Pathology & Oncology Research

, Volume 25, Issue 2, pp 711–721 | Cite as

Early Hereditary Diffuse Gastric Cancer (eHDGC) is Characterized by Subtle Genomic Instability and Active DNA Damage Response

  • Soroush Nasri
  • Bostjan Humara
  • Ahmad Anjomshoaa
  • Nourodin Moradi
  • Naghmeh GholipourEmail author
  • Sakineh Mashjoor
  • Peng Zhang
Original Article


Diffuse gastric cancer (DGC) is one of the two primary types of stomach cancer. Carriers of germline mutations in the gene encoding E-cadherin are predisposed to DGC. The primary aim of the present study was to determine if genomic instability is an early event in DGC and how it may lead to disease progression. Chromosomal aberrations in early intramucosal hereditary diffuse gastric cancer (eHDGC) were assessed using array comparative genomic hybridization (array CGH). Notably, no aneuploidy or other large-scale chromosomal rearrangements were detected. Instead, all aberrations affected small regions (< 4.8 Mb) and were predominantly deletions. Analysis of DNA sequence patterns revealed that essentially all aberrations possessed the characteristics of common fragile sites. These results and the results of subsequent immunohistochemical examinations demonstrated that unlike advanced DGC, eHDGCs is characterized by low levels of genomic instability at fragile sites. Furthermore, they express an active DNA damage response, providing a molecular basis for the observed indolence of eHDGC. This finding is an important step to understanding the pathology underlying natural history of DGC and supports a revision of the current definition of eHDGC as a malignant disease.


Genomic instability Diffuse gastric cancer Array CGH DNA fragility 



This research was supported by HS and JC Anderson Charitable Trust and the Health Research Council of New Zealand.

Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflict of interest.

Supplementary material

12253_2018_547_MOESM1_ESM.docx (26 kb)
ESM 1 (DOCX 25 kb)


