Hereditary Diffuse Gastric Cancer and Other Gastric Cancers Associated with Hereditary Predisposition Syndromes

  • Fátima CarneiroEmail author
  • Carla Oliveira
  • Raquel Seruca
Part of the Molecular Pathology Library book series (MPLB, volume 7)


Gastric cancer is a heterogeneous and highly prevalent disease, being the fourth most common cancer and the second leading cause of cancer-associated death worldwide. Most cases of gastric cancer are sporadic, and familial aggregation occurs in about 10 % of the cases. In 1998, Guilford et al identified the first inherited gastric cancer syndrome, which was designated as Hereditary Diffuse Gastric Cancer (HDGC) and shown to be caused by germline alterations at the E-cadherin/CDH1 gene. In HDGC families, penetrance of gastric cancer is >80 % at the age of 80 in both genders, and lobular breast cancer is 60 % in women by age 80. To date, 120 families/probands have been described to harbor 99 different germline CDH1 alterations, mainly point mutations and large deletions. A third of all HDGC families described so far carry recurrent CDH1 alterations. Full screening of the CDH1 gene (genetic testing) is recommended in families/patients fulfilling the HDGC criteria. Total gastrectomy is the only reliable intervention and therefore is recommended for carriers of CDH1 pathogenic alterations. In this chapter, we will discuss the currently accepted definition and clinical criteria for HDGC syndrome, as well as the guidelines for genetic counseling and molecular screening. Moreover, molecular pathology, frequency and type of CDH1 germline alterations, other candidate genes and CDH1 associated syndromes, as well as available animal models and cell culture models of disease will be presented. Finally, treatment options, prophylactic gastrectomy, and potential molecular targets for therapy will be discussed in light of the knowledge obtained so far from patients/families and from basic research experiments.


Gastric Cancer Lynch Syndrome Diffuse Gastric Cancer Lobular Breast Cancer Hereditary Diffuse Gastric Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Globocan 2008. Accessed November 12, 2010.Google Scholar
  2. 2.
    Laurén P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histoclinical classification. Acta Pathol Microbiol Scand. 1965;64:31–49.PubMedGoogle Scholar
  3. 3.
    Lauwers GY, Carneiro F, Graham DY, Curado M-P, Franceschi S, Montgomery E, Tatematsu M, Hattori T. Gastric carcinoma. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO Classification of Tumours of the Digestive System. 4th ed. IARC: Lyon; 2010:48–58.Google Scholar
  4. 4.
    Henson DE, Dittus C, Younes M, et al. Differential trends in the intestinal and diffuse types of gastric carcinoma in the United States, 1973–2000: increase in the signet ring cell type. Arch Pathol Lab Med. 2004;128:765–770.PubMedGoogle Scholar
  5. 5.
    Miyahara R, Niwa Y, Matsuura T, et al. Prevalence and prognosis of gastric cancer detected by screening in a large Japanese population: data from a single institute over 30 years. J Gastroenterol Hepatol. 2007;22:1435–1442.PubMedCrossRefGoogle Scholar
  6. 6.
    Ekstrom AM, Serafini M, Nyren O, et al. Dietary antioxidant intake and the risk of cardia cancer and noncardia cancer of the intestinal and diffuse types: a population-based case–control study in Sweden. Int J Cancer. 2000;87:133–140.PubMedCrossRefGoogle Scholar
  7. 7.
    Palli D, Galli M, Caporaso NE, et al. Family history and risk of stomach cancer in Italy. Cancer Epidemiol Biomarkers Prev. 1994;3:15–18.PubMedGoogle Scholar
  8. 8.
    Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392:402–405.PubMedCrossRefGoogle Scholar
  9. 9.
    Vasen HF, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology. 1996;110:1020–1027.PubMedCrossRefGoogle Scholar
  10. 10.
    Varley JM, McGown G, Thorncroft M, et al. An extended Li-Fraumeni kindred with gastric carcinoma and a codon 175 mutation in TP53. J Med Genet. 1995;32:942–945.PubMedCrossRefGoogle Scholar
  11. 11.
    La Vecchia C, Negri E, Franceschi S, et al. Family history and the risk of stomach and colorectal cancer. Cancer. 1992;70:50–55.PubMedCrossRefGoogle Scholar
  12. 12.
    Gayther SA, Gorringe KL, Ramus SJ, et al. Identification of germline E-cadherin mutations in gastric cancer families of European origin. Cancer Res. 1998;58:4086–4089.PubMedGoogle Scholar
  13. 13.
    Richards FM, McKee SA, Rajpar MH, et al. Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer. Hum Mol Genet. 1999;8:607–610.PubMedCrossRefGoogle Scholar
  14. 14.
    Guilford PJ, Hopkins JB, Grady WM, et al. E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer. Hum Mutat. 1999;14:249–255.PubMedCrossRefGoogle Scholar
  15. 15.
    Berx G, Cleton-Jansen AM, Nollet F, et al. E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. EMBO J. 1995;14:6107–115.PubMedGoogle Scholar
  16. 16.
    Shore EM, Nelson WJ. Biosynthesis of the cell adhesion molecule uvomorulin (E-cadherin) in Madin-Darby canine kidney epithelial cells. J Biol Chem. 1991;266:19672–19680.PubMedGoogle Scholar
  17. 17.
    Ringwald M, Schuh R, Vestweber D, et al. The structure of cell adhesion molecule uvomorulin. Insights into the molecular mechanism of Ca2+−dependent cell adhesion. The. EMBO J. 1987;6:3647–3653.PubMedGoogle Scholar
  18. 18.
