Molecular Pathology and Diagnostics in Esophago-gastric Cancer

  • Rodney E. Shackelford
  • Maisoun Qassim Abdelbaqi
  • Khaldoon Almhanna
  • Kenneth Meredith
  • Domenico CoppolaEmail author
Part of the Cancer Growth and Progression book series (CAGP, volume 16)


Esophageal and gastric cancers are the eighth and fourth most common cancers worldwide, respectively. Because of their often-aggressive clinical courses and high fatality rates, they represent the sixth and second most common causes of cancer deaths worldwide. The diagnosis of these malignancies is mainly established by their clinical presentation, combined with biopsy and subsequent histologic analysis of hematoxylin-eosin-stained tissue sections. Recently, however, molecular studies have become increasingly important in establishing a diagnosis and prognosis and guiding the clinical management of these malignancies. For some subtypes of these malignancies, such as hereditary diffuse gastric cancer, molecular diagnostics is central in establishing a diagnosis and in determining appropriate clinical management. Here, we review current methods and recommendations for molecular-genetic testing for esophageal and gastric cancers and briefly discuss future possible applications of this technology to these malignancies.


Esophageal cancer Gastric cancer Gastrointestinal stromal tumor CDX2 miRNA Microarray H. pylori Diffuse gastric carcinoma 



Barrett’s esophagitis


Denaturing high-performance liquid chromatography


Esophageal adenocarcinoma


Esophageal squamous cell carcinoma


Esophageal squamous dysplasia


Gastrointestinal stromal tumors




Non-steroidal anti-inflammatory drugs


Days post-operatively


  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108PubMedGoogle Scholar
  2. 2.
    Miller BA, Kolonel LN, Bernstein L, Young JL, Swanson GM, West D, Key CR, Liff JM, Glover CS, Alexander GA et al (eds) (1996) Racial/Ethnic patterns of cancer in the United States 1988–1992. NIH publication no. 96–4104. National Cancer Institute, BethesdaGoogle Scholar
  3. 3.
    Kamangar F, Chow WH, Abnet CC, Dawsey SM (2009) Environmental causes of esophageal cancer. Gastroenterol Clin North Am 38:27–57PubMedGoogle Scholar
  4. 4.
    Daly JM, Fry WA, Little AG, Winchester DP, McKee RF, Stewart AK, Fremgen AM (2000) Esophageal cancer: results of an American College of Surgeons Patient Care Evaluation Study. J Am Coll Surg 190:562–572PubMedGoogle Scholar
  5. 5.
    Blot WJ, Devesa SS, Kneller RW, Fraumeni JF (1991) Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 265:1287–1289PubMedGoogle Scholar
  6. 6.
    Botterweck AA, Schouten LJ, Volovics A, Dorant E, van Den Brandt PA (2000) Trends in incidence of adenocarcinoma of the oesophagus and gastric cardia in ten European countries. Int J Epidemiol 29:645–654PubMedGoogle Scholar
  7. 7.
    Hongo M, Nagasaki Y, Shoji T (2009) Epidemiology of esophageal cancer: orient to occident, effects of chronology, geography and ethnicity. J Gastroenterol Hepatol 24:729–735PubMedGoogle Scholar
  8. 8.
    Devesa SS, Blot WJ, Fraumeni JF Jr (1998) Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 83:2049–2053PubMedGoogle Scholar
  9. 9.
    Newnham A, Quinn MJ, Babb P, Kang JY, Majeed A (2003) Trends in the subsite and morphology of oesophageal and gastric cancer in England and Wales 1971–1998. Aliment Pharmacol Ther 17:665–676PubMedGoogle Scholar
  10. 10.
    Craver LF (1932) Clinical study of etiology of gastric and esophageal carcinoma. Am J Cancer 16:68–102Google Scholar
  11. 11.
    Watson WL (1939) Cancer of the esophagus: some etiological considerations. Am J Roentgenol 41:420–424Google Scholar
  12. 12.
    Boffetta P, Garfinkel L (1990) Alcohol drinking and mortality among men enrolled in an American cancer society prospective study. Epidemiology 1:342–348PubMedGoogle Scholar
  13. 13.
    Freedman ND, Abnet CC, Leitzmann MF, Mouw T, Subar AF, Hollenbeck AR, Schatzkin A (2007) A prospective study of tobacco, alcohol, and the risk of esophageal and gastric cancer subtypes. Am J Epidemiol 165:1424–1433PubMedGoogle Scholar
  14. 14.
    Morita M, Kumashiro R, Kubo N, Nakashima Y, Yoshida R, Yoshinaga K, Saeki H, Emi Y, Kakeji Y, Sakaguchi Y, Toh Y, Maehara Y (2010) Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: epidemiology, clinical findings, and prevention. Int J Clin Oncol 15:126–134PubMedGoogle Scholar
  15. 15.
    Testino G, Borro P (2010) Alcohol and gastrointestinal oncology. World J Gastrointest Oncol 2:322–325PubMedGoogle Scholar
  16. 16.
    Yu HS, Oyama T, Isse T, Kitagawa K, Pham TT, Tanaka M, Kawamoto T (2010) Formation of acetaldehyde-derived DNA adducts due to alcohol exposure. Chem Biol Interact 188:367–375PubMedGoogle Scholar
  17. 17.
    Millonig G, Wang Y, Homann N, Bernhardt F, Qin H, Mueller S, Bartsch H, Seitz HK (2011) Ethanol-mediated carcinogenesis in the human esophagus implicates CYP2E1 induction and the generation of carcinogenic DNA-lesions. Int J Cancer 128:533–540PubMedGoogle Scholar
  18. 18.
    Boffetta P, Hashibe M (2006) Alcohol and cancer. Lancet Oncol 7:149–156PubMedGoogle Scholar
  19. 19.
    U.S. Department of Health and Human Services (USDHHS) (1989) Reducing the health consequences of smoking: 25 years of progress: a report of the surgeon general. US Government Press Office, Washington, DCGoogle Scholar
  20. 20.
    Hecht SS (1999) Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 91:1194–1210PubMedGoogle Scholar
  21. 21.
    Moeller DW, Sun LS (2010) Chemical and radioactive carcinogens in cigarettes: associated health impacts and responses of the tobacco industry, U.S. congress, and federal regulatory agencies. Health Phys 99:674–679PubMedGoogle Scholar
  22. 22.
    Wang GQ, Abnet CC, Shen Q, Lewin KJ, Sun XD, Roth MJ, Qiao YL, Mark SD, Dong ZW, Taylor PR, Dawsey SM (2005) Histological precursors of oesophageal squamous cell carcinoma: results from a 13 year prospective follow up study in a high risk population. Gut 54:187–192PubMedGoogle Scholar
  23. 23.
    Castellsagué X, Muñoz N, De Stefani E, Victora C, Castelletto R, Rolón P, Quintana M (1999) Independent and joint effects of tobacco smoking and alcohol drinking on the risk of esophageal cancer in men and women. Int J Cancer 82:657–664PubMedGoogle Scholar
  24. 24.