  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108CrossRefGoogle Scholar
  2. 2.
    Crew KD (2006) Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol 12:354–362CrossRefGoogle Scholar
  3. 3.
    Lauren P (1965) The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 64:31–49CrossRefGoogle Scholar
  4. 4.
    Ekstrom AM, Hansson LE, Signorello LB, Lindgren A, Bergstrom R, Nyren O (2000) Decreasing incidence of both major histologic subtypes of gastric adenocarcinoma-a population-based study in Sweden. Br J Cancer 83:391–396CrossRefGoogle Scholar
  5. 5.
    Henson DE, Dittus C, Younes M, Nguyen H, Albores-Saavedra J (2004) 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 128:765–770Google Scholar
  6. 6.
    Kattan MW, Karpeh MS, Mazumdar M, Brennan MF (2003) Postoperative nomogram for disease-specific survival after an R0 resection for gastric carcinoma. J Clin Oncol 21:3647–3650CrossRefGoogle Scholar
  7. 7.
    Stone J, Bevan S, Cunningham D, Hill A, Rahman N, Peto J, Marossy A, Houlston RS (1999) Low frequency of germline E-cadherin mutations in familial and nonfamilial gastric cancer. Br J Cancer 79:1935–1937CrossRefGoogle Scholar
  8. 8.
    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 392:402–405CrossRefGoogle Scholar
  9. 9.
    Becker KF, Atkinson MJ, Reich U, Becker I, Nekarda H, Siewert JR, Höfler H (1994) E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. Cancer Res 54:3845–3852Google Scholar
  10. 10.
    Tamura G, Yin J, Wang S, Fleisher AS, Zou T, Abraham JM, Kong D, Smolinski KN, Wilson KT, James SP, Silverberg SG, Nishizuka S, Terashima M, Motoyama T, Meltzer SJ (2000) E-cadherin gene promoter hypermethylation in primary human gastric carcinomas. J Natl Cancer Inst 92:569–573CrossRefGoogle Scholar
  11. 11.
    Machado JC, Oliveira C, Carvalho R, Soares P, Berx G, Caldas C, Seruca R, Carneiro F, Sobrinho-Simöes M (2001) E-cadherin gene (CDH1) promoter methylation as the second hit in sporadic diffuse gastric carcinoma. Oncogene 20:1525–1528CrossRefGoogle Scholar
  12. 12.
    Blair V, Martin I, Shaw D, Winship I, Kerr D, Arnold J, Harawira P, McLeod M, Parry S, Charlton A, Findlay M, Cox B, Humar B, More H, Guilford P (2006) Hereditary diffuse gastric cancer: diagnosis and management. Clin Gastroenterol Hepatol 4:262–275CrossRefGoogle Scholar
  13. 13.
    Humar B, Fukuzawa R, Blair V, Dunbier A, More H, Charlton A, , Kim WH, Reeve AE, Martin I, Guilford P (2007) Destabilized adhesion in the gastric proliferative zone and c-Src kinase activation mark the development of early diffuse gastric cancer. Cancer Res 67: 2480–2489CrossRefGoogle Scholar
  14. 14.
    Le Borgne R, Bellaiche Y, Schweisguth F (2002) Drosophila E-cadherin regulates the orientation of asymmetric cell division in the sensory organ lineage. Curr Biol 12:95–104CrossRefGoogle Scholar
  15. 15.
    Schluter MA, Pfarr CS, Pieczynski J, Whiteman EL, Hurd TW, Fan S, Liu CJ, Margolis B (2009) Trafficking of Crumbs3 during cytokinesis is crucial for lumen formation. Mol Biol Cell 20(22):4652–4663CrossRefGoogle Scholar
  16. 16.
    Stehbens SJ, Akhmanova A, Yap AS (2009) Microtubules and cadherins: aneglected partnership. Front Biosci 14:3159–3167CrossRefGoogle Scholar
  17. 17.
    Nasri S, Anjomshoaa A, Song S, Guilford P, McNoe L, Black M, Phillips V, Reeve A, Humar B (2010) Oligonucleotide array outperforms SNP array on formalin-fixed paraffin-embedded clinical samples. Cancer Genet Cytogenet 198(1):1–6CrossRefGoogle Scholar
  18. 18.
    Cleveland WS (1979) Robust locally weighted regression and smoothing scatterplots. J Am Stat Assoc 74(368):829–836CrossRefGoogle Scholar
  19. 19.
    van Dijk MC, Rombout PD, Boots-Sprenger SH, Straatman H, Bernsen MR, Ruiter DJ, Jeuken JW (2005) Multiplex ligation-dependent probe amplification for the detection of chromosomal gains and losses in formalin-fixed tissue. Diagn Mol Pathol 14(1):9–16CrossRefGoogle Scholar
  20. 20.
    Sarai A, Mazur J, Nussinov R, Jernigan RL (1989) Sequence dependence of DNA conformational flexibility. Biochem 28(19):7842–7849CrossRefGoogle Scholar
  21. 21.
    Mishmar D, Rahat A, Scherer SW, Nyakatura G, Hinzmann B, Kohwi Y, Mandel-Gutfroind Y, Lee JR, Drescher B, Sas DE, Margalit H (1998) Molecular characterization of a common fragile site (FRA7H) on human chromosome 7 by the cloning of a simian virus 40 integration site. Proc Natl Acad Sci U S A 95:8141–8146CrossRefGoogle Scholar
  22. 22.