    Blaschuk OW, Sullivan R, David S, et al. Identification of a cadherin cell adhesion recognition sequence. Dev Biol. 1990;39:227–229.CrossRefGoogle Scholar
  19. 19.
    Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14:1837–1851.PubMedGoogle Scholar
  20. 20.
    Nagar B, Overduin M, Ikura M, et al. Structural basis of calcium-induced E-cadherin rigidification and dimerization. Nature. 1996;380:360–364.PubMedCrossRefGoogle Scholar
  21. 21.
    Caldas C, Carneiro F, Lynch HT, et al. Familial gastric cancer: overview and guidelines for management. J Med Genet. 1999;36:873–880.PubMedGoogle Scholar
  22. 22.
    Carneiro F, Oliveira C, Suriano G, et al. Molecular pathology of familial gastric cancer, with an emphasis on Hereditary Diffuse Gastric Cancer (HDGC). J Clin Pathol. 2008;61:25–30.PubMedCrossRefGoogle Scholar
  23. 23.
    Fitzgerald RC, Hardwick R, Huntsman D, et al. on behalf of the International Gastric Cancer Linkage Consortium. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet. 2010;47:436–444.PubMedCrossRefGoogle Scholar
  24. 24.
    Pharoah PD, Guilford P, Caldas C. 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. 2001;121:1348–1353.PubMedCrossRefGoogle Scholar
  25. 25.
    Blair V, Martin I, Shaw D, et al. Hereditary diffuse gastric cancer: diagnosis and management. Clin Gastroenterol Hepatol. 2006;4:262–275.PubMedCrossRefGoogle Scholar
  26. 26.
    Kaurah P, MacMillan A, Boyd N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007;297:2360–2372.PubMedCrossRefGoogle Scholar
  27. 27.
    Oliveira C, Senz J, Kaurah P, et al. Germline CDH1 deletions in hereditary diffuse gastric cancer families. Hum Mol Genet. 2009;18:1545–1555.PubMedCrossRefGoogle Scholar
  28. 28.
    Pinheiro H, Bordeira-Carriço R, Seixas S, et al. Allele-specific CDH1 downregulation and hereditary diffuse gastric cancer. Hum Mol Genet. 2010;19:943–952.PubMedCrossRefGoogle Scholar
  29. 29.
    Carneiro F, Huntsman DG, Smyrk TC, et al. Model of the early development of diffuse gastric cancer in E-cadherin mutation carriers and its implications for patient screening. J Pathol. 2004;203:681–687.PubMedCrossRefGoogle Scholar
  30. 30.
    Charlton A, Blair V, Shaw D, et al. Hereditary diffuse gastric cancer: predominance of multiple foci of signet ring cell carcinoma in distal stomach and transitional zone. Gut. 2004;53:814–820.PubMedCrossRefGoogle Scholar
  31. 31.
    Rogers WM, Dobo E, Norton JA, et al. Risk-reducing total gastrectomy for germline mutations in E-cadherin (CDH1): pathologic fi ndings with clinical implications. Am J Surg Pathol. 2008;32:799–809.PubMedCrossRefGoogle Scholar
  32. 32.
    Shaw D, Blair V, Framp A, et al. Chromoendoscopic surveillance in hereditary diffuse gastric cancer: an alternative to prophylactic gastrectomy? Gut. 2005;54:461–468.PubMedCrossRefGoogle Scholar
  33. 33.
    Huntsman DG, Carneiro F, Lewis FR, et al. Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations. N Engl J Med. 2001;344:1904–1909.PubMedCrossRefGoogle Scholar
  34. 34.
    Norton JA, Ham CM, Van Dam J, et al. CDH1 truncating mutations in the Ecadherin gene: an indication for total gastrectomy to treat hereditary diffuse gastric cancer. Ann Surg. 2007;245:873–879.PubMedCrossRefGoogle Scholar
  35. 35.
    Barber M, Save V, Carneiro F, et al. Histopathological and ­molecular analysis of gastrectomy specimens from hereditary diffuse gastric cancer patients has implications for endoscopic surveillance of individuals at risk. J Pathol. 2008;216:286–294.PubMedCrossRefGoogle Scholar
  36. 36.
    Hebbard PC, MacMillan A, Huntsman D, et al. Prophylactic total gastrectomy (PTG) for hereditary diffuse gastric cancer (HDGC): the Newfoundland experience with 23 patients. Ann Surg Oncol. 2009;16:1890–1895.PubMedCrossRefGoogle Scholar
  37. 37.
    Chun YS, Lindor NM, Smyrk TC, et al. Germline E-cadherin gene mutations: is prophylactic total gastrectomy indicated? Cancer. 2001;92:181–187.PubMedCrossRefGoogle Scholar
  38. 38.
    Oliveira C, de Bruin J, Nabais S, et al. Intragenic deletion of CDH1 as the inactivating mechanism of the wild-type allele in a HDGC tumour. Oncogene. 2004;23:2236–2240.PubMedCrossRefGoogle Scholar
  39. 39.
    Oliveira C, Seruca R, Carneiro F. Genetics, pathology, and clinics of familial gastric cancer. Int J Surg Pathol. 2006;14:21–33.PubMedCrossRefGoogle Scholar
  40. 40.
    Corso G, Pedrazzani C, Pinheiro H, et al. E-cadherin genetic screening and clinico-pathologic characteristics of early onset gastric cancer. Eur J Cancer. 2010;47:631–639.PubMedCrossRefGoogle Scholar
  41. 41.
    Masciari S, Larsson N, Senz J, et al. Germline E-cadherin mutations in familial lobular breast cancer. J Med Genet. 2007;44:726–731.PubMedCrossRefGoogle Scholar
  42. 42.
