

  • Kim TM, Jung SH, Kim MS, Baek IP, Park SW, Lee SH, Lee HH, Kim SS, Chung YJ, Lee SH (2014) The mutational burdens and evolutionary ages of early gastric cancers are comparable to those of advanced gastric cancers. J Pathol 234(3):365–374. doi:10.1002/path.4401

    Article  CAS  PubMed  Google Scholar 

  • Koeppel M, Garcia-Alcalde F, Glowinski F, Schlaermann P, Meyer TF (2015) Helicobacter pylori infection causes characteristic DNA damage patterns in human cells. Cell Rep 11(11):1703–1713. doi:10.1016/j.celrep.2015.05.030

    Article  CAS  PubMed  Google Scholar 

  • Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, Cheng E, Davis MJ, Goh G, Choi M, Ariyan S, Narayan D, Dutton-Regester K, Capatana A, Holman EC, Bosenberg M, Sznol M, Kluger HM, Brash DE, Stern DF, Materin MA, Lo RS, Mane S, Ma S, Kidd KK, Hayward NK, Lifton RP, Schlessinger J, Boggon TJ, Halaban R (2012) Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 44(9):1006–1014. doi:10.1038/ng.2359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lange SS, Takata K, Wood RD (2011) DNA polymerases and cancer. Nat Rev Cancer 11(2):96–110. doi:10.1038/nrc2998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lau WM, Teng E, Chong HS, Lopez KA, Tay AY, Salto-Tellez M, Shabbir A, So JB, Chan SL (2014) CD44v8-10 is a cancer-specific marker for gastric cancer stem cells. Cancer Res 74(9):2630–2641. doi:10.1158/0008-5472.CAN-13-2309

    Article  CAS  PubMed  Google Scholar 

  • Lauren P (1965) The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 64:31–49

    CAS  PubMed  Google Scholar 

  • Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortés ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Lee RS, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CW, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499(7457):214–218. doi:10.1038/nature12213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee BM, Jang JJ, Kim HS (1998) Benzo[a]pyrene diol-epoxide-I-DNA and oxidative DNA adducts associated with gastric adenocarcinoma. Cancer Lett 125(1–2):61–68

    Article  CAS  PubMed  Google Scholar 

  • Lin DC, Hao JJ, Nagata Y, Xu L, Shang L, Meng X, Sato Y, Okuno Y, Varela AM, Ding LW, Garg M, Liu LZ, Yang H, Yin D, Shi ZZ, Jiang YY, Gu WY, Gong T, Zhang Y, Xu X, Kalid O, Shacham S, Ogawa S, Wang MR, Koeffler HP (2014) Genomic and molecular characterization of esophageal squamous cell carcinoma. Nat Genet 46(5):467–473. doi:10.1038/ng.2935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu M, Schatz DG (2009) Balancing AID and DNA repair during somatic hypermutation. Trends Immunol 30(4):173–181. doi:10.1016/j.it.2009.01.007

    Article  PubMed  Google Scholar 

  • Machado AM, Figueiredo C, Touati E, Máximo V, Sousa S, Michel V, Carneiro F, Nielsen FC, Seruca R, Rasmussen LJ (2009) Helicobacter pylori infection induces genetic instability of nuclear and mitochondrial DNA in gastric cells. Clin Cancer Res 15(9):2995–3002. doi:10.1158/1078-0432.CCR-08-2686

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto Y, Marusawa H, Kinoshita K, Endo Y, Kou T, Morisawa T, Azuma T, Okazaki IM, Honjo T, Chiba T (2007) Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat Med 13(4):470–476

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto Y, Marusawa H, Kinoshita K, Niwa Y, Sakai Y, Chiba T (2010) Up-regulation of activation-induced cytidine deaminase causes genetic aberrations at the CDKN2b-CDKN2a in gastric cancer. Gastroenterology 139(6):1984–1994. doi:10.1053/j.gastro.2010.07.010