    Humar B, Guilford P (2009) Hereditary diffuse gastric cancer: a manifestation of lost cell polarity. Cancer Sci 100(7):1151–1157CrossRefGoogle Scholar
  23. 23.
    Mimata A, Fukamachi H, Eishi Y, Yuasa Y (2011) Loss of E-cadherin in mouse gastric epithelial cells induces signet ring-like cells, a possible precursor lesion of diffuse gastric cancer. Cancer Sci 102(5):942–950CrossRefGoogle Scholar
  24. 24.
    Thoma CR, Toso A, Gutbrodt KL, Reggi SP, Frew IJ, Schraml P, Hergovich A, Moch H, Meraldi P, Krek W (2009) VHL loss causes spindle misorientation and chromosome instability. Nature Cell Biol 11(8):994–1001CrossRefGoogle Scholar
  25. 25.
    Little SE, Vuononvirta R, Reis-Filho JS, Natrajan R, Iravani M, Fenwick K, Mackay A, Ashworth A, Pritchard-Jones K, Jones C (2006) Array CGH using whole genome amplification of fresh-frozen and formalin-fixed, paraffin-embedded tumor DNA. Genomics 87(2):298–306CrossRefGoogle Scholar
  26. 26.
    Mc Sherry EA, Mc Goldrick A, Kay EW, Hopkins AM, Gallagher WM, Dervan PA (2007) Formalin-fixed paraffin-embedded clinical tissues show spurious copy number changes in array-CGH profiles. Clin Genet 72(5):441–447CrossRefGoogle Scholar
  27. 27.
    Talseth-Palmer BA, Bowden NA, Hill A, Meldrum C, Scott RJ (2008) Whole genome amplification and its impact on CGH array profiles. BMC Res Notes 1(1):56CrossRefGoogle Scholar
  28. 28.
    De Smith AJ, Tsalenko A, Sampas N, Scheffer A, Yamada NA, Tsang P, Ben-Dor A, Yakhini Z, Ellis RJ, Bruhn L, Laderman S (2007) Array CGH analysis of copy number variation identifies 1284 new genes variant in healthy white males: implications for association studies of complex diseases. Hum Mol Genet 16(23):2783–2794CrossRefGoogle Scholar
  29. 29.
    Brunet A, Armengol L, Heine D, Rosell J, García-Aragonés M, Gabau E, Estivill X, Guitart M (2009) BAC array CGH in patients with Velocardiofacial syndrome-like features reveals genomic aberrations on chromosome region 1q21. 1. BMC Med Genet 10(1):144CrossRefGoogle Scholar
  30. 30.
    Ambros IM, Brunner B, Aigner G, Bedwell C, Beiske K, Bénard J, Bown N, Combaret V, Couturier J, Defferrari R, Gross N (2011) A multilocus technique for risk evaluation of patients with neuroblastoma. Clin Cancer Res 17(4):792–804CrossRefGoogle Scholar
  31. 31.
    Shen Y, Wu BL (2009) Microarray-based genomic DNA profiling technologies in clinical molecular diagnostics. Clin Chem 55(4):659–669CrossRefGoogle Scholar
  32. 32.
    Hills A, Ahn JW, Donaghue C, Thomas H, Mann K, Ogilvie CM (2010) MLPA for confirmation of array CGH results and determination of inheritance. Mol Cytogen 3(1):19CrossRefGoogle Scholar
  33. 33.
    Cook JG (2009) Replication licensing and the DNA damage checkpoint. Front Biosci (Landmark edition) 14:5013CrossRefGoogle Scholar
  34. 34.
    Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421(6922):499–506CrossRefGoogle Scholar
  35. 35.
    Abraham RT (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 15(17):2177–2196CrossRefGoogle Scholar
  36. 36.
    Kumagai A, Dunphy WG (2006) How cells activate ATR. Cell Cycle 5(12):1265–1268CrossRefGoogle Scholar
  37. 37.
    Casper AM, Durkin SG, Arlt MF, Glover TW (2004) Chromosomal instability at common fragile sites in Seckel syndrome. Am J Hum Genet 75(4):654–660CrossRefGoogle Scholar
  38. 38.
    Durkin SG, Glover TW (2007) Chromosome fragile sites. Annu Rev Genet 41:169–192CrossRefGoogle Scholar
  39. 39.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674CrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2018

Authors and Affiliations

  • Soroush Nasri
    • 1
    • 2
  • Bostjan Humara
    • 1
  • Ahmad Anjomshoaa
    • 1
    • 3
  • Nourodin Moradi
    • 2
  • Naghmeh Gholipour
    • 2
    • 4
    Email author
  • Sakineh Mashjoor
    • 5
  • Peng Zhang
    • 6
  1. 1.Cancer Genetics Laboratory, Department of BiochemistryUniversity of OtagoDunedinNew Zealand
  2. 2.Milad Center for Medical GeneticsSariIran
  3. 3.Department of Medical Genetics, Faculty of MedicineKerman University of Medical SciencesKermanIran
  4. 4.Department of Medical GeneticsNational Institute of Genetic Engineering and BiotechnologyTehranIran
  5. 5.Department of Marine biology, Faculty of Marine Science and TechnologyHormozgan UniversityBandar AbbasIran
  6. 6.Division of Biomedical Science and Biochemistry, Research School of Biology, ANU College of Medicine, Biology and EnvironmentAustralian National UniversityCanberraAustralia

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