    Schrader KA, Masciari S, Boyd N, et al. Hereditary diffuse gastric cancer: association with lobular breast cancer. Fam Cancer. 2008;7:73–82.PubMedCrossRefGoogle Scholar
  43. 43.
    Guilford P, Humar B, Blair V. Hereditary diffuse gastric cancer: translation of CDH1 germline mutations into clinical practice. Gastric Cancer. 2010;13:1–10.PubMedCrossRefGoogle Scholar
  44. 44.
    Oliveira C, Ferreira P, Nabais S, et al. E-Cadherin (CDH1) and TP53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients. Eur J Cancer. 2004;40:1897–1903.PubMedCrossRefGoogle Scholar
  45. 45.
    Suriano G, Yew S, Ferreira P, et al. Characterization of a recurrent germ line mutation of the Ecadherin gene: implications for genetic testing and clinical management. Clin Cancer Res. 2005;11:5401–5409.PubMedCrossRefGoogle Scholar
  46. 46.
    Yabuta T, Shinmura K, Tani M, et al. E-cadherin gene variants in gastric cancer families whose probands are diagnosed with diffuse gastric cancer. Int J Cancer. 2002;101:434–441.PubMedCrossRefGoogle Scholar
  47. 47.
    Wang Y, Song JP, Ikeda M, et al. Ile-Leu substitution (I415L) in germline E-cadherin gene (CDH1) in Japanese familial gastric cancer. Jpn J Clin Oncol. 2003;33:17–20.PubMedCrossRefGoogle Scholar
  48. 48.
    Figueiredo C, Machado JC, Pharoah P, et al. Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst. 2002;94:1680–1687.PubMedCrossRefGoogle Scholar
  49. 49.
    Machado JC, Figueiredo C, Canedo P, et al. A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology. 2003;125:364–371.PubMedCrossRefGoogle Scholar
  50. 50.
    Bacani JT, Soares M, Zwingerman R, et al. CDH1/E-cadherin germline mutations in early-onset gastric cancer. J Med Genet. 2006;43:867–872.PubMedCrossRefGoogle Scholar
  51. 51.
    Oliveira C, Bordin MC, Grehan N, et al. Screening E-cadherin in gastric cancer families reveals germline mutations only in hereditary diffuse gastric cancer kindred. Hum Mutat. 2002;19:510–517.PubMedCrossRefGoogle Scholar
  52. 52.
    More H, Humar B, Weber W, et al. Identification of seven novel germline mutations in the human E-cadherin (CDH1) gene. Hum Mutat. 2007;28:203–211.PubMedCrossRefGoogle Scholar
  53. 53.
    Moran CJ, Joyce M, McAnena OJ. CDH1 associated gastric cancer: a report of a family and review of the literature. Eur J Surg Oncol. 2005;31:259–264.PubMedCrossRefGoogle Scholar
  54. 54.
    Humar B, Toro T, Graziano F, et al. Novel germline CDH1 mutations in hereditary diffuse gastric cancer families. Hum Mutat. 2002;19:518–525.PubMedCrossRefGoogle Scholar
  55. 55.
    Shinmura K, Kohno T, Takahashi M, et al. Familial gastric cancer: clinicopathological characteristics, RER phenotype and germline p53 and E-cadherin mutations. Carcinogenesis. 999;20:1127–1131.PubMedCrossRefGoogle Scholar
  56. 56.
    Dussaulx-Garin L, Blayau M, Pagenault M, et al. A new mutation of E-cadherin gene in familial gastric linitis plastica cancer with extra-digestive dissemination. Eur J Gastroenterol Hepatol. 2001;13:711–715.PubMedCrossRefGoogle Scholar
  57. 57.
    Keller G, Vogelsang H, Becker I, et al. Diffuse type gastric and lobular breast carcinoma in a familial gastric cancer patient with an E-cadherin germline mutation. Am J Pathol. 1999;155:337–342.PubMedCrossRefGoogle Scholar
  58. 58.
    Brooks-Wilson AR, Kaurah P, Suriano G, et al. Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria. J Med Genet. 2004;41:508–517.PubMedCrossRefGoogle Scholar
  59. 59.
    Frebourg T, Oliveira C, Hochain P, et al. Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer. J Med Genet. 2006;43:138–142.PubMedCrossRefGoogle Scholar
  60. 60.
    Mateus AR, Simoes-Correia J, Figueiredo J, et al. E-cadherin mutations and cell motility: a genotype-phenotype correlation. Exp Cell Res. 2009;315:1393–1402.PubMedCrossRefGoogle Scholar
  61. 61.
    Yoon K, Ku J, Yang H, et al. Germline mutations of E-cadherin gene in Korean familial gastric cancer patients. J Hum Genet. 1999;44:177–180.PubMedCrossRefGoogle Scholar
  62. 62.
    Jonsson BA, Bergh A, Stattin P, et al. Germline mutations in E-cadherin do not explain association of hereditary prostate cancer, gastric cancer and breast cancer. Int J Cancer. 2002;98:838–843.PubMedCrossRefGoogle Scholar
  63. 63.
    Roviello F, Corso G, Pedrazzani C, et al. Hereditary diffuse gastric cancer and E-cadherin: description of the first germline mutation in an Italian family. Eur J Surg Oncol. 2007;33:448–451.PubMedCrossRefGoogle Scholar
  64. 64.
    Mayrbaeurl B, Keller G, Schauer W, et al. Germline mutation of the E-cadherin gene in three sibling cases with advanced gastric cancer: clinical consequences for the other family members. Eur J Gastroenterol Hepatol. 2010;22:306–310.PubMedCrossRefGoogle Scholar
  65. 65.
