Skip to main content
SpringerLink
Log in

First-degree relatives of early-onset gastric cancer patients show a high risk for gastric cancer: phenotype and genotype profile

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

First-degree relatives (FDR) of early-onset gastric cancer (EOGC) is presumed to be a population with a distinct molecular and phenotypic profile, regarding the prevalence of gastric premalignant conditions and the association with Helicobacter pylori infection and host proinflammatory gene polymorphisms. A case–control study was conducted with FDR of EOGC patients (n = 103) and age and gender matched controls (n = 101; ranging from spouses to neighbors and dyspeptics). Upper endoscopy was performed, Operative Link on Gastritis Assessment (OLGA) system used for staging and H. pylori (cagA and vacA) and host IL1B-511, IL1RN intron2 VNTR and IFNGR1-56 genotyping. Seventy percent of cases showed atrophy, while 19 % presented with high-stage gastritis (OLGA stage III or IV) (p < 0.001); gastric dysplasia was present in seven cases (vs none in controls) (p = 0.007). In cases, H. pylori was present in 82 % (vs 62 % in controls; p = 0.004) with vacA s1 and vacA m1 + strains significantly associated with the presence of atrophy; individuals homozygous for IL1B–511*T present a significantly higher risk for dysplasia. An increased global prevalence of IFNGR1-56*T/*T polymorphism (37 % in cases vs 24 % in controls; p = 0.03) was observed with no association with atrophic changes or dysplasia. All trends observed were kept when comparing FDR of EOGC with spouses, neighbors, or dyspeptic controls. We demonstrated that FDR of EOGC patients have an increased prevalence of high-risk OLGA stages and dysplasia that seem to be associated with high virulence H. pylori strains and pro-inflammatory host genotypes, including a possible population-specific risk marker. FDR of EOGC patients may merit specific management through endoscopic and histopathological adequate assessment of gastric mucosa and surveillance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Kamangar F, Dores GM, Anderson WF (2006) Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 24(14):2137–2150. doi:10.1200/JCO.2005.05.2308

    Article  PubMed  Google Scholar 

  2. Correa P, Houghton J (2007) Carcinogenesis of Helicobacter pylori. Gastroenterology 133(2):659–672. doi:10.1053/j.gastro.2007.06.026

    Article  PubMed  CAS  Google Scholar 

  3. Filipe MI, Munoz N, Matko I, Kato I, Pompe-Kirn V, Jutersek A, Teuchmann S, Benz M, Prijon T (1994) Intestinal metaplasia types and the risk of gastric cancer: a cohort study in Slovenia. Int J Cancer 57(3):324–329

    Article  PubMed  CAS  Google Scholar 

  4. Cassaro M, Rugge M, Gutierrez O, Leandro G, Graham DY, Genta RM (2000) Topographic patterns of intestinal metaplasia and gastric cancer. Am J Gastroenterol 95(6):1431–1438. doi:10.1111/j.1572-0241.2000.02074.x

    Article  PubMed  CAS  Google Scholar 

  5. Dinis-Ribeiro M, Lopes C, da Costa-Pereira A, Guilherme M, Barbosa J, Lomba-Viana H, Silva R, Moreira-Dias L (2004) A follow-up model for patients with atrophic chronic gastritis and intestinal metaplasia. J Clin Pathol 57(2):177–182

    Article  PubMed  CAS  Google Scholar 

  6. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7–14 June 1994 (1994). IARC Monogr Eval Carcinog Risks Hum 61:1–241

    Google Scholar 

  7. Figueiredo C, Machado JC, Pharoah P, Seruca R, Sousa S, Carvalho R, Capelinha AF, Quint W, Caldas C, van Doorn LJ, Carneiro F, Sobrinho-Simoes M (2002) Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst 94(22):1680–1687

    Article  PubMed  CAS  Google Scholar 

  8. Amieva MR, El-Omar EM (2008) Host-bacterial interactions in Helicobacter pylori infection. Gastroenterology 134(1):306–323. doi:10.1053/j.gastro.2007.11.009

    Article  PubMed  CAS  Google Scholar 

  9. Machado JC, Figueiredo C, Canedo P, Pharoah P, Carvalho R, Nabais S, Castro Alves C, Campos ML, Van Doorn LJ, Caldas C, Seruca R, Carneiro F, Sobrinho-Simoes M (2003) A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology 125(2):364–371