    Pitt JI (2000) Toxigenic fungi and mycotoxins. Br Med Bull 56:184–192PubMedGoogle Scholar
  25. 25.
    Pitt JI, Basílico JC, Abarca ML, López C (2000) Mycotoxins and toxigenic fungi. Med Mycol 38(Suppl 1):41–46PubMedGoogle Scholar
  26. 26.
    Riley RT, Wang E, Schroeder JJ, Smith ER, Plattner RD, Abbas H, Yoo HS, Merrill AH Jr (1996) Evidence for disruption of sphingolipid metabolism as a contributing factor in the toxicity and carcinogenicity of fumonisins. Nat Toxins 4:3–15PubMedGoogle Scholar
  27. 27.
    Sun G, Wang S, Hu X, Su J, Huang T, Yu J, Tang L, Gao W, Wang JS (2007) Fumonisin B1 contamination of home-grown corn in high-risk areas for esophageal and liver cancer in China. Food Addit Contam 24:181–185PubMedGoogle Scholar
  28. 28.
    Marasas WF (2001) Discovery and occurrence of the fumonisins: a historical perspective. Environ Health Perspect 109(Suppl 2):239–243PubMedGoogle Scholar
  29. 29.
    Lim CW, Parker HM, Vesonder RF, Haschek WM (1996) Intravenous fumonisin B1 induces cell proliferation and apoptosis in the rat. Nat Toxins 4:34–41PubMedGoogle Scholar
  30. 30.
    Hewer T, Rose E, Ghadirian P, Castegnaro M, Malaveille C, Bartsch H, Day N (1978) Ingested mutagens from opium and tobacco pyrolysis products and cancer of the oesophagus. Lancet 2:494–496PubMedGoogle Scholar
  31. 31.
    Malaveille C, Friesen M, Camus AM, Garren L, Hautefeuille A, Béréziat JC, Ghadirian P, Day NE, Bartsch H (1982) Mutagens produced by the pyrolysis of opium and its alkaloids as possible risk factors in cancer of the bladder and oesophagus. Carcinogenesis 3:577–585PubMedGoogle Scholar
  32. 32.
    Nasrollahzadeh D, Kamangar F, Aghcheli K, Sotoudeh M, Islami F, Abnet CC, Shakeri R, Pourshams A, Marjani HA, Nouraie M, Khatibian M, Semnani S, Ye W, Boffetta P, Dawsey SM, Malekzadeh R (2008) Opium, tobacco, and alcohol use in relation to oesophageal squamous cell carcinoma in a high-risk area of Iran. Br J Cancer 98:1857–1863PubMedGoogle Scholar
  33. 33.
    Loria D, Barrios E, Zanetti R (2009) Cancer and yerba mate consumption: a review of possible associations. Rev Panam Salud Publica 25:530–539PubMedGoogle Scholar
  34. 34.
    Szymańska K, Matos E, Hung RJ, Wünsch-Filho V, Eluf-Neto J, Menezes A, Daudt AW, Brennan P, Boffetta P (2010) Drinking of maté and the risk of cancers of the upper aerodigestive tract in Latin America: a case–control study. Cancer Causes Control 21:1799–1806PubMedGoogle Scholar
  35. 35.
    Sewram V, De Stefani E, Brennan P, Boffetta P (2003) Maté consumption and the risk of squamous cell esophageal cancer in Uruguay. Cancer Epidemiol Biomarkers Prev 12:508–513PubMedGoogle Scholar
  36. 36.
    Vieira MA, Maraschin M, Rovaris AA, Amboni RD, Pagliosa CM, Xavier JJ, Amante ER (2010) Occurrence of polycyclic aromatic hydrocarbons throughout the processing stages of erva-mate (Ilex paraguariensis). Food Addit Contam Part A Chem Anal Control Expo Risk Assess 27:776–782PubMedGoogle Scholar
  37. 37.
    Kamangar F, Schantz MM, Abnet CC, Fagundes RB, Dawsey SM (2008) High levels of carcinogenic polycyclic aromatic hydrocarbons in mate drinks. Cancer Epidemiol Biomarkers Prev 17:1262–1268PubMedGoogle Scholar
  38. 38.
    Fagundes RB, Abnet CC, Strickland PT, Kamangar F, Roth MJ, Taylor PR, Dawsey SM (2006) Higher urine 1-hydroxy pyrene glucuronide (1-OHPG) is associated with tobacco smoke exposure and drinking maté in healthy subjects from Rio Grande do Sul, Brazil. BMC Cancer 6:139PubMedGoogle Scholar
  39. 39.
    Mbulaiteye SM, Hisada M, El-Omar EM (2009) Helicobacter pylori associated global gastric cancer burden. Front Biosci 14:1490–1504Google Scholar
  40. 40.
    Islami F, Kamangar F (2008) Helicobacter pylori and esophageal cancer risk – a meta-analysis. Cancer Prev Res 1:329–338Google Scholar
  41. 41.
    Rokkas T, Pistiolas D, Sechopoulos P, Robotis I, Margantinis G (2007) Relationship between Helicobacter pylori infection and esophageal neoplasia: a meta-analysis. Clin Gastroenterol Hepatol 5:1413–1417PubMedGoogle Scholar
  42. 42.
    Spechler SJ (2002) Barrett’s esophagus. N Engl J Med 346:836–842PubMedGoogle Scholar
  43. 43.
    Schubert ML (2008) Gastric secretion. Curr Opin Gastroenterol 24:659–664PubMedGoogle Scholar
  44. 44.
    Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW (2011) Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 377:31–41PubMedGoogle Scholar
  45. 45.
    Corley DA, Kerlikowske K, Verma R, Buffler P (2003) Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis. Gastroenterology 124:47–56PubMedGoogle Scholar
  46. 46.
    Wang F, Lv ZS, Fu YK (2010) Nonsteroidal anti-inflammatory drugs and esophageal inflammation - Barrett’s esophagus - adenocarcinoma sequence: a meta-analysis. Dis Esophagus. doi: 10.1111/j.1442-2050.2010.01153.x [Epub ahead of print]Google Scholar
  47. 47.
    Shaheen N, Ransohoff DF (2002) Gastroesophageal reflux, Barrett esophagus, and esophageal cancer: scientific review. JAMA 287:1972–1981PubMedGoogle Scholar
  48. 48.
    Shaheen NJ, Richter JE (2009) Barrett’s oesophagus. Lancet 373:850–861PubMedGoogle Scholar
  49. 49.
    Wang KK, Sampliner RE, The Practice Parameters Committee of the American College of Gastroenterology (2008) Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett’s esophagus. Am J Gastroenterol 103:788–797PubMedGoogle Scholar
  50. 50.
    Playford RJ (2006) New British Society of Gastroenterology (BSG) guidelines for the diagnosis and management of Barrett’s oesophagus. Gut 55:442PubMedGoogle Scholar
  51. 51.
    Schnell TG, Sontag SJ, Chejfec G et al (2001) Long-term nonsurgical management of Barrett’s esophagus with high-grade dysplasia. Gastroenterology 120:1607–1619PubMedGoogle Scholar
  52. 52.
