Document Type : Original Article


1 Pediatric 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

2 Department of Genetics and Molecular Biology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran

3 Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran


Background: Hereditary diffuse gastric cancer (HDGC) is a hereditable form of diffuse gastric cancer with very aggressive tumors, poor prognosis, and delayed clinical signs.
Method: We assessed 17 probands identified with HDGC upon gastrectomy according to the histopathological criteria confirmed by a pathologist and familial history. We extracted DNA from peripheral blood and formalin fixed paraffin-embedded tissues. DNA sequencing was done following PCR amplification of 16 exons and exon/intron boundaries of the CDH1 gene and exon 2 of CTNNA1 gene. The Multiplex Ligation-dependent Probe Amplification technique was performed on patients with no pathogenic variants in sequencing.
Results: Totally, 17 probands comprising seven males and 10 females were assessed. In three patients, we recognized the tumors in the early TNM stage (I, II), while in 14 cases, tumors were observed in the late stages (III, IV). Overall, DNA sequencing of the CDH1 gene identified 16 variants (seven exonic including five new variants and nine intronic containing six new variants). Moreover, Multiplex Ligation-dependent Probe Amplification detected one deletion in exon 1 of two patients.
Conclusion: Our results showed that E-cadherin deficiency in HDGC was related to CDH1 gene point mutations and large deletion with high heterogeneity, which should be considered in the diagnosis and treatment of HDGC patients.


How to cite this article:

Kheirollahi M, Saneipour M, Tabatabaiefar MA, Zeinalian M, Minakari M, Moridnia A. New variants in the CDH1 gene in Iranian families with hereditary diffuse gastric cancer. Middle East J Cancer. 2020;11(4): 493-501. doi: 10. 30476/mejc.2020.81478.1016.

1.         Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.

2.         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.
3.         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.
4.         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.
5.         Ekström AM, Serafini M, Nyrén O, Hansson LE, Ye W, Wolk A. 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(1):133-40.

6.         Ingrid P Vogelaar, Rachel S van der Post,  Tanya M Bisseling, J Han JM van Krieken,              Marjolijn JL Ligtenberg,  Nicoline Hoogerbrugge. Familial gastric cancer: detection             of a hereditary cause helps to understand its etiology. Hered Cancer Clin Pract. 2012;10(1):18-24

7.         Donner I, Kiviluoto T, Ristimäki A, Aaltonen LA, Vahteristo P. Exome sequencing reveals three novel candidate predisposition genes for diffuse gastric cancer. Fam Cancer. 2015;14(2):241-6.
8.         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. doi: 10.1136/jmedgenet-2015-103094.
9.         Worthley D, Phillips K, Wayte N, Schrader K, Healey S, Kaurah P, et al. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome. Gut. 2012;61(5):774-779.
10.       Majewski IJ, Kluijt I, Cats A, Scerri TS, de Jong D, Kluin RJ, et al. An α-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer. J Pathol. 2013;229(4):621-9. doi: 10.1002/path.4152.
11.       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.
12.       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.
13.       Richards FM, McKee SA, Rajpar MH, Cole TR, Evans DGR, 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.
14.       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.
15.       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.
16.       Kaurah P, MacMillan A, Boyd N, Senz J, De Luca A, Chun N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007;297(21):2360-72.
17.       Oliveira C, Senz J, Kaurah P, Pinheiro H, Sanges R, Haegert A, et al. Germline CDH1 deletions in hereditary diffuse gastric cancer families. Hum Mol Genet. 2009;18(9):1545-55.
18.       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.
19.       Yamada H, Shinmura K, Ito H, Kasami M, Sasaki N, Shima H, et al. Germline alterations in the CDH1 gene in familial gastric cancer in the Japanese population. Cancer Sci. 2011;102(10):1782-8.
20.       Stemmler MP. Cadherins in development and cancer. Mol Biosyst. 2008;4(8):835-50.
21.       Park J-G, Yang H-K, Kim WH, Caldas C, Yokota J, Guilford PJ. Report on the first meeting of the International Collaborative Group on Hereditary Gastric Cancer. J Natl Cancer Inst. 2000;92(21):1781-2.
22.       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.
23.       Benusiglio PR, Malka D, Rouleau E, De Pauw A, Buecher B, Noguès C, 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.
24.       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(1):80-8.
25.       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.
26.       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. Haematol. 2011;96(7):987-95.
27.       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.
28.       Ghaffari S, 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.
29.       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.
30.       Molinaro V, Pensotti V, Marabelli M, Feroce I, Barile M, Pozzi S, et al. Complementary molecular approaches reveal heterogeneous CDH1 germline defects in Italian patients with hereditary diffuse gastric cancer (HDGC) syndrome. Gene Chromosome Canc. 2014;53(5):432-5.