    Article  PubMed  CAS  Google Scholar 

  10. Huang JQ, Zheng GF, Sumanac K, Irvine EJ, Hunt RH (2003) Meta-analysis of the relationship between cagA seropositivity and gastric cancer. Gastroenterology 125(6):1636–1644

    Article  PubMed  Google Scholar 

  11. Basso D, Zambon C, Letley D, Stranges A, Marchet A, Rhead J, Schiavon S, Guariso G, Ceroti M, Nitti D (2008) Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms. Gastroenterology 135(1):91–99. doi:10.1053/j.gastro.2008.03.041

    Article  PubMed  CAS  Google Scholar 

  12. Gonzalez CA, Figueiredo C, Lic CB, Ferreira RM, Pardo ML, Ruiz Liso JM, Alonso P, Sala N, Capella G, Sanz-Anquela JM (2011) Helicobacter pylori cagA and vacA genotypes as predictors of progression of gastric preneoplastic lesions: a long-term follow-up in a high-risk area in Spain. Am J Gastroenterol 106(5):867–874. doi:10.1038/ajg.2011.1

    Article  PubMed  CAS  Google Scholar 

  13. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N, Lanyon G, Martin M, Fraumeni JF Jr, Rabkin CS (2000) Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404(6776):398–402. doi:10.1038/35006081

    Article  PubMed  CAS  Google Scholar 

  14. Yin M, Hu Z, Tan D, Ajani JA, Wei Q (2009) Molecular epidemiology of genetic susceptibility to gastric cancer: focus on single nucleotide polymorphisms in gastric carcinogenesis. Am J Transl Res 1(1):44–54

    PubMed  CAS  Google Scholar 

  15. Persson C, Canedo P, Machado JC, El-Omar EM, Forman D (2010) Polymorphisms in inflammatory response genes and their association with gastric cancer: a huge systematic review and meta-analyses. Am J Epidemiol. doi:10.1093/aje/kwq370

    PubMed  Google Scholar 

  16. Canedo P, Corso G, Pereira F, Lunet N, Suriano G, Figueiredo C, Pedrazzani C, Moreira H, Barros H, Carneiro F, Seruca R, Roviello F, Machado JC (2008) The interferon gamma receptor 1 (IFNGR1) -56C/T gene polymorphism is associated with increased risk of early gastric carcinoma. Gut 57(11):1504–1508. doi:10.1136/gut.2007.143578

    Article  PubMed  CAS  Google Scholar 

  17. Yaghoobi M, Bijarchi R, Narod SA (2009) Family history and the risk of gastric cancer. Br J Cancer 102(2):237–242. doi:10.1038/sj.bjc.6605380

    Article  PubMed  Google Scholar 

  18. Rokkas T, Sechopoulos P, Pistiolas D, Margantinis G, Koukoulis G (2010) Helicobacter pylori infection and gastric histology in first-degree relatives of gastric cancer patients: a meta-analysis. Eur J Gastroenterol Hepatol 22(9):1128–1133. doi:10.1097/MEG.0b013e3283398d37

    Article  PubMed  Google Scholar 

  19. Milne AN, Offerhaus GJ (2010) Early-onset gastric cancer: learning lessons from the young. World J Gastrointest Oncol 2(2):59–64. doi:10.4251/wjgo.v2.i2.59

    Article  PubMed  Google Scholar 

  20. Kokkola A, Sipponen P (2001) Gastric carcinoma in young adults. Hepatogastroenterology 48(42):1552–1555

    PubMed  CAS  Google Scholar 

  21. Marcos-Pinto R, Dinis-Ribeiro M, Carneiro F, Machado JC, Figueiredo C, Reis CA, Ferreira J, Areias J (2012) First degree relatives and familial aggregation of gastric cancer: who to choose for control in case–control studies? Fam Cancer 11(1):137–143. doi:10.1007/s10689-011-9488-0

    Article  PubMed  Google Scholar 

  22. Dixon MF, Genta RM, Yardley JH, Correa P (1996) Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 20(10):1161–1181

    Article  PubMed  CAS  Google Scholar 

  23. Lauwers GYCF, Graham DY, Curado M-P, Franceschi S, Montgomery E, Tatematsu M, Hattori T (2010) Gastric carcinoma. WHO classification of tumours of the digestive system, Fourthth edn. IARC Press, Lyon

