Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

  • Rachel S. van der Post
  • Irene Gullo
  • Carla Oliveira
  • Laura H. Tang
  • Heike I. Grabsch
  • Maria O’Donovan
  • Rebecca C. Fitzgerald
  • Han van Krieken
  • Fátima CarneiroEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 908)


Familial clustering is seen in 10 % of gastric cancer cases and approximately 1–3 % of gastric cancer arises in the setting of hereditary diffuse gastric cancer (HDGC). In families with HDGC, gastric cancer presents at young age. HDGC is predominantly caused by germline mutations in CDH1 and in a minority by mutations in other genes, including CTNNA1. Early stage HDGC is characterized by a few, up to dozens of intramucosal foci of signet ring cell carcinoma and its precursor lesions. These include in situ signet ring cell carcinoma and pagetoid spread of signet ring cells. Advanced HDGC presents as poorly cohesive/diffuse type carcinoma, normally with very few typical signet ring cells, and has a poor prognosis. Currently, it is unknown which factors drive the progression towards aggressive disease, but it is clear that most intramucosal lesions will not have such progression.

Immunohistochemical profile of early and advanced HDGC is often characterized by abnormal E-cadherin immunoexpression, including absent or reduced membranous expression, as well as “dotted” or cytoplasmic expression. However, membranous expression of E-cadherin does not exclude HDGC. Intramucosal HDGC (pT1a) presents with an “indolent” phenotype, characterized by typical signet ring cells without immunoexpression of Ki-67 and p53, while advanced carcinomas (pT > 1) display an “aggressive” phenotype with pleomorphic cells, that are immunoreactive for Ki-67 and p53. These features show that the IHC profile is different between intramucosal and more advanced HDGC, providing evidence of phenotypic heterogeneity, and may help to define predictive biomarkers of progression from indolent to aggressive, widely invasive carcinomas.


Hereditary Gastric cancer Signet-ring cell Stomach E-cadherin Immunohistochemistry CDH1 CTNNA1 


  1. 1.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F., GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Accessed on day/month/year, 2012.
  2. 2.
    Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumours of the digestive system. IARC Sci Publ 2010; 4th ed., 2010.Google Scholar
  3. 3.
    Lauren P. 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. 1965;64:31–49.PubMedGoogle Scholar
  4. 4.
    Kawasaki K, et al. Family history of cancer in Japanese gastric cancer patients. Gastric Cancer. 2007;10(3):173–5.PubMedCrossRefGoogle Scholar
  5. 5.
    La Vecchia C, et al. Family history and the risk of stomach and colorectal cancer. Cancer. 1992;70(1):50–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Hemminki K, Sundquist J, Ji J. Familial risk for gastric carcinoma: an updated study from Sweden. Br J Cancer. 2007;96(8):1272–7.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Carneiro F. Pathology of hereditary gastric cancer. In: Corso G, Roviello F, editors. Spotlight on familial and hereditary gastric cancer. Dordrecht: Springer; 2013. p. 141–56.CrossRefGoogle Scholar
  8. 8.
    Caldas C, et al. Familial gastric cancer: overview and guidelines for management. J Med Genet. 1999;36(12):873–80.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Worthley DL, et al. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome. Gut. 2012;61(5):774–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Oliveira C, et al. Familial gastric cancer: genetic susceptibility, pathology, and implications for management. Lancet Oncol. 2015;16(2):e60–70.PubMedCrossRefGoogle Scholar
  11. 11.
    Park YJ, Shin KH, Park JG. Risk of gastric cancer in hereditary nonpolyposis colorectal cancer in Korea. Clin Cancer Res. 2000;6(8):2994–8.PubMedGoogle Scholar
  12. 12.
    Capelle LG, et al. Risk and epidemiological time trends of gastric cancer in Lynch syndrome carriers in the Netherlands. Gastroenterology. 2010;138(2):487–92.PubMedCrossRefGoogle Scholar
  13. 13.
    Sereno M, et al. Gastric tumours in hereditary cancer syndromes: clinical features, molecular biology and strategies for prevention. Clin Transl Oncol. 2011;13(9):599–610.PubMedCrossRefGoogle Scholar
  14. 14.
