Journal of Isfahan Medical School

Journal of Isfahan Medical School

Comparative Study on Mutations in CDH1 Gene in Iranian Patients with Hereditary Diffuse Gastric Cancer (HDGC) and Sporadic Diffuse Gastric Cancer (SDGC)

Document Type : Original Article(s)

Authors
Abbas Moridnia 1
Majid Kheirollahi 2
Mohammad Amin Tabatabaeefar 3
Mehrdad Zeinalian 4
1 Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
2 Associate Professor, Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease AND Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
3 Associate Professor, Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
4 Assistant Professor, Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
Abstract
Background: Gastric cancer (GC) is the fourth common cancer worldwide and the second cause of mortality among all cancers. Mutations in the CDH1 gene are the most common cause of hereditary diffuse gastric cancer (HDGC) and sporadic diffuse gastric cancer (SDGC). CDH1 gene encode for E-cadherin protein. We compared the nucleotide alterations and copy number variations in CDH1 gene between Iranian patients with HDGC and SDGC.Methods: We evaluated 45 patients including 17 cases with HDGC and 28 cases with SDGC identified according to the histopathological criteria and familial history. DNA extraction was obtained from peripheral blood and formalin-fixed paraffin-embedded (FFPE) tissues. The DNA sequencing was completed using polymerase chain reaction (PCR) amplification of 16 exons of the CDH1 gene. Multiplex ligation-dependent probe amplification (MLPA) method was accomplished on samples with no pathogenic variants in sequencing.Findings: Synonymous substitution of L116L and A692A was detected in patients with HDGC and SDGC; but non-synonymous substitution of D777E, c.889delA, and c.1177delA deletions only detected in patients with HDGC. MLPA results revealed one deletion in exon 1 of CDH1 gene in patients with HDGC and one deletion in exon 2, and one duplication in exon 9 of CDH1 gene in patients with SDGC.Conclusion: According to the results, different variants in CDH1 gene was presented in patients with HDGC and SDGC that emphasis the survey of CDH1 variants and especially detected variants in this study in the diagnosis of diffuse gastric cancer disease.
Keywords
CDH1
Diffuse gastric cancer
Iran
  1. Mehrabani D, Hosseini SV, Rezaianzadeh A, Amini M, Mehrabani G, Tarrahi MJ. Prevalence of stomach cancer in Shiraz, Southern Iran. J Res Med Sci 2013; 18(4): 335-7.
  2. Almasi Z, Rafiemanesh H, Salehiniya H. Epidemiology characteristics and trends of incidence and morphology of stomach cancer in Iran. Asian Pac J Cancer Prev 2015; 16(7): 2757-61.
  3. Henson DE, Dittus C, Younes M, Nguyen H, Albores-Saavedra J. 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(7): 765-70.
  4. Palli D, Galli M, Caporaso NE, Cipriani F, Decarli A, Saieva C, et al. Family history and risk of stomach cancer in Italy. Cancer Epidemiol Biomarkers Prev 1994; 3(1): 15-8.
  5. Donner I, Kiviluoto T, Ristimaki A, Aaltonen LA, Vahteristo P. Exome sequencing reveals three novel candidate predisposition genes for diffuse gastric cancer. Fam Cancer 2015; 14(2): 241-6.
  6. Worthley DL, Phillips KD, Wayte N, Schrader KA, Healey S, Kaurah P, et al. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): A new autosomal dominant syndrome. Gut 2012; 61(5): 774-9.
  7. Pinheiro H, Oliveira C, Seruca R, Carneiro F. Hereditary diffuse gastric cancer - pathophysiology and clinical management. Best Pract Res Clin Gastroenterol 2014; 28(6): 1055-68.
  8. Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H, et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol 2015; 1(1): 23-32.
  9. Majewski IJ, Kluijt I, Cats A, Scerri TS, de JD, Kluin RJ, et al. An alpha-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer. J Pathol 2013; 229(4): 621-9.
  10. Davis PA, Sano T. The difference in gastric cancer between Japan, USA and Europe: what are the facts? what are the suggestions? Crit Rev Oncol Hematol 2001; 40(1): 77-94.
  11. Richards FM, McKee SA, Rajpar MH, Cole TR, Evans DG, Jankowski JA, et al. Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer. Hum Mol Genet 1999; 8(4): 607-10.
  12. Guilford PJ, Hopkins JB, Grady WM, Markowitz SD, Willis J, Lynch H, et al. E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer. Hum Mutat 1999; 14(3): 249-55.
  13. Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, et al. E-cadherin germline mutations in familial gastric cancer. Nature 1998; 392(6674): 402-5.
  14. Kaurah P, MacMillan A, Boyd N, Senz J, De LA, Chun N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 2007; 297(21): 2360-72.
  15. Yamada M, Fukagawa T, Nakajima T, Asada K, Sekine S, Yamashita S, et al. Hereditary diffuse gastric cancer in a Japanese family with a large deletion involving CDH1. Gastric Cancer 2014; 17(4): 750-6.
  16. van der Post RS, Vogelaar IP, Carneiro F, Guilford P, Huntsman D, Hoogerbrugge N, et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet 2015; 52(6): 361-74.
  17. Chu CM, Chen CJ, Chan DC, Wu HS, Liu YC, Shen CY, et al. CDH1 polymorphisms and haplotypes in sporadic diffuse and intestinal gastric cancer: a case-control study based on direct sequencing analysis. World J Surg Oncol 2014; 12: 80.
  18. Oliveira C, Bordin MC, Grehan N, Huntsman D, Suriano G, Machado JC, et al. Screening E-cadherin in gastric cancer families reveals germline mutations only in hereditary diffuse gastric cancer kindred. Hum Mutat 2002; 19(5): 510-7.
  19. Jacobs G, Hellmig S, Huse K, Titz A, Franke A, Kwiatkowski R, et al. Polymorphisms in the 3'-untranslated region of the CDH1 gene are a risk factor for primary gastric diffuse large B-cell lymphoma. Haematologica 2011; 96(7): 987-95.
  20. Corso G, Pedrazzani C, Pinheiro H, Fernandes E, Marrelli D, Rinnovati A, et al. E-cadherin genetic screening and clinico-pathologic characteristics of early onset gastric cancer. Eur J Cancer 2011; 47(4): 631-9.
  21. Ghaffari SR, Rafati M, Sabokbar T, Dastan J. A novel truncating mutation in the E-cadherin gene in the first Iranian family with hereditary diffuse gastric cancer. Eur J Surg Oncol 2010; 36(6): 559-62.
  22. Sugimoto S, Yamada H, Takahashi M, Morohoshi Y, Yamaguchi N, Tsunoda Y, et al. Early-onset diffuse gastric cancer associated with a de novo large genomic deletion of CDH1 gene. Gastric Cancer 2014; 17(4): 745-9.
Journal of Isfahan Medical School
Volume 35, Issue 432 - Serial Number 432
March and April 2017
Pages 622-628

  • Receive Date 22 February 2017
  • Accept Date 06 April 2022