    Google Scholar 

  24. Rugge M, Genta RM (2005) Staging gastritis: an international proposal. Gastroenterology 129(5):1807–1808. doi:10.1053/j.gastro.2005.09.056

    Article  PubMed  Google Scholar 

  25. van Doorn NE, Namavar F, van Doorn LJ, Durrani Z, Kuipers EJ, Vandenbroucke-Grauls CM (1999) Analysis of vacA, cagA, and IS605 genotypes and those determined by PCR amplification of DNA between repetitive sequences of Helicobacter pylori strains isolated from patients with nonulcer dyspepsia or mucosa-associated lymphoid tissue lymphoma. J Clin Microbiol 37(7):2348–2349

    PubMed  Google Scholar 

  26. van Doorn LJ, Figueiredo C, Sanna R, Plaisier A, Schneeberger P, de Boer W, Quint W (1998) Clinical relevance of the cagA, vacA, and iceA status of Helicobacter pylori. Gastroenterology 115(1):58–66

    Article  PubMed  Google Scholar 

  27. Machado JC, Pharoah P, Sousa S, Carvalho R, Oliveira C, Figueiredo C, Amorim A, Seruca R, Caldas C, Carneiro F, Sobrinho-Simoes M (2001) Interleukin 1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma. Gastroenterology 121(4):823–829

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  29. Oliveira C, Ferreira P, Nabais S, Campos L, Ferreira A, Cirnes L, Alves CC, Veiga I, Fragoso M, Regateiro F, Dias LM, Moreira H, Suriano G, Machado JC, Lopes C, Castedo S, Carneiro F, Seruca R (2004) E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germ line mutations contribute to genetic predisposition in Portuguese gastric cancer patients. Eur J Cancer 40(12):1897–1903. doi:10.1016/j.ejca.2004.04.027

    Article  PubMed  CAS  Google Scholar 

  30. Milne AN, Sitarz R, Carvalho R, Carneiro F, Offerhaus GJ (2007) Early onset gastric cancer: on the road to unraveling gastric carcinogenesis. Curr Mol Med 7(1):15–28

    Article  PubMed  CAS  Google Scholar 

  31. Correa P, Shiao YH (1994) Phenotypic and genotypic events in gastric carcinogenesis. Cancer Res 54(7 Suppl):1941s–1943s

    PubMed  CAS  Google Scholar 

  32. Umeyama K, Sowa M, Kamino K, Kato Y, Satake K (1982) Gastric carcinoma in young adults in Japan. Anticancer Res 2(5):283–286

    PubMed  CAS  Google Scholar 

  33. Kong X, Wang JL, Chen HM, Fang JY (2012) Comparison of the clinicopathological characteristics of young and elderly patients with gastric carcinoma: a meta analysis. J Surg Oncol 106(3):346–352. doi:10.1002/jso.23004

    Article  PubMed  Google Scholar 

  34. Rugge M, Correa P, Dimario F, Elomar E, Fiocca R, Geboes K, Genta R, Graham D, Hattori T, Malfertheiner P (2008) OLGA staging for gastritis: a tutorial. Dig Liver Dis 40(8):650–658. doi:10.1016/j.dld.2008.02.030

    Article  PubMed  CAS  Google Scholar 

  35. Rugge M, Meggio A, Pennelli G, Piscioli F, Giacomelli L, De Pretis G, Graham DY (2007) Gastritis staging in clinical practice: the OLGA staging system. Gut 56(5):631–636. doi:10.1136/gut.2006.106666

    Article  PubMed  Google Scholar 

  36. Rugge M, De Boni M, Pennelli G, De Bona M, Giacomelli L, Fassan M, Basso D, Plebani M, Graham DY (2010) Gastritis OLGA-staging and gastric cancer risk: a 12-year clinico-pathological follow-up study. Aliment Pharmacol Ther. doi:10.1111/j.1365-2036.2010.04277.x

    PubMed  Google Scholar 

  37. Brenner H, Bode G, Boeing H (2000) Helicobacter pylori infection among offspring of patients with stomach cancer. Gastroenterology 118(1):31–35

    Article  PubMed  CAS  Google Scholar 

  38. El-Omar EM, Oien K, Murray LS, El-Nujumi A, Wirz A, Gillen D, Williams C, Fullarton G, McColl KE (2000) Increased prevalence of precancerous changes in relatives of gastric cancer patients: critical role of H. pylori. Gastroenterology 118(1):22–30