    Anand G, Katz PO (2010) Gastroesophageal reflux disease and obesity. Gastroenterol Clin North Am 39:39–46PubMedGoogle Scholar
  53. 53.
    Abnet CC, Freedman ND, Hu N, Wang Z, Yu K, Shu XO, Yuan JM, Zheng W, Dawsey SM, Dong LM, Lee MP, Ding T, Qiao YL, Gao YT, Koh WP, Xiang YB, Tang ZZ, Fan JH, Wang C, Wheeler W, Gail MH, Yeager M, Yuenger J, Hutchinson A, Jacobs KB, Giffen CA, Burdett L, Fraumeni JF Jr, Tucker MA, Chow WH, Goldstein AM, Chanock SJ, Taylor PR (2010) A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma. Nat Genet 42:764–767PubMedGoogle Scholar
  54. 54.
    Wang LD, Zhou FY, Li XM, Sun LD, Song X, Jin Y, Li JM, Kong GQ, Qi H, Cui J, Zhang LQ, Yang JZ, Li JL, Li XC, Ren JL, Liu ZC, Gao WJ, Yuan L, Wei W, Zhang YR, Wang WP, Sheyhidin I, Li F, Chen BP, Ren SW, Liu B, Li D, Ku JW, Fan ZM, Zhou SL, Guo ZG, Zhao XK, Liu N, Ai YH, Shen FF, Cui WY, Song S, Guo T, Huang J, Yuan C, Huang J, Wu Y, Yue WB, Feng CW, Li HL, Wang Y, Tian JY, Lu Y, Yuan Y, Zhu WL, Liu M, Fu WJ, Yang X, Wang HJ, Han SL, Chen J, Han M, Wang HY, Zhang P, Li XM, Dong JC, Xing GL, Wang R, Guo M, Chang ZW, Liu HL, Guo L, Yuan ZQ, Liu H, Lu Q, Yang LQ, Zhu FG, Yang XF, Feng XS, Wang Z, Li Y, Gao SG, Qige Q, Bai LT, Yang WJ, Lei GY, Shen ZY, Chen LQ, Li EM, Xu LY, Wu ZY, Cao WK, Wang JP, Bao ZQ, Chen JL, Ding GC, Zhuang X, Zhou YF, Zheng HF, Zhang Z, Zuo XB, Dong ZM, Fan DM, He X, Wang J, Zhou Q, Zhang QX, Jiao XY, Lian SY, Ji AF, Lu XM, Wang JS, Chang FB, Lu CD, Chen ZG, Miao JJ, Fan ZL, Lin RB, Liu TJ, Wei JC, Kong QP, Lan Y, Fan YJ, Gao FS, Wang TY, Xie D, Chen SQ, Yang WC, Hong JY, Wang L, Qiu SL, Cai ZM, Zhang XJ (2010) Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies susceptibility loci at PLCE1 and C20orf54. Nat Genet 42:759–763PubMedGoogle Scholar
  55. 55.
    Lao-Sirieix P, Caldas C, Fitzgerald RC (2010) Genetic predisposition to gastro-oesophageal cancer. Curr Opin Genet Dev 20:210–217PubMedGoogle Scholar
  56. 56.
    Robertson EV, Jankowski JA (2008) Genetics of gastroesophageal cancer: paradigms, paradoxes, and prognostic utility. Am J Gastroenterol 103:443–449PubMedGoogle Scholar
  57. 57.
    Jaluria P, Konstantopoulos K, Betenbaugh M, Shiloach J (2007) A perspective on microarrays: current applications, pitfalls, and potential uses. Microb Cell Fact 6:4PubMedGoogle Scholar
  58. 58.
    Selaru FM, Zou T, Xu Y, Shustova V, Yin J, Mori Y, Sato F, Wang S, Olaru A, Shibata D, Greenwald BD, Krasna MJ, Abraham JM, Meltzer SJ (2002) Global gene expression profiling in Barrett’s esophagus and esophageal cancer: a comparative analysis using cDNA microarrays. Oncogene 21:475–478PubMedGoogle Scholar
  59. 59.
    Greenawalt DM, Duong C, Smyth GK, Ciavarella ML, Thompson NJ, Tiang T, Murray WK, Thomas RJ, Phillips WA (2007) Gene expression profiling of esophageal cancer: comparative analysis of Barrett’s esophagus, adenocarcinoma, and squamous cell carcinoma. Int J Cancer 120:1914–1921PubMedGoogle Scholar
  60. 60.
    Helm J, Enkemann SA, Coppola D, Barthel JS, Kelley ST, Yeatman TJ (2005) Dedifferentiation precedes invasion in the progression from Barrett’s metaplasia to esophageal adenocarcinoma. Clin Cancer Res 11:2478–2485PubMedGoogle Scholar
  61. 61.
    Warrington JA, Nair A, Mahadevappa M et al (2000) Comparison of human adult and fetal expression and identification of 535 housekeeping/maintenance genes. Physiol Genomics 2:143–147PubMedGoogle Scholar
  62. 62.
    Wang XW, Gao HJ, Fang DC (2008) Advances in gene chip technique in Barrett’s metaplasia and adenocarcinoma. J Dig Dis 9:68–71PubMedGoogle Scholar
  63. 63.
    Takahashi S, Miura N, Harada T, Wang Z, Wang X, Tsubokura H, Oshima Y, Hasegawa J, Inagaki Y, Shiota G (2010) Prognostic impact of clinical course-specific mRNA expression profiles in the serum of perioperative patients with esophageal cancer in the ICU: a case control study. J Transl Med 8:103PubMedGoogle Scholar
  64. 64.
    Bartel DP (2004) microRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297PubMedGoogle Scholar
  65. 65.
    Bartel DP (2009) microRNAs: target recognition and regulatory functions. Cell 136:215–233PubMedGoogle Scholar
  66. 66.
    Farazi TA, Spitzer JI, Morozov P, Tuschl T (2011) miRNAs in human cancer. J Pathol 223:102–115PubMedGoogle Scholar
  67. 67.
    Schee K, Fodstad Ø, Flatmark K (2010) MicroRNAs as biomarkers in colorectal cancer. Am J Pathol 177:1592–1599PubMedGoogle Scholar
  68. 68.
    Nikiforova MN, Chiosea SI, Nikiforov YE (2009) MicroRNA expression profiles in thyroid tumors. Endocr Pathol 20:85–91PubMedGoogle Scholar
  69. 69.
    Li T, Li D, Sha J, Sun P, Huang Y (2009) MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells. Biochem Biophys Res Commun 383:280–285PubMedGoogle Scholar
  70. 70.
    Bartels CL, Tsongalis GJ (2010) MicroRNAs: novel biomarkers for human cancer. Ann Biol Clin (Paris) 68:263–272Google Scholar
  71. 71.
    Rovira C, Güida MC, Cayota A (2010) MicroRNAs and other small silencing RNAs in cancer. IUBMB Life 62:859–868PubMedGoogle Scholar
  72. 72.