    Keller G, 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(6):e89.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Oliveira C, et al. E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients. Eur J Cancer. 2004;40(12):1897–903.PubMedCrossRefGoogle Scholar
  16. 16.
    Masciari S, et al. Gastric cancer in individuals with Li-Fraumeni syndrome. Genet Med. 2011;13(7):651–7.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Iwama T, Mishima Y, Utsunomiya J. The impact of familial adenomatous polyposis on the tumorigenesis and mortality at the several organs. Its rational treatment. Ann Surg. 1993;217(2):101–8.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Lynch HT, et al. FAP, gastric cancer, and genetic counseling featuring children and young adults: a family study and review. Fam Cancer. 2010;9(4):581–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Giardiello FM, Trimbath JD. Peutz-Jeghers syndrome and management recommendations. Clin Gastroenterol Hepatol. 2006;4(4):408–15.PubMedCrossRefGoogle Scholar
  20. 20.
    Giardiello FM, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology. 2000;119(6):1447–53.PubMedCrossRefGoogle Scholar
  21. 21.
    van Lier MG, et al. High cancer risk and increased mortality in patients with Peutz-Jeghers syndrome. Gut. 2011;60(2):141–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Howe JR, Mitros FA, Summers RW. The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol. 1998;5(8):751–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Pollock J, Welsh JS. Clinical cancer genetics: part I: gastrointestinal. Am J Clin Oncol. 2011;34(3):332–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Jakubowska A, et al. BRCA2 gene mutations in families with aggregations of breast and stomach cancers. Br J Cancer. 2002;87(8):888–91.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Friedenson B. BRCA1 and BRCA2 pathways and the risk of cancers other than breast or ovarian. MedGenMed. 2005;7(2):60.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Jones EG. Familial gastric cancer. N Z Med J. 1964;63:287–96.PubMedGoogle Scholar
  27. 27.
    Guilford P, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392(6674):402–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Berx G, et al. Cloning and characterization of the human invasion suppressor gene E-cadherin (CDH1). Genomics. 1995;26(2):281–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Berx G, et al. Mutations of the human E-cadherin (CDH1) gene. Hum Mutat. 1998;12(4):226–37.PubMedCrossRefGoogle Scholar
  30. 30.
    van Roy F, Berx G. The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci. 2008;65(23):3756–88.PubMedCrossRefGoogle Scholar
  31. 31.
    Suriano G, et al. Characterization of a recurrent germ line mutation of the E-cadherin gene: implications for genetic testing and clinical management. Clin Cancer Res. 2005;11(15):5401–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Oliveira C, Seruca R, Carneiro F. Genetics, pathology, and clinics of familial gastric cancer. Int J Surg Pathol. 2006;14(1):21–33.PubMedCrossRefGoogle Scholar
  33. 33.
    Kaurah P, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007;297(21):2360–72.PubMedCrossRefGoogle Scholar
  34. 34.
    Benusiglio PR, et al. CDH1 germline mutations and the hereditary diffuse gastric and lobular breast cancer syndrome: a multicentre study. J Med Genet. 2013;50(7):486–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H, Schrader KA, Schaeffer DF, Shumansky K, Zogopoulos G, Santos TA, Claro I, Carvalho J, Nielsen C, Padilla S, Lum A, Talhouk A, Baker-Lange K, Richardson S, Lewis I, Lindor NM, Pennell E, MacMillan A, Fernandez B, Keller G, Lynch H, Shah SP, Guilford P, Gallinger S, Corso G, Roviello F, Caldas C, Oliveira C, Pharoah PD, Huntsman DG. Hereditary diffuse gastric cancer syndrome CDH1 mutations and beyond. JAMA Oncol. 2015;1(1):23–32.PubMedCrossRefGoogle Scholar
  36. 36.
    Rimm DL, et al. Alpha 1(E)-catenin is an actin-binding and -bundling protein mediating the attachment of F-actin to the membrane adhesion complex. Proc Natl Acad Sci U S A. 1995;92(19):8813–7.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Koslov ER, et al. Alpha-catenin can form asymmetric homodimeric complexes and/or heterodimeric complexes with beta-catenin. J Biol Chem. 1997;272(43):27301–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Vasioukhin V, et al. Hyperproliferation and defects in epithelial polarity upon conditional ablation of alpha-catenin in skin. Cell. 2001;104(4):605–17.PubMedCrossRefGoogle Scholar
  39. 39.