    Barber M, Murrell A, Ito Y, et al. Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer. J Pathol. 2008;216:295–306.PubMedCrossRefGoogle Scholar
  66. 66.
    Rodriguez-Sanjuan JC, Fontalba A, Mayorga M, et al. A novel mutation in the E-cadherin gene in the fi rst family with hereditary diffuse gastric cancer reported in Spain. Eur J Surg Oncol. 2006;32:1110–1113.PubMedCrossRefGoogle Scholar
  67. 67.
    Keller G, Vogelsang H, Becker I, et al. Germline mutations of the E-cadherin (CDH1) and TP53 genes, rather than of RUNX3 and HPP1, contribute to genetic predisposition in German gastric cancer patients. J Med Genet. 2004;41:e89.PubMedCrossRefGoogle Scholar
  68. 68.
    Suriano G, Oliveira C, Ferreira P, et al. Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands. Hum Mol Genet. 2003;12:575–582.PubMedCrossRefGoogle Scholar
  69. 69.
    Oliveira C, Sousa S, Pinheiro H, et al. Quantification of epigenetic and genetic second hits in CDH1 during hereditary diffuse gastric cancer syndrome progression. Gastroenterology. 009;136:2137–2148.PubMedCrossRefGoogle Scholar
  70. 70.
    Simões-Correia J, Figueiredo J, Oliveira C, et al. Endoplasmic reticulum quality control: a new mechanism of E-cadherin regulation and its implication in cancer. Hum Mol Genet. 2008;17:3566–3576.PubMedCrossRefGoogle Scholar
  71. 71.
    Ghaffari SR, Dastan J, Rafati M, et al. Novel human pathological mutations. Gene symbol: CDH1. Disease: gastric cancer. Hum Genet. 2009;125:337.PubMedGoogle Scholar
  72. 72.
    Caron O, Schielke A, Svrcek M, et al. Usefulness of prophylactic gastrectomy in a novel large hereditary diffuse gastric cancer (HDGC) family. Am J Gastroenterol. 2008;103:2160–2161.PubMedCrossRefGoogle Scholar
  73. 73.
    Li QL, Ito K, Sakakura C, et al. Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell. 2002;109:113–124.PubMedCrossRefGoogle Scholar
  74. 74.
    Shibata DM, Sato F, Mori Y, et al. Hypermethylation of HPP1 is associated with hMLH1 hypermethylation in gastric adenocarcinomas. Cancer Res. 2002;62:5637–5640.PubMedGoogle Scholar
  75. 75.
    Park WS, Lee JH, Shin MS, et al. Inactivating mutations of the caspase-10 gene in gastric cancer. Oncogene. 2002;21:2919–2925.PubMedCrossRefGoogle Scholar
  76. 76.
    Takaku K, Miyoshi H, Matsunaga A, et al. Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice. Cancer Res. 1999;59:6113–6117.PubMedGoogle Scholar
  77. 77.
    Lynch HT, Grady W, Suriano G, et al. Gastric cancer: new genetic developments. J Surg Oncol. 2005;90:114–33.PubMedCrossRefGoogle Scholar
  78. 78.
    Duh FM, Scherer SW, Tsui LC, et al. Gene structure of the human MET proto-oncogene. Oncogene. 1997;15:1583–1586.PubMedCrossRefGoogle Scholar
  79. 79.
    Nakajima M, Sawada H, Yamada Y, et al. The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer. 1999;85:1894–1902.PubMedGoogle Scholar
  80. 80.
    Lee JH, Han SU, Cho H, et al. A novel germ line juxtamembrane Met mutation in human gastric cancer. Oncogene. 2000;19:4947–4953.PubMedCrossRefGoogle Scholar
  81. 81.
    Kim I-J, Park J-H, Kang HC, et al. A novel germline mutation in the MET extracellular domain in a Korean patient with the diffuse type of familial gastric cancer. J Med Genet. 2003;40:97.CrossRefGoogle Scholar
  82. 82.
    Chen JD, Kearns S, Porter T, et al. MET mutation and familial gastric cancer. J Med Genet. 2001;38:e26.PubMedCrossRefGoogle Scholar
  83. 83.
    Biedermann K, Vogelsang H, Becker I, et al. Desmoglein 2 is expressed abnormally rather than mutated in familial and sporadic gastric cancer. J Pathol. 2005;207:199–206.PubMedCrossRefGoogle Scholar
  84. 84.
    Grady WM, Willis J, Guilford PJ, et al. Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nat Genet. 2000;26:16–17.PubMedCrossRefGoogle Scholar
  85. 85.
    Corso G, Roviello F, Paredes J, et al. Characterization of the P373L E-cadherin germline missense mutation and implication for clinical management. Eur J Surg Oncol. 2007;33:1061–1067.PubMedCrossRefGoogle Scholar
  86. 86.
    Humar B, Guilford P. Hereditary diffuse gastric cancer and lost cell polarity: a short path to cancer. Future Oncol. 2008;4:229–239.PubMedCrossRefGoogle Scholar
  87. 87.
    Humar B, Fukuzawa R, Blair V, et al. Destabilized adhesion in the gastric proliferative zone and c-Src kinase activation mark the development of early diffuse gastric cancer. Cancer Res. 2007;67:2480–2489.PubMedCrossRefGoogle Scholar
  88. 88.
    Avizienyte E, Frame MC. Src and FAK signalling controls adhesion fate and the epithelial-to-mesenchymaltransition. Curr Opin Cell Biol. 2005;17:542–547.PubMedCrossRefGoogle Scholar
  89. 89.