    Visone R, Croce CM (2009) miRNAs and cancer. Am J Pathol 174:1131–1138PubMedGoogle Scholar
  73. 73.
    Xie XH, Lu J, Kulbokas EJ, Golub TR, Mootha V, Lindblad-Toh K, Lander ES (2005) Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals. Nature 434:338–345PubMedGoogle Scholar
  74. 74.
    Shyu AB, Wilkinson MF, van Hoof A (2008) Messenger RNA regulation: to translate or to degrade. EMBO J 27:471–481PubMedGoogle Scholar
  75. 75.
    Vrba L, Jensen TJ, Garbe JC, Heimark RL, Cress AE, Dickinson S, Stampfer MR, Futscher BW (2010) Role for DNA methylation in the regulation of miR-200c and miR-141 expression in normal and cancer cells. PLoS One 5:e8697PubMedGoogle Scholar
  76. 76.
    Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838PubMedGoogle Scholar
  77. 77.
    Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, Iuliano R, Palumbo T, Pichiorri F, Roldo C, Garzon R, Sevignani C, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM (2005) A microRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 353:1793–1801PubMedGoogle Scholar
  78. 78.
    Zhang C, Wang C, Chen X, Yang C, Li K, Wang J, Dai J, Hu Z, Zhou X, Chen L, Zhang Y, Li Y, Qiu H, Xing J, Liang Z, Ren B, Yang C, Zen K, Zhang CY (2010) Expression profile of microRNAs in serum: a fingerprint for esophageal squamous cell carcinoma. Clin Chem 56:1871–1879PubMedGoogle Scholar
  79. 79.
    Chen ZL, Zhao XH, Wang JW, Li BZ, Wang Z, Sun J, Tan FW, Ding DP, Xu XH, Zhou F, Tan XG, Hang J, Shi SS, Feng XL, He J (2011) microRNA-92a promotes lymph node metastasis of human esophageal squamous cell carcinoma via E-cadherin. J Biol Chem 286:10725–10734PubMedGoogle Scholar
  80. 80.
    Fassan M, Volinia S, Palatini J, Pizzi M, Baffa R, De Bernard M, Battaglia G, Parente P, Croce CM, Zaninotto G, Ancona E, Rugge M (2011) MicroRNA expression profiling in human Barrett’s carcinogenesis. Int J Cancer 129:1661–1670PubMedGoogle Scholar
  81. 81.
    Matsushima K, Isomoto H, Kohno S, Nakao K (2010) MicroRNAs and esophageal squamous cell carcinoma. Digestion 82:138–144PubMedGoogle Scholar
  82. 82.
    Hu Y, Correa AM, Hoque A, Guan B, Ye F, Huang J, Swisher SG, Wu TT, Ajani JA, Xu XC (2011) Prognostic significance of differentially expressed miRNAs in esophageal cancer. Int J Cancer 128:132–143PubMedGoogle Scholar
  83. 83.
    Kano M, Seki N, Kikkawa N, Fujimura L, Hoshino I, Akutsu Y, Chiyomaru T, Enokida H, Nakagawa M, Matsubara H (2010) miR-145, miR-133a and miR-133b: tumor suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma. Int J Cancer 127:2804–2814PubMedGoogle Scholar
  84. 84.
    Maru DM, Singh RR, Hannah C, Albarracin CT, Li YX, Abraham R, Romans AM, Yao H, Luthra MG, Anandasabapathy S, Swisher SG, Hofstetter WL, Rashid A, Luthra R (2009) MicroRNA-196a is a potential marker of progression during Barrett’s metaplasia-dysplasia-invasive adenocarcinoma sequence in esophagus. Am J Pathol 174:1940–1948PubMedGoogle Scholar
  85. 85.
    Guo Y, Chen Z, Zhang L, Zhou F, Shi S, Feng X, Li B, Meng X, Ma X, Luo M, Shao K, Li N, Qiu B, Mitchelson K, Cheng J, He J (2008) Distinctive microRNA profiles relating to patient survival in esophageal squamous cell carcinoma. Cancer Res 68:26–33PubMedGoogle Scholar
  86. 86.
    Hiyoshi Y, Kamohara H, Karashima R, Sato N, Imamura Y, Nagai Y, Yoshida N, Toyama E, Hayashi N, Watanabe M, Baba H (2009) MicroRNA-21 regulates the proliferation and invasion in esophageal squamous cell carcinoma. Clin Cancer Res 15:1915–1922PubMedGoogle Scholar
  87. 87.
    Ogawa R, Ishiguro H, Kuwabara Y, Kimura M, Mitsui A, Katada T, Harata K, Tanaka T, Fujii Y (2009) Expression profiling of micro-RNAs in human esophageal squamous cell carcinoma using RT-PCR. Med Mol Morphol 42:102–109PubMedGoogle Scholar
  88. 88.
    Kan T, Sato F, Ito T, Matsumura N, David S, Cheng Y, Agarwal R, Paun BC, Jin Z, Olaru AV, Selaru FM, Hamilton JP, Yang J, Abraham JM, Mori Y, Meltzer SJ (2009) The miR-106b-25 polycistron, activated by genomic amplification, functions as an oncogene by suppressing p21 and Bim. Gastroenterology 136:1689–1700PubMedGoogle Scholar
  89. 89.
    Ivanovska I, Ball AS, Diaz RL, Magnus JF, Kibukawa M, Schelter JM, Kobayashi SV, Lim L, Burchard J, Jackson AL, Linsley PS, Cleary MA (2008) MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression. Mol Cell Biol 28:2167–2174PubMedGoogle Scholar
  90. 90.
    Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, de Martino I, Iliopoulos D, Pilozzi E, Liu CG, Negrini M, Cavazzini L, Volinia S, Alder H, Ruco LP, Baldassarre G, Croce CM, Vecchione A (2008) E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell 13:272–286PubMedGoogle Scholar
  91. 91.
    Shackelford RE, Kaufmann WK, Paules RS (2000) Oxidative stress and cell cycle checkpoint function. Free Radic Biol Med 28:1387–1404PubMedGoogle Scholar
  92. 92.
    Kan T, Meltzer SJ (2009) MicroRNAs in Barrett’s esophagus and esophageal adenocarcinoma. Curr Opin Pharmacol 9:727–732PubMedGoogle Scholar
  93. 93.
    Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT, Barbisin M, Xu NL, Mahuvakar VR, Andersen MR, Lao KQ, Livak KJ, Guegler KJ (2005) Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res 33:e179PubMedGoogle Scholar
  94. 94.
    Zhou SL, Wang LD (2010) Circulating microRNAs: novel biomarkers for esophageal cancer. World J Gastroenterol 16:2348–2354PubMedGoogle Scholar
  95. 95.
    Seitz HK, Stickel F (2007) Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 7:599–612PubMedGoogle Scholar
  96. 96.
    Raghunathan L, Hsu LC, Klisak I, Sparkes RS, Yoshida A, Mohandas T (1988) Regional localization of the human genes for aldehyde dehydrogenase-1 and aldehyde dehydrogenase-2. Genomics 2:267–269PubMedGoogle Scholar
  97. 97.