    Majewski IJ, et al. An alpha-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer. J Pathol. 2013;229(4):621–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Jakubowska A, et al. A high frequency of BRCA2 gene mutations in Polish families with ovarian and stomach cancer. Eur J Hum Genet. 2003;11(12):955–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Moran A, et al. Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations. Fam Cancer. 2012;11(2):235–42.PubMedCrossRefGoogle Scholar
  42. 42.
    Risch HA, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001;68(3):700–10.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Johannsson O, et al. Incidence of malignant tumours in relatives of BRCA1 and BRCA2 germline mutation carriers. Eur J Cancer. 1999;35(8):1248–57.PubMedCrossRefGoogle Scholar
  44. 44.
    Gaston D, et al. Germline mutations in MAP3K6 are associated with familial gastric cancer. PLoS Genet. 2014;10(10):e1004669.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Fitzgerald RC, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet. 2010;47(7):436–44.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Oliveira C, et al. Germline CDH1 deletions in hereditary diffuse gastric cancer families. Hum Mol Genet. 2009;18(9):1545–55.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Van der Post RS, Vogelaar IP, Carneiro F, Guilford P, Huntsman D, Hoogerbrugge N, Caldas C, Chelcun Schreiber KE, Hardwick R, Ausems MG, Bardram L, Benusiglio PR, Bisseling TM, Blair V, Bleiker E, Boussioutas A, Cats A, Coit D, DeGregorio L, Figueiredo J, Ford JM, Heijkoop E, Hermens R, Humar B, Kaurah P, Keller G, Lai J, Ligtenberg MJL, O’Donovan M, Oliveira C, Pinheiro H, Ragunath K, Rasenberg E, Richardson S, Roviello F, Schackert HK, Seruca R, Taylor A, Ter Huurne A, Tischkowitz M, Tjon S, Joe A, Van Dijck B, Van Grieken NC, van Hillegersberg R, Van Sandick JW, Vehof R, Van Krieken JH, Fitzgerald RC. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet. 2015;52(6):361–74.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Lim YC, et al. Prospective cohort study assessing outcomes of patients from families fulfilling criteria for hereditary diffuse gastric cancer undergoing endoscopic surveillance. Gastrointest Endosc. 2014;80(1):78–87.PubMedCrossRefGoogle Scholar
  49. 49.
    Grady WM, et al. Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nat Genet. 2000;26(1):16–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Oliveira C, et al. Intragenic deletion of CDH1 as the inactivating mechanism of the wild-type allele in an HDGC tumour. Oncogene. 2004;23(12):2236–40.PubMedCrossRefGoogle Scholar
  51. 51.
    Barber M, et al. Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer. J Pathol. 2008;216(3):295–306.PubMedCrossRefGoogle Scholar
  52. 52.
    Oliveira C, et al. Quantification of epigenetic and genetic 2nd hits in CDH1 during hereditary diffuse gastric cancer syndrome progression. Gastroenterology. 2009;136(7):2137–48.PubMedCrossRefGoogle Scholar
  53. 53.
    Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9.CrossRefGoogle Scholar
  54. 54.
    Lee YS, Cho CY, Lee GK, Lee S, Kim YW, Jho S, Kim HM, Hong SH, Hwang JA, Kim SY, Hong D, Choi IJ, Kim BC, Kim BC, Kim CH, Choi H, Kim Y, Kim KW, Kong G, Kim HL, Bhak J, Lee SH, Lee JS. Genomic profile analysis of diffuse-type gastric cancers. Genome Biol. 2014;15(4):R55.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Wang K, et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet. 2014;46(6):573–82.PubMedCrossRefGoogle Scholar
  56. 56.
    Wang K, et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat Genet. 2011;43(12):1219–23.PubMedCrossRefGoogle Scholar
  57. 57.
    Zang ZJ, et al. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet. 2012;44(5):570–4.PubMedCrossRefGoogle Scholar
  58. 58.