    Article  PubMed  CAS  Google Scholar 

  39. Leung WK, Ng EK, Lam CC, Chan KF, Chan WY, Auyeung AC, Wu JC, Ching JY, Lau JY, Sung JJ (2006) Helicobacter pylori infection in 1st degree relatives of Chinese gastric cancer patients. Scand J Gastroenterol 41(3):274–279. doi:10.1080/00365520510024269

    Article  PubMed  Google Scholar 

  40. Motta CR, Cunha MP, Queiroz DM, Cruz FW, Guerra EJ, Mota RM, Braga LL (2008) Gastric precancerous lesions and Helicobacter pylori infection in relatives of gastric cancer patients from Northeastern Brazil. Digestion 78(1):3–8. doi:10.1159/000151297

    Article  PubMed  Google Scholar 

  41. Shin CM, Kim N, Yang HJ, Cho SI, Lee HS, Kim JS, Jung HC, Song IS (2010) Stomach cancer risk in gastric cancer relatives: interaction between Helicobacter pylori infection and family history of gastric cancer for the risk of stomach cancer. J Clin Gastroenterol 44(2):e34–e39. doi:10.1097/MCG.0b013e3181a159c4

    Article  PubMed  Google Scholar 

  42. Li L, Genta RM, Go MF, Gutierrez O, Kim JG, Graham DY (2002) Helicobacter pylori strain and the pattern of gastritis among first-degree relatives of patients with gastric carcinoma. Helicobacter 7(6):349–355

    Article  PubMed  Google Scholar 

  43. Rugge M, Busatto G, Cassaro M, Shiao YH, Russo V, Leandro G, Avellini C, Fabiano A, Sidoni A, Covacci A (1999) Patients younger than 40 years with gastric carcinoma: Helicobacter pylori genotype and associated gastritis phenotype. Cancer 85(12):2506–2511. doi:10.1002/(SICI)1097-0142(19990615)85:12<2506

    Article  PubMed  CAS  Google Scholar 

  44. Koshida Y, Koizumi W, Sasabe M, Katoh Y, Okayasu I (2000) Association of Helicobacter pylori-dependent gastritis with gastric carcinomas in young Japanese patients: histopathological comparison of diffuse and intestinal type cancer cases. Histopathology 37(2):124–130

    Article  PubMed  CAS  Google Scholar 

  45. Feng Y, Zhang J, Dai L, Wang P, Zang J, Li Y, Wang K (2008) Inflammatory cytokine gene polymorphisms in gastric cancer cases’ and controls’ family members from Chinese areas at high cancer prevalence. Cancer Lett 270(2):250–259. doi:10.1016/j.canlet.2008.05.013

    Article  PubMed  CAS  Google Scholar 

  46. Sitarz R, de Leng WW, Polak M, Morsink FH, Bakker O, Polkowski WP, Maciejewski R, Offerhaus GJ, Milne AN (2008) IL-1B–31T > C promoter polymorphism is associated with gastric stump cancer but not with early onset or conventional gastric cancers. Virchows Arch 453(3):249–255. doi:10.1007/s00428-008-0642-5

    Article  PubMed  CAS  Google Scholar 

  47. Smythies LE, Waites KB, Lindsey JR, Harris PR, Ghiara P, Smith PD (2000) Helicobacter pylori-induced mucosal inflammation is Th1 mediated and exacerbated in IL-4, but not IFN-gamma, gene-deficient mice. J Immunol 165(2):1022–1029

    PubMed  CAS  Google Scholar 

  48. Thye T, Burchard GD, Nilius M, Muller-Myhsok B, Horstmann RD (2003) Genomewide linkage analysis identifies polymorphism in the human interferon-gamma receptor affecting Helicobacter pylori infection. Am J Hum Genet 72(2):448–453. doi:10.1086/367714

    Article  PubMed  CAS  Google Scholar 

  49. 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 (2004) Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 291(2):187–194. doi:10.1001/jama.291.2.187

    Article  PubMed  CAS  Google Scholar 

  50. Rokkas T, Pistiolas D, Sechopoulos P, Robotis I, Margantinis G (2007) The long-term impact of Helicobacter pylori eradication on gastric histology: a systematic review and meta-analysis. Helicobacter 12(Suppl 2):32–38. doi:10.1111/j.1523-5378.2007.00563.x