    Hsu LC, Chang WC, Yoshida A (1989) Genomic structure of the human cytosolic aldehyde dehydrogenase gene. Genomics 5:857–865PubMedGoogle Scholar
  98. 98.
    Novoradovsky A, Tsai SJ, Goldfarb L, Peterson R, Long JC, Goldman D (1995) Mitochondrial aldehyde dehydrogenase polymorphism in Asian and American Indian populations: detection of new ALDH2 alleles. Alcohol Clin Exp Res 19:1105–1110PubMedGoogle Scholar
  99. 99.
    Yoshida A, Huang IY, Ikawa M (1984) Molecular abnormality of an inactive aldehyde dehydrogenase variant commonly found in Orientals. Proc Natl Acad Sci USA 81:258–261PubMedGoogle Scholar
  100. 100.
    Enomoto N, Takase S, Yasuhara M, Takada A (1991) Acetaldehyde metabolism in different aldehyde dehydrogenase-2 genotypes. Alcohol Clin Exp Res 15:141–144PubMedGoogle Scholar
  101. 101.
    Brooks PJ, Enoch MA, Goldman D, Li TK, Yokoyama A (2009) The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption. PLoS Med 6:e50PubMedGoogle Scholar
  102. 102.
    Matsuda T, Yabushita H, Kanaly RA, Shibutani S, Yokoyama A (2006) Increased DNA damage in ALDH2-deficient alcoholics. Chem Res Toxicol 19:1374–1378PubMedGoogle Scholar
  103. 103.
    Lewis SJ, Smith GD (2005) Alcohol, ALDH2, and esophageal cancer: a meta-analysis which illustrates the potentials and limitations of a Mendelian randomization approach. Cancer Epidemiol Biomarkers Prev 14:1967–1971PubMedGoogle Scholar
  104. 104.
    Yokoyama A, Muramatsu T, Ohmori T, Higuchi S, Hayashida M, Ishii H (1996) Esophageal cancer and aldehyde dehydrogenase-2 genotypes in Japanese males. Cancer Epidemiol Biomarkers Prev 5:99–102PubMedGoogle Scholar
  105. 105.
    Yokoyama A, Muramatsu T, Omori T, Yokoyama T, Matsushita S, Higuchi S, Maruyama K, Ishii H (2001) Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal and stomach cancers in Japanese alcoholics. Carcinogenesis 22:433–439PubMedGoogle Scholar
  106. 106.
    Matsuo K, Hamajima N, Shinoda M, Hatooka S, Inoue M, Takezaki T, Tajima K (2001) Gene–environment interaction between an aldehyde dehydrogenase-2 (ALDH2) polymorphism and alcohol consumption for the risk of esophageal cancer. Carcinogenesis 22:913–916PubMedGoogle Scholar
  107. 107.
    Landi S, Gemignani F, Gioia-Patricola L, Chabrier A, Canzian F (2003) Evaluation of a microarray for genotyping polymorphisms related to xenobiotic metabolism and DNA repair. Biotechniques 35:816–820, 822, 824–7PubMedGoogle Scholar
  108. 108.
    Itoga S, Nanmoku T, Uchimoto T, Sunaga M, Nezu M, Tomonaga T, Harada S, Nomura F (2004) Comparative analyses of four different methods of genotyping ALDH2. Alcohol Clin Exp Res 28(8 Suppl Proceedings):117S–122SPubMedGoogle Scholar
  109. 109.
    Guillem PG (2005) How to make a Barrett esophagus: pathophysiology of columnar metaplasia of the esophagus. Dig Dis Sci 50:415–424PubMedGoogle Scholar
  110. 110.
    Silberg DG, Furth EE, Taylor JK, Schuck T, Chiou T, Traber PG (1997) CDX1 protein expression in normal, metaplastic, and neoplastic human alimentary tract epithelium. Gastroenterology 113:478–486PubMedGoogle Scholar
  111. 111.
    Mutoh H, Hakamata Y, Sato K, Eda A, Yanaka I, Honda S, Osawa H, Kaneko Y, Sugano K (2002) Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice. Biochem Biophys Res Commun 294:470–479PubMedGoogle Scholar
  112. 112.
    Silberg DG, Sullivan J, Kang E, Swain GP, Moffett J, Sund NJ, Sackett SD, Kaestner KH (2002) Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Gastroenterology 122:689–696PubMedGoogle Scholar
  113. 113.
    Mutoh H, Sakurai S, Satoh K, Osawa H, Hakamata Y, Takeuchi T, Sugano K (2004) Cdx1 induced intestinal metaplasia in the transgenic mouse stomach: comparative study with Cdx2 transgenic mice. Gut 53:1416–1423PubMedGoogle Scholar
  114. 114.
    Mutoh H, Satoh K, Kita H, Sakamoto H, Hayakawa H, Yamamoto H, Isoda N, Tamada K, Ido K, Sugano K (2005) Cdx2 specifies the differentiation of morphological as well as functional absorptive enterocytes of the small intestine. Int J Dev Biol 49:867–871PubMedGoogle Scholar
  115. 115.
    Chawengsaksophak K, James R, Hammond VE, Kontgen F, Beck F (1997) Homeosis and intestinal tumours in Cdx2 mutant mice. Nature 386:84–87PubMedGoogle Scholar
  116. 116.
    Tamai Y, Nakajima R, Ishikawa T, Takaku K, Seldin MF, Taketo MM (1999) Colonic hamartoma development by anomalous duplication in Cdx2 knockout mice. Cancer Res 59:2965–2970PubMedGoogle Scholar
  117. 117.
    Gao N, White P, Kaestner KH (2009) Establishment of intestinal identity and epithelial mesenchymal signaling by Cdx2. Dev Cell 16:588–599PubMedGoogle Scholar
  118. 118.
    Vallböhmer D, DeMeester SR, Peters JH, Oh DS, Kuramochi H, Shimizu D, Hagen JA, Danenberg KD, Danenberg PV, DeMeester TR, Chandrasoma PT (2006) Cdx-2 expression in squamous and metaplastic columnar epithelia of the esophagus. Dis Esophagus 19:260–266PubMedGoogle Scholar
  119. 119.
    Phillips RW, Frierson HF Jr, Moskaluk CA (2003) Cdx2 as a marker of epithelial intestinal differentiation in the esophagus. Am J Surg Pathol 27:1442–1447PubMedGoogle Scholar
  120. 120.
    Groisman GM, Amar M, Meir A (2004) Expression of the intestinal marker Cdx2 in the columnar-lined esophagus with and without intestinal (Barrett’s) metaplasia. Mod Pathol 17:1282–1288PubMedGoogle Scholar
  121. 121.
    Slack JM, Colleypriest BJ, Quinlan JM, Yu WY, Farrant MJ, Tosh D (2010) Barrett’s metaplasia: molecular mechanisms and nutritional influences. Biochem Soc Trans 38:313–319PubMedGoogle Scholar
  122. 122.