    Liang H, Kim YH. Identifying molecular drivers of gastric cancer through next-generation sequencing. Cancer Lett. 2013;340(2):241–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Carneiro F, 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(2):681–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Rogers WM, et al. Risk-reducing total gastrectomy for germline mutations in E-cadherin (CDH1): pathologic findings with clinical implications. Am J Surg Pathol. 2008;32(6):799–809.PubMedCrossRefGoogle Scholar
  61. 61.
    Charlton A, et al. Hereditary diffuse gastric cancer: predominance of multiple foci of signet ring cell carcinoma in distal stomach and transitional zone. Gut. 2004;53(6):814–20.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Shaw D, et al. Chromoendoscopic surveillance in hereditary diffuse gastric cancer: an alternative to prophylactic gastrectomy? Gut. 2005;54(4):461–8.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Huntsman DG, et al. Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations. N Engl J Med. 2001;344(25):1904–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Chun YS, et al. Germline E-cadherin gene mutations: is prophylactic total gastrectomy indicated? Cancer. 2001;92(1):181–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Fujita H, et al. Endoscopic surveillance of patients with hereditary diffuse gastric cancer: biopsy recommendations after topographic distribution of cancer foci in a series of 10 CDH1-mutated gastrectomies. Am J Surg Pathol. 2012;36(11):1709–17.PubMedCrossRefGoogle Scholar
  66. 66.
    Blair V, et al. Hereditary diffuse gastric cancer: diagnosis and management. Clin Gastroenterol Hepatol. 2006;4(3):262–75.PubMedCrossRefGoogle Scholar
  67. 67.
    Barber ME, 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(3):286–94.PubMedCrossRefGoogle Scholar
  68. 68.
    Humar B, 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(6):2480–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Norton JA, et al. CDH1 truncating mutations in the E-cadherin gene: an indication for total gastrectomy to treat hereditary diffuse gastric cancer. Ann Surg. 2007;245(6):873–9.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    da Cunha CB, et al. De novo expression of CD44 variants in sporadic and hereditary gastric cancer. Lab Invest. 2010;90(11):1604–14.PubMedCrossRefGoogle Scholar
  71. 71.
    Guarino M. Src signaling in cancer invasion. J Cell Physiol. 2010;223(1):14–26.PubMedGoogle Scholar
  72. 72.
    Lee JM, et al. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006;172(7):973–81.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Ferreira AC, et al. E-cadherin impairment increases cell survival through Notch-dependent upregulation of Bcl-2. Hum Mol Genet. 2012;21(2):334–43.PubMedCrossRefGoogle Scholar
  74. 74.
    Ferreira P, et al. Loss of functional E-cadherin renders cells more resistant to the apoptotic agent taxol in vitro. Exp Cell Res. 2005;310(1):99–104.PubMedCrossRefGoogle Scholar
  75. 75.
    Ma I, Allan AL. The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem Cell Rev. 2011;7(2):292–306.PubMedCrossRefGoogle Scholar
  76. 76.
    Deng S, et al. Distinct expression levels and patterns of stem cell marker, aldehyde dehydrogenase isoform 1 (ALDH1), in human epithelial cancers. PLoS One. 2010;5(4):e10277.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Zhi QM, et al. Salinomycin can effectively kill ALDH(high) stem-like cells on gastric cancer. Biomed Pharmacother. 2011;65(7):509–15.PubMedCrossRefGoogle Scholar
  78. 78.
    Katsuno Y, et al. Coordinated expression of REG4 and aldehyde dehydrogenase 1 regulating tumourigenic capacity of diffuse-type gastric carcinoma-initiating cells is inhibited by TGF-beta. J Pathol. 2012;228(3):391–404.PubMedCrossRefGoogle Scholar
  79. 79.
    Wakamatsu Y, et al. Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer. Pathol Int. 2012;62(2):112–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Wu C, et al. Lgr5 expression as stem cell marker in human gastric gland and its relatedness with other putative cancer stem cell markers. Gene. 2013;525(1):18–25.PubMedCrossRefGoogle Scholar
  81. 81.