    Gionti E, Capasso O, Capasso O, Cancedda R. The culture of chick embryo chondrocytes and the controlof their differentiated functions in vitro. Transformation by rous sarcoma virus induces a switch in the collagen type synthesis and enhances fibronectin expression. J Biol Chem. 1983;258:7190–7194.PubMedGoogle Scholar
  90. 90.
    da Cunha CB, Oliveira C, Wen X, et al. De novo expression of CD44 variants in sporadic and hereditary gastric cancer. Lab Invest. 2010;90:1604–1614.PubMedCrossRefGoogle Scholar
  91. 91.
    Ponta H, Wainwright D, Herrlich P. Molecules in focus The CD44 protein family. Int J Biochem Cell Biol. 1998;30:299–305.PubMedCrossRefGoogle Scholar
  92. 92.
    Riethmacher D, Brinkmann V, Birchmeier C. A targeted mutation in the mouse E-cadherin gene results in defective preimplantation development. Proc Natl Acad Sci. 1995;92:855–859.CrossRefGoogle Scholar
  93. 93.
    Humar B, Blair V, Charlton A, et al. E-cadherin deficiency initiates gastric signet-ring cell carcinoma in mice and man. Cancer Res. 2009;69:2050–2056.PubMedCrossRefGoogle Scholar
  94. 94.
    Karam R, Carvalho J, Bruno I, et al. The NMD mRNA surveillance pathway downregulates aberrant E-cadherin transcripts in gastric cancer cells and in CDH1 mutation carriers. Oncogene. 2008;27:4255–4260.PubMedCrossRefGoogle Scholar
  95. 95.
    Suriano G, Mulholland D, de Wever O, et al. The intracellular E-cadherin germline mutation V832 M lacks the ability to mediate cell-cell adhesion and to suppress invasion. Oncogene. 2003;22:5716–5719.PubMedCrossRefGoogle Scholar
  96. 96.
    Suriano G, Ferreira P, Mateus AR, et al. Genetics of hereditary diffuse gastric cancer: progress and future challenges. Future Oncol. 2006;2:363–370.PubMedCrossRefGoogle Scholar
  97. 97.
    Suriano G, Seixas S, Rocha J, Seruca R. A model to infer the pathogenic significance of CDH1 germline missense variants. J Mol Med. 2006;84:1023–1031.PubMedCrossRefGoogle Scholar
  98. 98.
    Fitzgerald RC, Caldas C. Clinical implications of E-cadherin associated hereditary diffuse gastric cancer. Gut. 2004;53:775–778.PubMedCrossRefGoogle Scholar
  99. 99.
    Boterberg T, Vennekens KM, Thienpont M, et al. Internalization of the E-cadherin/catenin complex and scattering of human mammary carcinoma cells MCF-7/AZ after treatment with conditioned medium from human skin squamous carcinoma cells COLO 16. Cell Adhes Commun. 2000;7:299–310.PubMedCrossRefGoogle Scholar
  100. 100.
    Suriano G, Oliveira MJ, Huntsman D, et al. E-cadherin germline missense mutations and cell phenotype: evidence for the independence of cell invasion on the motile capabilities of the cells. Hum Mol Genet. 2003;12:3007–3016.PubMedCrossRefGoogle Scholar
  101. 101.
    Pereira PS, Teixeira A, Pinho S, et al. E-cadherin missense mutations, associated with hereditary diffuse gastric cancer (HDGC) syndrome, display distinct invasive behaviors and genetic interactions with the Wnt and Notch pathways in Drosophila epithelia. Hum Mol Genet. 2006;15:1704–1712.PubMedCrossRefGoogle Scholar
  102. 102.
    Mateus AR, Seruca R, Machado JC, et al. EGFR regulates RhoA-GTP dependent cell motility in E-cadherin mutant cells. Hum Mol Genet. 2007;16:1639–1647.PubMedCrossRefGoogle Scholar
  103. 103.
    Bajpai S, Correia J, Feng Y, et al. {alpha}-Catenin mediates initial E-cadherin-dependent cell-cell recognition and subsequent bond strengthening. Proc Natl Acad Sci USA. 2008;105:18331–18336.PubMedCrossRefGoogle Scholar
  104. 104.
    Lewis FR, Mellinger JD, Hayashi A, et al. Prophylactic total gastrectomy for familial gastric cancer. Surgery. 2001;130:612–619.PubMedCrossRefGoogle Scholar
  105. 105.
    van Kouwen MC, Drenth JP, Oyen WJ, et al. [18 F]Fluoro-2-deoxy-D-glucose positron emission tomography detects gastric carcinoma in an early stage in an asymptomatic E-cadherin mutation carrier. Clin Cancer Res. 2004;10:6456–6459.PubMedCrossRefGoogle Scholar
  106. 106.
    Oliveira C, Moreira H, Seruca R, et al. Role of pathology in the identification of Hereditary Diffuse Gastric Cancer: Report of a Portuguese family. Virchows Arch. 2005;446:181–184.PubMedCrossRefGoogle Scholar
  107. 107.
    Oelschlager BK, Yigit T, Kaufman JA, Pellegrini CA. Hereditary diffuse gastric cancer. Med Gen Med. 2005;7:16.Google Scholar
  108. 108.
    Newman EA, Mulholland MW. Prophylactic gastrectomy for hereditary diffuse gastric cancer syndrome. J Am Coll Surg. 2006;202:612–617.PubMedCrossRefGoogle Scholar
  109. 109.
    Francis WP, Rodrigues DM, Perez NE, et al. Prophylactic laparoscopic-assisted total gastrectomy for hereditary diffuse gastric cancer. JSLS. 2007;11:142–147.PubMedGoogle Scholar
  110. 110.