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto T, Shimizu T, Nishijima N, Ikeda A, Eso Y, Matsumoto Y, Chiba T, Marusawa H (2015a) Hepatic inflammation facilitates transcription-associated mutagenesis via AID activity and enhances liver tumorigenesis. Carcinogenesis 36(8):904–913. doi:10.1093/carcin/bgv065

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto T, Shimizu T, Takai A, Marusawa H (2015b) Exploring the mechanisms of gastrointestinal cancer development using deep sequencing analysis. Cancers (Basel) 7(2):1037–1051. doi:10.3390/cancers7020823

    Article  Google Scholar 

  • Morisawa T, Marusawa H, Ueda Y, Iwai A, Okazaki IM, Honjo T, Chiba T (2008) Organ-specific profiles of genetic changes in cancers caused by activation-induced cytidine deaminase expression. Int J Cancer 123(12):2735–2740. doi:10.1002/ijc.23853

    Article  CAS  PubMed  Google Scholar 

  • Nagarajan N, Bertrand D, Hillmer AM, Zang ZJ, Yao F, Jacques PÉ, Teo AS, Cutcutache I, Zhang Z, Lee WH, Sia YY, Gao S, Ariyaratne PN, Ho A, Woo XY, Veeravali L, Ong CK, Deng N, Desai KV, Khor CC, Hibberd ML, Shahab A, Rao J, Wu M, Teh M, Zhu F, Chin SY, Pang B, So JB, Bourque G, Soong R, Sung WK, Tean Teh B, Rozen S, Ruan X, Yeoh KG, Tan PB, Ruan Y (2012) Whole-genome reconstruction and mutational signatures in gastric cancer. Genome Biol 13(12):R115. doi:10.1186/gb-2012-13-12-r115

    Article  PubMed  PubMed Central  Google Scholar 

  • Nagata N, Akiyama J, Marusawa H, Shimbo T, Liu Y, Igari T, Nakashima R, Watanabe H, Uemura N, Chiba T (2014) Enhanced expression of activation-induced cytidine deaminase in human gastric mucosa infected by Helicobacter pylori and its decrease following eradication. J Gastroenterol 49(3):427–435. doi:10.1007/s00535-013-0808-z

    Article  CAS  PubMed  Google Scholar 

  • Naito Y, Yoshikawa T (2002) Molecular and cellular mechanisms involved in Helicobacter pylori-induced inflammation and oxidative stress. Free Radic Biol Med 33(3):323–336

    Article  CAS  PubMed  Google Scholar 

  • Nam KT, Lee HJ, Sousa JF, Weis VG, O’Neal RL, Finke PE, Romero-Gallo J, Shi G, Mills JC, Peek RM Jr, Konieczny SF, Goldenring JR (2010) Mature chief cells are cryptic progenitors for metaplasia in the stomach. Gastroenterology 139(6):2028–2037. e9. doi:10.1053/j.gastro.2010.09.005

  • Nicolai S, Rossi A, Di Daniele N, Melino G, Annicchiarico-Petruzzelli M, Raschellà G (2015) DNA repair and aging: the impact of the p53 family. Aging (Albany NY) 7(12):1050–1065

    Article  PubMed Central  Google Scholar 

  • Nielsen M, Hes FJ, Nagengast FM, Weiss MM, Mathus-Vliegen EM, Morreau H, Breuning MH, Wijnen JT, Tops CM, Vasen HF (2007) Germline mutations in APC and MUTYH are responsible for the majority of families with attenuated familial adenomatous polyposis. Clin Genet 71(5):427–433

    Article  CAS  PubMed  Google Scholar 

  • Noguchi C, Ishino H, Tsuge M, Fujimoto Y, Imamura M, Takahashi S, Chayama K (2005) G to A hypermutation of hepatitis B virus. Hepatology 41(3):626–633