    Takahashi H, et al. A combination of nuclear beta-catenin and atypical scores as useful diagnostic markers for borderline malignancy of gastric tumours. Histopathology. 2014;65(6):828–38.PubMedCrossRefGoogle Scholar
  82. 82.
    Xiao-shan Li QX, Xiang-yang F, Wei-sheng L. ALDH1A1 overexpression is associated with the progression and prognosis in gastric cancer. BMC Cancer. 2014;14:705.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Fricke E, et al. Relationship between E-cadherin gene mutation and p53 gene mutation, p53 accumulation, Bcl-2 expression and Ki-67 staining in diffuse-type gastric carcinoma. Int J Cancer. 2003;104(1):60–5.PubMedCrossRefGoogle Scholar
  84. 84.
    Yildirim M, et al. Prognostic significance of p53 in gastric cancer: a meta-analysis. Asian Pac J Cancer Prev. 2015;16(1):327–32.PubMedCrossRefGoogle Scholar
  85. 85.
    Busuttil RA, et al. Role of p53 in the progression of gastric cancer. Oncotarget. 2014;5(23):12016–26.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Teh M, Lee YS. An immunohistochemical study of p53 protein in the different histological subtypes of gastric carcinoma. Pathology. 1994;26(4):432–4.PubMedCrossRefGoogle Scholar
  87. 87.
    Brito MJ, et al. Expression of p53 in early (T1) gastric carcinoma and precancerous adjacent mucosa. Gut. 1994;35(12):1697–700.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Ranzani GN, et al. p53 gene mutations and protein nuclear accumulation are early events in intestinal type gastric cancer but late events in diffuse type. Cancer Epidemiol Biomarkers Prev. 1995;4(3):223–31.PubMedGoogle Scholar
  89. 89.
    Kakiuchi M, et al. Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet. 2014;46(6):583–7.PubMedCrossRefGoogle Scholar
  90. 90.
    Riethmacher D, Brinkmann V, Birchmeier C. A targeted mutation in the mouse E-cadherin gene results in defective preimplantation development. Proc Natl Acad Sci U S A. 1995;92(3):855–9.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Humar B, Blair V, Charlton A, More H, Martin I, Guilford P. E-cadherin deficiency initiates gastric signet-ring cell carcinoma in mice and man. Cancer Res. 2009;69(5):2050–6.PubMedCrossRefGoogle Scholar
  92. 92.
    Shimada S, et al. Synergistic tumour suppressor activity of E-cadherin and p53 in a conditional mouse model for metastatic diffuse-type gastric cancer. Gut. 2012;61(3):344–53.PubMedCrossRefGoogle Scholar
  93. 93.
    Mimata A, Fukamachi H, Eishi Y, Yuasa Y. Loss of E-cadherin in mouse gastric epithelial cells induces signet ring-like cells, a possible precursor lesion of diffuse gastric cancer. Cancer Sci. 2011;102(5):942–50.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Rachel S. van der Post
    • 1
  • Irene Gullo
    • 2
    • 3
    • 4
  • Carla Oliveira
    • 2
    • 3
  • Laura H. Tang
    • 5
  • Heike I. Grabsch
    • 6
  • Maria O’Donovan
    • 7
  • Rebecca C. Fitzgerald
    • 8
  • Han van Krieken
    • 1
  • Fátima Carneiro
    • 2
    • 3
    • 4
    Email author
  1. 1.Department of PathologyRadboud University Medical CentreNijmegenThe Netherlands
  2. 2.Department of PathologyCentro Hospitalar de São JoãoPortoPortugal
  3. 3.Department of Pathology and OncologyFaculdade de Medicina da Universidade do Porto (FMUP)PortoPortugal
  4. 4.Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Porto, Portugal and Instituto de Investigação e Inovação em SaúdeUniversidade do PortoPortoPortugal
  5. 5.Department of PathologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  6. 6.GROW School of Oncology and Developmental Biology and Department of PathologyMaastricht University Medical CentreMaastrichtThe Netherlands
  7. 7.Department of HistopathologyCambridge University Hospitals NHS TrustCambridgeUK
  8. 8.MRC Cancer Unit, Hutchison-MRC Research CentreUniversity of CambridgeCambridgeUK

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