    Stairs DB, Kong J, Lynch JP (2010) Cdx genes, inflammation, and the pathogenesis of intestinal metaplasia. Prog Mol Biol Transl Sci 96:231–270PubMedGoogle Scholar
  123. 123.
    Weimann A, Zimmermann M, Gross M, Slevogt H, Rieger A, Morawietz L (2010) CDX2 and LI-cadherin expression in esophageal mucosa: use of both markers can facilitate the histologic diagnosis of Barrett’s esophagus and carcinoma. Int J Surg Pathol 18:330–337PubMedGoogle Scholar
  124. 124.
    Weimann A, Rieger A, Zimmermann M, Gross M, Hoffmann P, Slevogt H, Morawietz L (2010) Comparison of six immunohistochemical markers for the histologic diagnosis of neoplasia in Barrett’s esophagus. Virchows Arch 457:537–545PubMedGoogle Scholar
  125. 125.
    Clarke CA, McConnell RB (1954) Six cases of carcinoma of the oesophagus occurring in one family. BMJ 2:1137–1138PubMedGoogle Scholar
  126. 126.
    Howel-Evans W, McConnell RB, Clarke CA, Sheppard PM (1958) Carcinoma of the oesophagus with keratosis palmaris et plantaris (tylosis). A study of two families. Q J Med 27:413–442PubMedGoogle Scholar
  127. 127.
    Lucker GPH, Van de Kerkhof PCM, Steijlen PM (1994) The hereditary palmoplantar keratoses: an updated review and classification. Br J Dermatol 131:1–14PubMedGoogle Scholar
  128. 128.
    Kelsell DP, Stevens HP (1999) The palmoplantar keratodermas: much more than palms and soles. Mol Med Today 36:107–113Google Scholar
  129. 129.
    Stevens HP, Kelsell DP, Bryant SP, Bishop DT, Spurr NK, Weissenbach J, Marger D, Marger RS, Leigh IM (1996) Linkage of an American pedigree with palmoplantar keratoderma and malignancy to 17q24: literature survey and proposed updated classification of the keratodermas. Arch Dermatol 132:640–651PubMedGoogle Scholar
  130. 130.
    Hennies HC, Hagedorn M, Reis A (1995) Palmoplantar keratoderma in association with carcinoma of the esophagus maps to chromosome 17q distal the keratin gene cluster. Genomics 29:537–540PubMedGoogle Scholar
  131. 131.
    Risk JM, Evans KE, Jones J, Langan JE, Rowbottom L, McRonald FE, Mills HS, Ellis A, Shaw JM, Leigh IM, Kelsell DP, Field JK (2002) Characterisation of a 500kb region on 17q25 and the exclusion of candidate genes as the familial tylosis oesophageal cancer (TOC) locus. Oncogene 21:6395–6402PubMedGoogle Scholar
  132. 132.
    Risk JM, Field EA, Field JK, Whittaker J, Fryer A, Ellis A, Shaw JM, Friedmann PS, Bishop DT, Bodmer J et al (1994) Tylosis oesophageal cancer mapped. Nat Genet 8:319–321PubMedGoogle Scholar
  133. 133.
    Kelsell DP, Risk JM, Leigh IM, Stevens HP, Ellis A, Hennies HC, Reis A, Weissenbach J, Bishop DT, Spurr NK, Field JK (1996) Close mapping of the focal non-epidermolytic palmoplantar keratoderma locus associated with oesophageal cancer. Hum Mol Genet 5:857–860PubMedGoogle Scholar
  134. 134.
    Langan JE, Cole CG, Huckle EJ, Byrne S, McRonald FE, Rowbottom L, Ellis A, Shaw JM, Leigh IM, Kelsell DP, Dunham I, Field JK, Risk JM (2004) Novel microsatellite markers and single nucleotide polymorphisms refine the tylosis with oesophageal cancer (TOC) minimal region on 17q25 to 42.5kb: sequencing does not identify causative gene. Hum Genet 114:534–540PubMedGoogle Scholar
  135. 135.
    Risk JM, Mills HS, Garde J, Dunn JR, Evans KE, Hollstein M, Field JK (1999) The tylosis oesophageal cancer (TOC) locus: more than just a familial cancer gene. Dis Esophagus 12:173–176PubMedGoogle Scholar
  136. 136.
    VonBrevern M, Hollstein MC, Risk JM, Garde J, Bennett WP, Harris CC, Muehlbauer KR, Field JK (1998) Loss of heterozygosity in sporadic oesophageal tumours in the tylosis oesophageal cancer (TOC) gene region of chromosome 17q. Oncogene 17:2101–2105Google Scholar
  137. 137.
    Iwaya T, Maesawa C, Kimura T, Ogasawara S, Ikeda K, Kimura Y, Noda Y, Ishida K, Sato N, Saito K, Masuda T (2005) Infrequent mutation of the human envoplakin gene is closely linked to the tylosis oesophageal cancer locus in sporadic oesophageal squamous cell carcinomas. Oncol Rep 13:703–707PubMedGoogle Scholar
  138. 138.
    Shahibi M, Noori Daloii MR, Langan JE et al (2004) An investigation of the tylosis with oesophageal cancer (TOC) locus in Iranian patients with oesophageal squamous cell carcinoma. Int J Oncol 25:389–395Google Scholar
  139. 139.
    Iwaya T, Maesawa C, Ogasawara S, Tamura G (1998) Tylosis esophageal cancer locus on chromosome 17q25.1 is commonly deleted in sporadic human esophageal cancer. Gastroenterology 114:1206–1210PubMedGoogle Scholar
  140. 140.
    McRonald FE, Liloglou T, Xinarianos G, Hill L, Rowbottom L, Langan JE, Ellis A, Shaw JM, Field JK, Risk JM (2006) Down-regulation of the cytoglobin gene, located on 17q25, in tylosis with oesophageal cancer (TOC): evidence for trans-allele repression. Hum Mol Genet 15:1271–1277PubMedGoogle Scholar
  141. 141.
    Bassett DR, Abel M, Moellering RC Jr, Rosenblatt G, Stokes J 3rd (1969) Dietary intake, smoking history, energy balance, and “stress” in relation to age, and to coronary heart disease risk in Hawaiian and Japanese men in Hawaii. Am J Clin Nutr 22:1504–1520PubMedGoogle Scholar
  142. 142.
    Coggon D, Osmond C, Barker DJ (1990) Stomach cancer and migration with England and Wales. Br J Cancer 61:573–574PubMedGoogle Scholar
  143. 143.
    International Agency for Research on Cancer (1994) IARC monograph on the evaluation of carcinogenic risks to humans. In: Schistosomes, liver flukes and Helicobacter pylori, vol 61. International Agency for Research on Cancer, LyonGoogle Scholar
  144. 144.
    Danesh J (1999) Helicobacter pylori infection and gastric cancer: systematic review of the epidemiological studies. Aliment Pharmacol Ther 13:851–856PubMedGoogle Scholar
  145. 145.