    Chung D, Yoon S, Lauwers G, et al. A women with a family history of gastric and breast cancer. N Engl J Med. 2007;357:283–291.PubMedCrossRefGoogle Scholar
  111. 111.
    Lynch HT, Kaurah P, Wirtzfeld D, et al. Hereditary diffuse gastric cancer: diagnosis, genetic counseling, and prophylactic total gastrectomy. Cancer. 2008;112:2655–2663.PubMedCrossRefGoogle Scholar
  112. 112.
    Gaya DR, Stuart RC, McKee RF, et al. E-cadherin mutation-associated diffuse gastric adenocarcinoma: penetrance and non-penetrance. Eur J Gastroenterol Hepatol. 2005;17:1425–1428.PubMedCrossRefGoogle Scholar
  113. 113.
    Koea JB, Karpeh MS, Brennan MF. Gastric cancer in young 524 patients: demographic, clinicopathological, and prognostic 525 factors in 92 patients. Ann Surg Oncol. 2000;7:346–351.PubMedCrossRefGoogle Scholar
  114. 114.
    Kaurah P, Fitzgerald R, Dwerryhouse S, Huntsman DG. Pregnancy after prophylactic total gastrectomy. Fam Cancer. 2010;9:331–334.PubMedCrossRefGoogle Scholar
  115. 115.
    Mareel M, Leroy A. Clinical, cellular, and molecular aspects of cancer invasion. Physiol Rev. 2003;83:337–376.PubMedGoogle Scholar
  116. 116.
    Yap AS, Kovacs EM. Direct cadherin-activated cell signaling: a view from the plasma membrane. J Cell Biol. 2003;160:11–16.PubMedCrossRefGoogle Scholar
  117. 117.
    Crepaldi T, Pollack AL, Prat M, et al. Targeting of the SF/HGF receptor to the basolateral domain of polarized epithelial cells. J Cell Biol. 1994;125:313–320.PubMedCrossRefGoogle Scholar
  118. 118.
    Hoschuetzky H, Aberle H, Kemler R. Beta-catenin mediates the interaction of the cadherin-catenin complex with epidermal growth factor receptor. J Cell Biol. 1994;127:1375–1380.PubMedCrossRefGoogle Scholar
  119. 119.
    Qian X, Karpova T, Sheppard AM, et al. E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases. EMBO J. 2004;23:1739–1748.PubMedCrossRefGoogle Scholar
  120. 120.
    Comoglio PM, Boccaccio C, Trusolino L. Interactions between growth factor receptors and adhesion molecules: breaking the rules. Curr Opin Cell Biol. 2003;15:565–571.PubMedCrossRefGoogle Scholar
  121. 121.
    Hermiston ML, Gordon JI. In vivo analysis of cadherin function in the mouse intestinal epithelium: essential roles in adhesion, maintenance of differentiation, and regulation of programmed cell death. J Cell Biol. 1995;129:489–506.PubMedCrossRefGoogle Scholar
  122. 122.
    Ruoslahti E, Reed JC. Anchorage dependence, integrins, and apoptosis. Cell. 1994;77:477–478.PubMedCrossRefGoogle Scholar
  123. 123.
    Frisch SM, Ruoslahti E. Integrins and anoikis. Curr Opin Cell Biol. 1997;9:701–706.PubMedCrossRefGoogle Scholar
  124. 124.
    Hirata K, Ajiki T, Okazaki T, et al. Frequent occurrence of abnormal E-cadherin/beta-catenin protein expression in advanced gallbladder cancers and its association with decreased apoptosis. Oncology. 2006;71:102–110.PubMedGoogle Scholar
  125. 125.
    Ferreira P, Oliveira MJ, Beraldi E, et al. Loss of functional E-cadherin renders cells more resistant to the apoptotic agent taxol in vitro. Exp Cell Res. 2005;310:99–104.PubMedCrossRefGoogle Scholar
  126. 126.
    Carvalho R, Milne AN, van Rees BP, et al. Early-onset gastric carcinomas display molecular characteristics distinct from gastric carcinomas occurring at a later age. J Pathol. 2004;204:75–83.PubMedCrossRefGoogle Scholar
  127. 127.
    Milne AN, Carvalho R, Morsink FM, et al. Early-onset gastric cancers have a different molecular expression profile than conventional gastric cancers. Mod Pathol. 2006;19:564–572.PubMedCrossRefGoogle Scholar
  128. 128.
    Mori M, Sugimachi K, Ohiwa T, et al. Early gastric carcinoma in Japanese patients under 30 years of age. Br J Surg. 1985;72:289–291.PubMedCrossRefGoogle Scholar
  129. 129.
    Nakamura T, Yao T, Niho Y, Tsuneyoshi M. A clinicopathological study in young patients with gastric carcinoma. J Surg Oncol. 1999;71:214–219.PubMedCrossRefGoogle Scholar
  130. 130.
    Ramos de la Medina A, Salgado-Nesme N, Torres-Villalobos G, Medina-Franco H. Clinicopathologic characteristics of gastric cancer in a young patient population. J Gastrointest Surg. 2004;8:240–244.PubMedCrossRefGoogle Scholar
  131. 131.
    McGill TW, Downey EC, Westbrook J, et al. Gastric carcinoma in children. J Pediatr Surg. 1993;28:1620–1621.PubMedCrossRefGoogle Scholar
  132. 132.
    Kokkola A, Sipponen P. Gastric carcinoma in young adults. Hepatogastroenterology. 2001;48:1552–1555.PubMedGoogle Scholar
  133. 133.