    Article  CAS  PubMed  Google Scholar 

  • Nones K, Waddell N, Wayte N, Patch AM, Bailey P, Newell F, Holmes O, Fink JL, Quinn MC, Tang YH, Lampe G, Quek K, Loffler KA, Manning S, Idrisoglu S, Miller D, Xu Q, Waddell N, Wilson PJ, Bruxner TJ, Christ AN, Harliwong I, Nourse C, Nourbakhsh E, Anderson M, Kazakoff S, Leonard C, Wood S, Simpson PT, Reid LE, Krause L, Hussey DJ, Watson DI, Lord RV, Nancarrow D, Phillips WA, Gotley D, Smithers BM, Whiteman DC, Hayward NK, Campbell PJ, Pearson JV, Grimmond SM, Barbour AP (2014) Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis. Nat Commun 5:5224. doi:10.1038/ncomms6224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okazaki IM, Hiai H, Kakazu N, Yamada S, Muramatsu M, Kinoshita K, Honjo T (2003) Constitutive expression of AID leads to tumorigenesis. J Exp Med 197(9):1173–1181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olivier M, Weninger A, Ardin M, Huskova H, Castells X, Vallée MP, McKay J, Nedelko T, Muehlbauer KR, Marusawa H, Alexander J, Hazelwood L, Byrnes G, Hollstein M, Zavadil J (2014) Modelling mutational landscapes of human cancers in vitro. Sci Rep 4:4482. doi:10.1038/srep04482

    Article  PubMed  PubMed Central  Google Scholar 

  • Park DI, Park SH, Kim SH, Kim JW, Cho YK, Kim HJ, Sohn CI, Jeon WK, Kim BI, Cho EY, Kim EJ, Chae SW, Sohn JH, Sung IK, Sepulveda AR, Kim JJ (2005) Effect of Helicobacter pylori infection on the expression of DNA mismatch repair protein. Helicobacter 10(3):179–184

    Article  CAS  PubMed  Google Scholar 

  • Pfeifer GP (2006) Mutagenesis at methylated CpG sequences. Curr Top Microbiol Immunol 301:259–281

    CAS  PubMed  Google Scholar 

  • Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P (2002) Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 21(48):7435–7451

    Article  CAS  PubMed  Google Scholar 

  • Popp C, Dean W, Feng S, Cokus SJ, Andrews S, Pellegrini M, Jacobsen SE, Reik W (2010) Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature 463(7284):1101–1105. doi:10.1038/nature08829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rayner E, van Gool IC, Palles C, Kearsey SE, Bosse T, Tomlinson I, Church DN (2016) A panoply of errors: polymerase proofreading domain mutations in cancer. Nat Rev Cancer 16(2):71–81. doi:10.1038/nrc.2015.12

    Article  CAS  PubMed  Google Scholar 

  • Rycaj K, Tang DG (2015) Cell-of-origin of cancer versus cancer stem cells: assays and interpretations. Cancer Res 75(19):4003–4011. doi:10.1158/0008-5472.CAN-15-0798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmitz K-M, Petersen-Mahrt SK (2012) AIDing the immune system-DIAbolic in cancer. Semin Immunol 24(4):241–245. doi:10.1016/j.smim.2012.07.001

    Article  CAS  PubMed  Google Scholar 

  • Shah SN, Hile SE, Eckert KA (2010) Defective mismatch repair, microsatellite mutation bias, and variability in clinical cancer phenotypes. Cancer Res 70(2):431–435. doi:10.1158/0008-5472.CAN-09-3049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shiloh Y, Ziv Y (2013) The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 14(4):197–210

    Article  CAS  Google Scholar 

  • Shimizu T, Choi E, Petersen CP, Noto JM, Romero-Gallo J, Piazuelo MB, Washington MK, Peek RM Jr, Goldenring JR (2016) Characterization of progressive metaplasia in the gastric corpus mucosa of Mongolian gerbils infected with Helicobacter pylori. J Pathol 239(4):399–410. doi:10.1002/path.4735

    Article  CAS  PubMed  Google Scholar 

  • Shimizu T, Marusawa H, Matsumoto Y, Inuzuka T, Ikeda A, Fujii Y, Minamiguchi S, Miyamoto S, Kou T, Sakai Y, Crabtree JE, Chiba T (2014) Accumulation of somatic mutations in TP53 in gastric epithelium with Helicobacter pylori infection. Gastroenterology 147(2):407–417. e3. doi:10.1053/j.gastro.2014.04.036