    Article  PubMed  Google Scholar 

  51. Lee KJ, Inoue M, Otani T, Iwasaki M, Sasazuki S, Tsugane S (2006) Gastric cancer screening and subsequent risk of gastric cancer: a large-scale population-based cohort study, with a 13-year follow-up in Japan. Int J Cancer 118(9):2315–2321. doi:10.1002/ijc.21664

    Article  PubMed  CAS  Google Scholar 

  52. Fukao A, Tsubono Y, Tsuji I, HI S, Sugahara N, Takano A (1995) The evaluation of screening for gastric cancer in Miyagi Prefecture, Japan: a population-based case–control study. Int J Cancer 60(1):45–48

    Article  PubMed  CAS  Google Scholar 

  53. De Vries AC, Haringsma J, Kuipers EJ (2007) The detection, surveillance and treatment of premalignant gastric lesions related to Helicobacter pylori infection. Helicobacter 12(1):1–15. doi:10.1111/j.1523-5378.2007.00475.x

    Article  PubMed  Google Scholar 

  54. Dinis-Ribeiro M, Areia M, de Vries AC, Marcos-Pinto R, Monteiro-Soares M, O’Connor A, Pereira C, Pimentel-Nunes P, Correia R, Ensari A, Dumonceau JM, Machado JC, Macedo G, Malfertheiner P, Matysiak-Budnik T, Megraud F, Miki K, O’Morain C, Peek RM, Ponchon T, Ristimaki A, Rembacken B, Carneiro F, Kuipers EJ (2012) Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED). Endoscopy 44(1):74–94. doi:10.1055/s-0031-1291491

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Prof. Leonor David for helpful suggestions and discussion and to Dr. Sollari Allegro for the support.

Study Support

This study was funded by “Fundação para a Ciência e Tecnologia” (SFRH/SINTD/60034/ 2009, SFRH/BD/45841/2008, and SFRH/BPD/84084/2012), ERA-NET Pathogenomics (HELDIVPAT–ERA-PTG/0001/2010) and Hospital Santo António.

Conflict of interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Institute of Biomedical Sciences, University of Porto (ICBAS/UP), Porto, Portugal

    Ricardo Marcos-Pinto, Carlos Lopes, Celso A. Reis, Isabel Pedroto & Jorge Areias

  2. Department of Gastroenterology, Centro Hospitalar do Porto, Largo do Prof. Abel Salazar, 4099, Porto, Portugal

    Ricardo Marcos-Pinto, José Ferreira, Isabel Pedroto & Jorge Areias

  3. Institute of Molecular Pathology and Immunology of the University of Porto, (IPATIMUP), Porto, Portugal

    Ricardo Marcos-Pinto, Fátima Carneiro, Céu Figueiredo, José Carlos Machado, Rui M. Ferreira, Celso A. Reis, Paulo Canedo & Cecília Durães

  4. Medical Faculty, University of Porto/CINTESIS, Porto, Portugal

    Ricardo Marcos-Pinto & Mário Dinis-Ribeiro

  5. Department of Pathology, Centro Hospitalar São João and Medical Faculty, University of Porto, Porto, Portugal

    Fátima Carneiro, Xiaogang Wen, Céu Figueiredo, José Carlos Machado, Rui M. Ferreira, Celso A. Reis & Paulo Canedo

  6. Department of Gastroenterology, Portuguese Oncology Institute, Porto, Portugal

    Mário Dinis-Ribeiro

  7. Department of Pathology, Centro Hospitalar do Porto, Porto, Portugal

    Carlos Lopes

Authors
  1. Ricardo Marcos-Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mário Dinis-Ribeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fátima Carneiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaogang Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carlos Lopes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Céu Figueiredo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. José Carlos Machado
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rui M. Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Celso A. Reis
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Paulo Canedo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Cecília Durães
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. José Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Isabel Pedroto
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jorge Areias
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ricardo Marcos-Pinto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Marcos-Pinto, R., Dinis-Ribeiro, M., Carneiro, F. et al. First-degree relatives of early-onset gastric cancer patients show a high risk for gastric cancer: phenotype and genotype profile. Virchows Arch 463, 391–399 (2013). https://doi.org/10.1007/s00428-013-1458-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-013-1458-5

Keywords

Search

Navigation