    Saito A, Kanai Y, Maesawa C, et al. Disruption of E-cadherin-mediated cell adhesion systems in gastric cancers in young patients. Jpn J Cancer Res. 1999;90:993–999.PubMedCrossRefGoogle Scholar
  134. 134.
    Zhang Y, Liu X, Fan Y, et al. Germline mutations and polymorphic variants in MMR, E-cadherin and MYH genes associated with familial gastric cancer in Jiangsu of China. Int J Cancer. 2006;119:2592–2596.PubMedCrossRefGoogle Scholar
  135. 135.
    de la Chapelle A. Genetic predisposition to colorectal cancer. Nat Rev Cancer. 2004;4:769–780.PubMedCrossRefGoogle Scholar
  136. 136.
    Gruber SB. New development in Lynch syndrome (hereditary nonpolyposis colorectal cancer) and Mismatch repair gene testing. Gastroenterology. 2006;130:577–587.PubMedCrossRefGoogle Scholar
  137. 137.
    Lynch HT, Smyrk TC, Watson P, et al. Genetics, natural history tumor spectrum, and pathology of hereditary non-polyposis colorectal cancer. An update review. Gastroenterology. 1993;104:1535–1549.PubMedGoogle Scholar
  138. 138.
    Capelle LG, Van Grieken NC, Lingsma HF, et al. Risk and epidemiological time trends of gastric cancer in Lynch syndrome carriers in the Netherlands. Gastroenterology. 2010;138:487–492.PubMedCrossRefGoogle Scholar
  139. 139.
    Aaltonen LA, Peltomaki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer. Science. 1993;260:812–816.PubMedCrossRefGoogle Scholar
  140. 140.
    Liu B, Parsons R, Papadopoulos N, et al. Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nat Med. 1996;2:169–174.PubMedCrossRefGoogle Scholar
  141. 141.
    Leite M, Corso G, Sousa S, et al. MSI phenotype and MMR alterations in familial and sporadic gastric cancer. Int J Cancer. 2010;128:1606–13.PubMedCrossRefGoogle Scholar
  142. 142.
    Oliveira C, Suriano G, Ferreira P, et al. Genetic screening for familial gastric cancer. Hered Cancer Clin Pract. 2004;2:51–64.PubMedCrossRefGoogle Scholar
  143. 143.
    Li FP, Fraumeni JF Jr. Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst. 1969;43:1365–173.PubMedGoogle Scholar
  144. 144.
    Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med. 1969;71:747–752.PubMedGoogle Scholar
  145. 145.
    Birch JM, Hartley AL, Tricker KJ, et al. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994;54:1298–1304.PubMedGoogle Scholar
  146. 146.
    Frebourg T, Barbier N, Yan YX, et al. Germ-line p53 mutations in 15 families with Li-Fraumeni syndrome. Am J Hum Genet. 1995;56:608–615.PubMedGoogle Scholar
  147. 147.
    MacGeoch C, Turner G, Bobrow LG, et al. Heterogeneity in Li-Fraumeni families: p53 mutation analysis and immunohistochemical staining. J Med Genet. 1995;32:186–190.PubMedCrossRefGoogle Scholar
  148. 148.
    Olivier M, Eeles R, Hollstein M, et al. The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat. 2002;19:607–614.PubMedCrossRefGoogle Scholar
  149. 149.
    Palmero EI, Achatz MI, Ashton-Prolla P, et al. Tumor protein 53 mutations and inherited cancer: beyond Li-Fraumeni syndrome. Curr Opin Oncol. 2010;22:64–69.PubMedCrossRefGoogle Scholar
  150. 150.
    Fenoglio-Preiser CM, Wang J, Stemmermann GN, Noffsinger A. TP53 and gastric carcinoma: a review. Hum Mutat. 2003;21:258–270.PubMedCrossRefGoogle Scholar
  151. 151.
    Gomyo Y, Osaki M, Kaibara N, Ito H. Numerical aberration and point mutation of p53 gene in human gastric intestinal metaplasia and well-differentiated adenocarcinoma: analysis by fluorescence in situ hybridization (FISH) and PCR-SSCP. Int J Cancer. 1996;66:594–599.PubMedCrossRefGoogle Scholar
  152. 152.
    Seruca R, David L, Holm R, et al. P53 mutations in gastric carcinomas. Br J Cancer. 1992;65:708–710.PubMedCrossRefGoogle Scholar
  153. 153.
    Seruca R, David L, Castedo S, et al. p53 alterations in gastric carcinoma: a study of 56 primary tumors and 204 nodal metastases. Cancer Genet Cytogenet. 1994;75:45–50.PubMedCrossRefGoogle Scholar
  154. 154.
    Seruca R, David L, Sobrinho-Simões M. Relationship between the expression of p53 and the aggressiveness of gastric carcinoma. J Pathol. 1997;181:349.PubMedCrossRefGoogle Scholar
  155. 155.
    Bell DW, Varley JM, Szydlo TE, et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999;286:2528–2531.PubMedCrossRefGoogle Scholar
  156. 156.
    Bachinski LL, Olufemi SE, Zhou X, et al. Genetic mapping of a third Li–Fraumeni syndrome predisposition locus to human chromosome 1q23. Cancer Res. 2005;65:427–431.PubMedGoogle Scholar
  157. 157.
    Lipton L, Tomlinson I. The genetics of FAP and FAP-like syndromes. Fam Cancer. 2006;5:221–226.PubMedCrossRefGoogle Scholar
  158. 158.
    Vasen HF, Möslein G, Alonso A, et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut. 2008;57:704–713.PubMedCrossRefGoogle Scholar
  159. 159.