  • Shinohara M, Io K, Shindo K, Matsui M, Sakamoto T, Tada K, Kobayashi M, Kadowaki N, Takaori-Kondo A (2012) APOBEC3B can impair genomic stability by inducing base substitutions in genomic DNA in human cells. Sci Rep 2:806. doi:10.1038/srep00806

    Article  PubMed  PubMed Central  Google Scholar 

  • Song Y, Li L, Ou Y, Gao Z, Li E, Li X, Zhang W, Wang J, Xu L, Zhou Y, Ma X, Liu L, Zhao Z, Huang X, Fan J, Dong L, Chen G, Ma L, Yang J, Chen L, He M, Li M, Zhuang X, Huang K, Qiu K, Yin G, Guo G, Feng Q, Chen P, Wu Z, Wu J, Ma L, Zhao J, Luo L, Fu M, Xu B, Chen B, Li Y, Tong T, Wang M, Liu Z, Lin D, Zhang X, Yang H, Wang J, Zhan Q (2014) Identification of genomic alterations in oesophageal squamous cell cancer. Nature 509(7498):91–95. doi:10.1038/nature13176

    Article  CAS  PubMed  Google Scholar 

  • Stavnezer J (2011) Complex regulation and function of activation-induced cytidine deaminase. Trends Immunol 32(5):194–201. doi:10.1016/j.it.2011.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stracker TH, Petrini JH (2011) The MRE11 complex: starting from the ends. Nat Rev Mol Cell Biol 12(2):90–103. doi:10.1038/nrm3047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stratton MR, Campbell PJ, Futreal PA (2009) The cancer genome. Nature 458(7239):719–724. doi:10.1038/nature07943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki H, Miura S, Imaeda H, Suzuki M, Han JY, Mori M, Fukumura D, Tsuchiya M, Ishii H (1996) Enhanced levels of chemiluminescence and platelet activating factor in urease-positive gastric ulcers. Free Radic Biol Med 20(3):449–454

    Article  CAS  PubMed  Google Scholar 

  • Toller IM, Neelsen KJ, Steger M, Hartung ML, Hottiger MO, Stucki M, Kalali B, Gerhard M, Sartori AA, Lopes M, Müller A (2011) Carcinogenic bacterial pathogen Helicobacter pylori triggers DNA double-strand breaks and a DNA damage response in its host cells. Proc Natl Acad Sci U S A 108(36):14944–14949. doi:10.1073/pnas.1100959108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsugawa H, Suzuki H, Saya H, Hatakeyama M, Hirayama T, Hirata K, Nagano O, Matsuzaki J, Hibi T (2012) Reactive oxygen species-induced autophagic degradation of Helicobacter pylori CagA is specifically suppressed in cancer stem-like cells. Cell Host Microbe 12(6):764–777. doi:10.1016/j.chom.2012.10.014

    Article  CAS  PubMed  Google Scholar 

  • Uchida M, Tsukamoto Y, Uchida T, Ishikawa Y, Nagai T, Hijiya N, Nguyen LT, Nakada C, Kuroda A, Okimoto T, Kodama M, Murakami K, Noguchi T, Matsuura K, Tanigawa M, Seto M, Ito H, Fujioka T, Takeuchi I, Moriyama M (2010) Genomic profiling of gastric carcinoma in situ and adenomas by array-based comparative genomic hybridization. J Pathol 221(1):96–105. doi:10.1002/path.2686

    Article  CAS  PubMed  Google Scholar 

  • van Gent DC, Hoeijmakers JH, Kanaar R (2001) Chromosomal stability and the DNA double-stranded break connection. Nat Rev Genet 2(3):196–206

    Article  PubMed  Google Scholar 

  • Wada T, Ishimoto T, Seishima R, Tsuchihashi K, Yoshikawa M, Oshima H, Oshima M, Masuko T, Wright NA, Furuhashi S, Hirashima K, Baba H, Kitagawa Y, Saya H, Nagano O (2013) Functional role of CD44v-xCT system in the development of spasmolytic polypeptide-expressing metaplasia. Cancer Sci 104(10):1323–1329. doi:10.1111/cas.12236