    Eslick GD, Lim LL, Byles JE, Xia HH, Talley NJ (1999) Association of Helicobacter pylori infection with gastric carcinoma: a meta-analysis. Am J Gastroenterol 94:2373–2379PubMedGoogle Scholar
  146. 146.
    Fukase K, Kato M, Kikuchi S, Inoue K, Uemura N, Okamoto S, Terao S, Amagai K, Hayashi S, Asaka M (2008) Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet 372:392–397PubMedGoogle Scholar
  147. 147.
    Wong BC, Lam SK, Wong WM, Chen JS, Zheng TT, Feng RE, Lai KC, Hu WH, Yuen ST, Leung SY, Fong DY, Ho J, Ching CK, Chen JS, China Gastric Cancer Study Group (2004) Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 291:187–194PubMedGoogle Scholar
  148. 148.
    Kandulski A, Selgrad M, Malfertheiner P (2008) Helicobacter pylori infection: a clinical overview. Dig Liver Dis 40:619–626PubMedGoogle Scholar
  149. 149.
    Peek RM Jr, Blaser MJ (2002) Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer 2:28–37PubMedGoogle Scholar
  150. 150.
    Hamajima N, Naito M, Kondo T, Goto Y (2006) Genetic factors involved in the development of Helicobacter pylori-related gastric cancer. Cancer Sci 97:1129–1138PubMedGoogle Scholar
  151. 151.
    Bagchi D, Bhattacharya G, Stohs SJ (1996) Production of reactive oxygen species by gastric cells in association with Helicobacter pylori. Free Radic Res 24:439–450PubMedGoogle Scholar
  152. 152.
    Papa A, Danese S, Sgambato A, Ardito R, Zannoni G, Rinelli A, Vecchio FM, Gentiloni-Silveri N, Cittadini A, Gasbarrini G, Gasbarrini A (2002) Role of Helicobacter pylori CagA + infection in determining oxidative DNA damage in gastric mucosa. Scand J Gastroenterol 37:409–413PubMedGoogle Scholar
  153. 153.
    Farinati F, Cardin R, Russo VM, Busatto G, Franco M, Rugge M (2003) Helicobacter pylori CagA status, mucosal oxidative damage and gastritis phenotype: a potential pathway to cancer? Helicobacter 8:227–234PubMedGoogle Scholar
  154. 154.
    Shirin H, Pinto JT, Liu LU, Merzianu M, Sordillo EM, Moss SF (2001) Helicobacter pylori decreases gastric mucosal glutathione. Cancer Lett 164:127–133PubMedGoogle Scholar
  155. 155.
    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 15:2995–3002PubMedGoogle Scholar
  156. 156.
    Crew KD, Neugut AI (2006) Epidemiology of gastric cancer. World J Gastroenterol 12:354–362PubMedGoogle Scholar
  157. 157.
    Tatematsu M, Takahashi M, Fukushima S, Hananouchi M, Shirai T (1975) Effects in rats of sodium chloride on experimental gastric cancers induced by N-methyl-N-nitro-N-nitrosoguanidine or 4-nitroquinoline-1-oxide. J Natl Cancer Inst 55:101–106PubMedGoogle Scholar
  158. 158.
    Hirayama T (1986) A large scale cohort study on cancer risk by diet with special reference to the risk reducing effects of greenyellow vegetable consumption. In: Hayashi Y, Nagao M, Sugimura T (ed) Diet, nutrition and cancer: proceedings of the 16th international symposium of the princess Takamatsu cancer research fund, VNU Science, Utrecht/Tokyo, pp 41–53Google Scholar
  159. 159.
    Hertog MG, Bueno-de-Mesquita HB, Fehily AM, Sweetnam PM, Elwood PC, Kromhout D (1996) Fruit and vegetable consumption and cancer mortality in the Caerphilly study. Cancer Epidemiol Biomarkers Prev 5:673–677PubMedGoogle Scholar
  160. 160.
    Kobayashi M, Tsubono Y, Sasazuki S, Sasaki S, Tsugane S (2002) Vegetables, fruit and risk of gastric cancer in Japan: a 10-year follow-up of the JPHC study cohort I. Int J Cancer 102:39–44PubMedGoogle Scholar
  161. 161.
    Wang ZY, Cheng SJ, Zhou ZC, Athar M, Khan WA, Bickers DR, Mukhtar H (1989) Antimutagenic activity of green tea polyphenols. Mutat Res 223:273–285PubMedGoogle Scholar
  162. 162.
    Wang ZY, Hong JY, Huang MT, Reuhl KR, Conney AH, Yang CS (1992) Inhibition of N-nitrosodiethylamine- and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced tumorigenesis in A/J mice by green tea and black tea. Cancer Res 52:1943–1947PubMedGoogle Scholar
  163. 163.
    Xu Y, Ho CT, Amin SG, Han C, Chung FL (1992) Inhibition of tobacco-specific nitrosamine-induced lung tumorigenesis in A/J mice by green tea and its major polyphenol as antioxidants. Cancer Res 52:3875–3879PubMedGoogle Scholar
  164. 164.
    Boehm K, Borrelli F, Ernst E, Habacher G, Hung SK, Milazzo S, Horneber M (2009) Green tea (Camellia sinensis) for the prevention of cancer. Cochrane Database Syst Rev 3:CD005004. doi: 10.1002/14651858.RevCD005004.pub2
  165. 165.
    Sjödahl K, Lu Y, Nilsen TI, Ye W, Hveem K, Vatten L, Lagergren J (2007) Smoking and alcohol drinking in relation to risk of gastric cancer: a population-based, prospective cohort study. Int J Cancer 120:128–132PubMedGoogle Scholar
  166. 166.
    Chao A, Thun MJ, Henley SJ, Jacobs EJ, McCullough ML, Calle EE (2002) Cigarette smoking, use of other tobacco products and stomach cancer mortality in US adults: the cancer prevention study II. Int J Cancer 101:380–389PubMedGoogle Scholar
  167. 167.
    Lagergren J, Bergstrom R, Nyren O (1999) Association between body mass and adenocarcinoma of the esophagus and gastric cardia. Ann Intern Med 130:883–890PubMedGoogle Scholar
  168. 168.
    Ekstrom AM, Serafini M, Nyren O, Hansson LE, Ye W, Wolk A (2000) Dietary antioxidant intake and the risk of cardia cancer and noncardia cancer of the intestinal and diffuse types: a population-basedcase-control study in Sweden. Int J Cancer 87:133–140PubMedGoogle Scholar
  169. 169.
    Pharoah PD, Guilford P, Caldas C (2001) International gastric cancer linkage consortium. Incidence of gastric cancer and breast cancer in CDH1 E-cadherin. Mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 121:1348–1353PubMedGoogle Scholar
  170. 170.
    Matsukuma KE, Mullins FM, Dietz L, Zehnder JL, Ford JM, Chun NM, Schrijver I (2001) Hereditary diffuse gastric cancer due to a previously undescribed CDH1 splice site mutation. Hum Pathol 41:1200–1203Google Scholar
  171. 171.
    Jones EG (1964) Familial gastric cancer. N Z Med J 63:287–296PubMedGoogle Scholar
  172. 172.
    Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, Taite H, Scoular R, Miller A, Reeve AE (1998) E-cadherin germline mutations in familial gastric cancer. Nature 392:402–405PubMedGoogle Scholar
  173. 173.
    Gayther SA, Gorringe KL, Ramus SJ, Huntsman D, Roviello F, Grehan N, Machado JC, Pinto E, Seruca R, Halling K, MacLeod P, Powell SM, Jackson CE, Ponder BA, Caldas C (1998) Identification of germ-line E-cadherin mutations in gastric cancer families of European origin. Cancer Res 58:4086–4089PubMedGoogle Scholar
  174. 174.
    Richards FM, McKee SA, Rajpar MH, Cole TR, Evans DG, Jankowski JA, McKeown C, Sanders DS, Maher ER (1999) Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer. Hum Mol Genet 8:607–610PubMedGoogle Scholar
  175. 175.
    Kaurah P, MacMillan A, Boyd N, Senz J, De Luca A, Chun N, Suriano G, Zaor S, Van Manen L, Gilpin C, Nikkel S, Connolly-Wilson M, Weissman S, Rubinstein WS, Sebold C, Greenstein R, Stroop J, Yim D, Panzini B, McKinnon W, Greenblatt M, Wirtzfeld D, Fontaine D, Coit D, Yoon S, Chung D, Lauwers G, Pizzuti A, Vaccaro C, Redal MA, Oliveira C, Tischkowitz M, Olschwang S, Gallinger S, Lynch H, Green J, Ford J, Pharoah P, Fernandez B, Huntsman D (2007) Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 297:2360–2372PubMedGoogle Scholar
  176. 176.
    Lugli A, Zlobec I, Singer G, Kopp Lugli A, Terracciano LM, Genta RM (2007) Napoleon Bonaparte’s gastric cancer: a clinicopathologic approach to staging, pathogenesis, and etiology. Nat Clin Pract Gastroenterol Hepatol 4:52–57PubMedGoogle Scholar
  177. 177.
    Caldas C, Carneiro F, Lynch HT, Yokota J, Wiesner GL, Powell SM, Lewis FR, Huntsman DG, Pharoah PD, Jankowski JA, MacLeod P, Vogelsang H, Keller G, Park KG, Richards FM, Maher ER, Gayther SA, Oliveira C, Grehan N, Wight D, Seruca R, Roviello F, Ponder BA, Jackson CE (1999) Familial gastric cancer: overview and guidelines for management. J Med Genet 36:873–880PubMedGoogle Scholar
  178. 178.
    Suriano G, Yew S, Ferreira P, Senz J, Kaurah P, Ford JM, Longacre TA, Norton JA, Chun N, Young S, Oliveira MJ, Macgillivray B, Rao A, Sears D, Jackson CE, Boyd J, Yee C, Deters C, Pai GS, Hammond LS, McGivern BJ, Medgyesy D, Sartz D, Arun B, Oelschlager BK, Upton MP, Neufeld-Kaiser W, Silva OE, Donenberg TR, Kooby DA, Sharma S, Jonsson BA, Gronberg H, Gallinger S, Seruca R, Lynch H, Huntsman DG (2005) Characterization of a recurrent germ line mutation of the E-cadherin gene: implications for genetic testing and clinical management. Clin Cancer Res 11:5401–5409PubMedGoogle Scholar
  179. 179.
    Joensuu H (2006) Gastrointestinal stromal tumor (GIST). Ann Oncol 17:280–286Google Scholar
  180. 180.
    West RB, Corless CL, Chen X, Rubin BP, Subramanian S (2004) The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol 165:107–113PubMedGoogle Scholar
  181. 181.
    Kim KM, Kang DW, Moon WS, Park JB, Park CK, Sohn JH, Jeong JS, Cho MY, Jin SY, Choi JS, Kang DY, Gastrointestinal Stromal Tumor Committee, The Korean Gastrointestinal Pathology Study Group (2005) Gastrointestinal stromal tumors in Koreans: incidence and the clinical, pathologic and immunohistochemical findings. J Korean Med Sci 20:977–984PubMedGoogle Scholar
  182. 182.
    Tryggvason G, Gislason HG, Magnusson MK, Jónasson JG (2005) Gastrointestinal stromal tumors in Iceland, 1990–2003: the Icelandic GIST study, a population-based incidence and pathologic risk stratification study. Int J Cancer 117:289–293PubMedGoogle Scholar
  183. 183.
    Goettsch WG, Bos SD, Breekveldt-Postma N, Casparie M, Herings RM, Hogendoorn PC (2005) Incidence of gastrointestinal stromal tumours is underestimated: results of a nation-wide study. Eur J Cancer 41:2868–2872PubMedGoogle Scholar
  184. 184.
    Agaram NP, Besmer P, Wong CC, Tianhua G, Socci ND, Maki RG, De Santis D, Brennan MF, Singer S, De Matteo RP, Antonescu CR (2007) Pathologic and molecular heterogeneity in imatinib-stable or imatinib-responsive gastrointestinal stromal tumors. Clin Cancer Res 13:170–181PubMedGoogle Scholar
  185. 185.
    Kim TW, Lee H, Kang YK, Choe MS, Ryu MH, Chang HM, Kim JS, Yook JH, Kim BS, Lee JS (2004) Prognostic significance of c-kit mutation in localized gastrointestinal stromal tumors. Clin Cancer Res 10:3076–3081PubMedGoogle Scholar
  186. 186.
    Heinrich MC, Maki RG, Corless CL, Antonescu CR, Harlow A, Griffith D, Town A, McKinley A, Ou WB, Fletcher JA, Fletcher CD, Huang X, Cohen DP, Baum CM, Demetri GD (2008) Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol 26:5352–5359PubMedGoogle Scholar
  187. 187.
    Wordsworth S, Papanicolas I, Buchanan J, Frayling I, Taylor J, Tomlinson I (2008) Molecular testing for somatic cancer mutations: a survey of current and future testing in UK laboratories. J Clin Pathol 61:373–376PubMedGoogle Scholar
  188. 188.
    Kontogianni-Katsarou K, Dimitriadis E, Lariou C, Kairi-Vassilatou E, Pandis N, Kondi-Paphiti A (2008) KIT exon 11 codon 557/558 deletion/insertion mutations define a subset of gastrointestinal stromal tumors with malignant potential. World J Gastroenterol 14:1891–1897PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Rodney E. Shackelford
    • 1
  • Maisoun Qassim Abdelbaqi
    • 2
  • Khaldoon Almhanna
    • 3
  • Kenneth Meredith
    • 3
  • Domenico Coppola
    • 4
    Email author
  1. 1.Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansUSA
  2. 2.Department of PathologyLSU Health Sciences Center ShreveportShreveportUSA
  3. 3.Department of GI OncologyH. Lee Moffitt Cancer Center & Research InstituteTampaUSA
  4. 4.Department of PathologyH. Lee Moffitt Cancer Center & Research InstituteTampaUSA

Personalised recommendations