    Coffey RJ Jr, Knight CD Jr, van Heerden JA, et al. Gastric adenocarcinoma complicating Gardner’s syndrome in a North American woman. Gastroenterology. 1985;88:1263–1266.PubMedGoogle Scholar
  160. 160.
    Park JG, Park KJ, Ahn YO, et al. Risk of gastric cancer among Korean familial adenomatous polyposis patients. Report of three cases. Dis Colon Rectum. 1992;35:996–998.PubMedCrossRefGoogle Scholar
  161. 161.
    Lynch HT, Snyder C, Davies JM, et al. FAP, gastric cancer, and genetic counseling featuring children and young adults: a family study and review. Fam Cancer. 2010;9:581–588.PubMedCrossRefGoogle Scholar
  162. 162.
    Knudsen AL, Bisgaard ML, Bulow S. Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Fam Cancer. 2003;2:43–55.PubMedCrossRefGoogle Scholar
  163. 163.
    Groden J, Thliveris A, Samowitz W, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell. 1991;66:589–600.PubMedCrossRefGoogle Scholar
  164. 164.
    Burt R, Neklason DW. Genetic testing for inherited colon cancer. Gastroenterology. 2005;128:1696–1716.PubMedCrossRefGoogle Scholar
  165. 165.
    Al-Tassan N, Chmiel NH, Maynard J, et al. Inherited variants of MYH associated with somatic G:CRT: A mutations in colorectal tumors. Nat Genet. 2002;30:227–232.PubMedCrossRefGoogle Scholar
  166. 166.
    Poulsen ML, Bisgaard ML. MUTYH Associated Polyposis (MAP). Curr Genomics. 2008;9:420–435.PubMedCrossRefGoogle Scholar
  167. 167.
    Vogt S, Jones N, Christian D, et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology. 2009;137:1976–1985.PubMedCrossRefGoogle Scholar
  168. 168.
    Attard TM, Giardiello FM, Argani P, Cuffari C. Fundic gland polyposis with high-grade dysplasia in a child with attenuated familial adenomatous polyposis and familial gastric cancer. J Pediatr Gastroenterol Nutr. 2001;32:215–218.PubMedCrossRefGoogle Scholar
  169. 169.
    Abraham SC, Park SJ, Mugartegui L, et al. Sporadic fundic gland polyps with epithelial dysplasia: evidence for preferential targeting for mutations in the adenomatous polyposis coli gene. Am J Pathol. 2002;161:1735–1742.PubMedCrossRefGoogle Scholar
  170. 170.
    Weinstock JV, Kawanishi H. Gastrointestinal polyposis with orocutaneous hamartomas (Cowden’s disease). Gastroenterology. 1978;74(5 Pt 1):890–895.PubMedGoogle Scholar
  171. 171.
    Al-Thihli K, Palma L, Marcus V, et al. A case of Cowden’s syndrome presenting with gastric carcinomas and gastrointestinal polyposis. Nat Clin Pract Gastroenterol Hepatol. 2009;6:184–189.PubMedCrossRefGoogle Scholar
  172. 172.
    Amos CI, Frazier ML, McGarrity TJ. Peutz Jeghers syndrome. In: Pagon RA, Bird TC, Dolan CR, Stephens K, (eds) GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2001. [updated 2010 Nov 2].Google Scholar
  173. 173.
    Buck JL, Harned RK, Lichtenstein JE, Sobin LH. Peutz-Jeghers syndrome. Radiographics. 1992;12:365–378.PubMedGoogle Scholar
  174. 174.
    Giardiello FM, Welsh SB, Hamilton SR, et al. Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med. 1987;316:1511–1514.PubMedCrossRefGoogle Scholar
  175. 175.
    Beggs AD, Latchford AR, Vasen HF, et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut. 2010;59:975–986.PubMedCrossRefGoogle Scholar
  176. 176.
    Takahashi M, Sakayori M, Takahashi S, et al. A novel germline mutation of the LKB1 gene in a patient with Peutz-Jeghers syndrome with early-onset gastric cancer. J Gastroenterol. 2004;39:1210–1214.PubMedCrossRefGoogle Scholar
  177. 177.
    Shinmura K, Goto M, Tao H, et al. A novel STK11 germline mutation in two siblings with Peutz-Jeghers syndrome complicated by primary gastric cancer. Clin Genet. 2005;67:81–86.PubMedCrossRefGoogle Scholar
  178. 178.
    van Lier MG, Wagner A, Mathus-Vliegen EM, et al. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol. 2010;105:1258–1264.PubMedCrossRefGoogle Scholar
  179. 179.
    Hemminki A, Markie D, Tomlinson I, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. 1998;391:184–187.PubMedCrossRefGoogle Scholar
  180. 180.
    Jenne DE, Reimann H, Nezu J, et al. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet. 1998;18:38–43.PubMedCrossRefGoogle Scholar
  181. 181.
    Alhopuro P, Phichith D, Tuupanen S, et al. Unregulated smooth-muscle myosin in human intestinal neoplasia. Proc Natl Acad Sci USA. 2008;105:5513–5518.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Fátima Carneiro
    • 1
    Email author
  • Carla Oliveira
    • 2
  • Raquel Seruca
    • 2
  1. 1.Department of Pathology and Cancer Genetics GroupInstitute of Molecular Pathology and Immunology of the University of Porto and Centro Hospitalar São João/Medical Faculty of the University of PortoPortoPortugal
  2. 2.Cancer Genetics GroupInstitute of Molecular Pathology and Immunology of the University of Porto and Medical Faculty of the University of PortoPortoPortugal

Personalised recommendations