    Article  CAS  PubMed  Google Scholar 

  • Wang K, Kan J, Yuen ST, Shi ST, Chu KM, Law S, Chan TL, Kan Z, Chan AS, Tsui WY, Lee SP, Ho SL, Chan AK, Cheng GH, Roberts PC, Rejto PA, Gibson NW, Pocalyko DJ, Mao M, Xu J, Leung SY (2011) Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat Genet 43(12):1219–1223. doi:10.1038/ng.982

    Article  CAS  PubMed  Google Scholar 

  • Wang K, Yuen ST, Xu J, Lee SP, Yan HH, Shi ST, Siu HC, Deng S, Chu KM, Law S, Chan KH, Chan AS, Tsui WY, Ho SL, Chan AK, Man JL, Foglizzo V, Ng MK, Chan AS, Ching YP, Cheng GH, Xie T, Fernandez J, Li VS, Clevers H, Rejto PA, Mao M, Leung SY (2014) Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet 46(6):573–582. doi:10.1038/ng.2983

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Simpson ER, Brown KA (2015) p53: protection against tumor growth beyond effects on cell cycle and apoptosis. Cancer Res 75(23):5001–5007. doi:10.1158/0008-5472.CAN-15-0563

    Article  CAS  PubMed  Google Scholar 

  • WHO (2010) Classification of tumours of the digestive system, 4th edn. IARC, Lyon

    Google Scholar 

  • Xu H, Chaturvedi R, Cheng Y, Bussiere FI, Asim M, Yao MD, Potosky D, Meltzer SJ, Rhee JG, Kim SS, Moss SF, Hacker A, Wang Y, Casero RA Jr, Wilson KT (2004) Spermine oxidation induced by Helicobacter pylori results in apoptosis and DNA damage: implications for gastric carcinogenesis. Cancer Res 64(23):8521–8525

    Article  CAS  PubMed  Google Scholar 

  • Yoshizawa N, Takenaka Y, Yamaguchi H, Tetsuya T, Tanaka H, Tatematsu M, Nomura S, Goldenring JR, Kaminishi M (2007) Emergence of spasmolytic polypeptide-expressing metaplasia in Mongolian gerbils infected with Helicobacter pylori. Lab Invest 87(12):1265–1276

    Article  CAS  PubMed  Google Scholar 

  • Zang ZJ, Cutcutache I, Poon SL, Zhang SL, McPherson JR, Tao J, Rajasegaran V, Heng HL, Deng N, Gan A, Lim KH, Ong CK, Huang D, Chin SY, Tan IB, Ng CC, Yu W, Wu Y, Lee M, Wu J, Poh D, Wan WK, Rha SY, So J, Salto-Tellez M, Yeoh KG, Wong WK, Zhu YJ, Futreal PA, Pang B, Ruan Y, Hillmer AM, Bertrand D, Nagarajan N, Rozen S, Teh BT, Tan P (2012) Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet 44(5):570–574. doi:10.1038/ng.2246

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Yoshiko Nagai for her help to draw the figures.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan

    Takahiro Shimizu, Tsutomu Chiba & Hiroyuki Marusawa

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  1. Takahiro Shimizu
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  2. Tsutomu Chiba
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  3. Hiroyuki Marusawa
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Correspondence to Tsutomu Chiba .

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  1. Division of Microbiology, Department of Biology, Friedrich Alexander University Erlangen/Nuremberg, Erlangen, Germany

    Nicole Tegtmeyer

  2. Divisioin of Microbiology, Department of Biology, Friedrich Alexander University Erlangen/Nuremberg, Erlangen, Germany

    Steffen Backert

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Shimizu, T., Chiba, T., Marusawa, H. (2017). Helicobacter pylori-Mediated Genetic Instability and Gastric Carcinogenesis. In: Tegtmeyer, N., Backert, S. (eds) Molecular Pathogenesis and Signal Transduction by Helicobacter pylori. Current Topics in Microbiology and Immunology, vol 400. Springer, Cham. https://doi.org/10.1007/978-3-319-50520-6_13

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