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Gastric Cancer
Published in: Gastric Cancer 4/2019

01-07-2019 | Case Report

Genetic analysis of a case of Helicobacter pylori-uninfected intramucosal gastric cancer in a family with hereditary diffuse gastric cancer

Authors: Taro Funakoshi, Shin’ichi Miyamoto, Nobuyuki Kakiuchi, Mitsuhiro Nikaido, Takeshi Setoyama, Akira Yokoyama, Takahiro Horimatsu, Atsushi Yamada, Masako Torishima, Shinji Kosugi, Hidetaka Yamada, Haruhiko Sugimura, Hironori Haga, Yoshiharu Sakai, Seishi Ogawa, Hiroshi Seno, Manabu Muto, Tsutomu Chiba

Published in: Gastric Cancer | Issue 4/2019

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Abstract

Germline mutations in CDH1, encoding E-cadherin, are known to be the causative mechanism of hereditary diffuse gastric cancer (HDGC). We encountered two cases of gastric cancer in a Japanese family with HDGC. A 28-year-old man (Case 1) died of advanced gastric cancer. His younger sister aged 27 (Case 2) was diagnosed with intramucosal signet ring cell carcinoma (SRCC). Both had identical germline CDH1 mutations, but Case 1 was positive for Helicobacter pylori infection, whereas Case 2 was negative. Case 2 underwent total gastrectomy. Whole-exome sequencing of an intramucosal SRCC in Case 2 revealed seven somatic mutations including one in CDH1. The six non-CDH1 mutations were classified as non-driver mutations. Decreased expression of E-cadherin in intramucosal SRCC was confirmed by immunohistochemistry. Our report demonstrated that CDH1 mutation was the only active driver mutation in Helicobacter pylori-uninfected intramucosal SRCC.
Literature
1.
Oliveira C, Pinheiro H, Figueiredo J, Seruca R, Carneiro F. Familial gastric cancer: genetic susceptibility, pathology, and implications for management. Lancet Oncol. 2015;16:e60–70.CrossRefPubMed
2.
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;1:23–32.CrossRefPubMed
3.
Huntsman DG, Carneiro F, Lewis FR, MacLeod PM, Hayashi A, Monaghan KG, et al. Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations. N Engl J Med. 2001;25:1904–9.CrossRef
4.
Charlton A, Blair V, Shaw D, Parry S, Guilford P, Martin IG. Hereditary diffuse gastric cancer: predominance of multiple foci of signet ring cell carcinoma in distal stomach and transitional zone. Gut. 2004;53:814–20.CrossRefPubMedPubMedCentral
5.
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;17:745–9.CrossRefPubMed
6.
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;17:750–6.CrossRefPubMed
7.
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;102:1782–8.CrossRefPubMed
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;52:361–74.CrossRefPubMedPubMedCentral
9.
Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478:64–9.CrossRef
10.
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. Genes Chromosomes Cancer. 2014;53:432–45.CrossRefPubMed
11.
Suriano G, Yew S, Ferreira P, Senz J, Kaurah P, Ford JM, 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;11:5401–9.CrossRefPubMed
12.
Kuboki Y, Yamashita S, Niwa T, Ushijima T, Nagatsuma A, Kuwata T, et al. Comprehensive analyses using next-generation sequencing and immunohistochemistry enable precise treatment in advanced gastric cancer. Ann Oncol. 2016;27:127–33.CrossRefPubMed
13.
Mateus AR, Simões-Correia J, Figueiredo J, Heindl S, Alves CC, Suriano G, et al. E-cadherin mutations and cell motility: a genotype-phenotype correlation. Exp Cell Res. 2009;315:1393–402.CrossRefPubMed
14.
Wang K, Yuen ST, Xu J, Lee SP, Yan HH, Shi ST, et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet. 2014;46:573–82.CrossRef
15.
Kakiuchi M, Nishizawa T, Ueda H, Gotoh K, Tanaka A, Hayashi A, et al. Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet. 2014;46:583–7.CrossRef
16.
Wong SS, Kim KM, Ting JC, Yu K, Fu J, Liu S, et al. Genomic landscape and genetic heterogeneity in gastric adenocarcinoma revealed by whole-genome sequencing. Nat Commun. 2014;5:5477.CrossRef
17.
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9.CrossRef
18.
Shimizu T, Marusawa H, Matsumoto Y, Inuzuka T, Ikeda A, Fujii Y, et al. Accumulation of somatic mutations in TP53 in gastric epithelium with Helicobacter pylori infection. Gastroenterology. 2014;147:407–17.e3.CrossRef
19.
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;69:2050–6.CrossRefPubMed
20.
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;102:942–50.CrossRefPubMed
21.
Hayakawa Y, Ariyama H, Stancikova J, Sakitani K, Asfaha S, Renz BW, et al. Mist1 expressing gastric stem cells maintain the normal and neoplastic gastric epithelium and are supported by a perivascular stem cell niche. Cancer Cell. 2015;28:800–14.CrossRefPubMedPubMedCentral
22.
Shimada S, Mimata A, Sekine M, Mogushi K, Akiyama Y, Fukamachi H, et al. Synergistic tumour suppressor activity of E-cadherin and p53 in a conditional mouse model for metastatic diffuse-type gastric cancer. Gut. 2012;61:344–53.CrossRefPubMed
23.
Matsuo T, Ito M, Takata S, Tanaka S, Yoshihara M, Chayama K. Low prevalence of Helicobacter pylori-negative gastric cancer among Japanese. Helicobacter. 2011;16:415–9.CrossRefPubMed
24.
Kamada T, Haruma K, Ito M, Inoue K, Manabe N, Matsumoto H, et al. Time trends in Helicobacter pylori infection and atrophic gastritis over 40 years in Japan. Helicobacter. 2015;20:192–8.CrossRefPubMed
25.
Okuda M, Osaki T, Lin Y, Yonezawa H, Maekawa K, Kamiya S, et al. Low prevalence and incidence of Helicobacter pylori infection in children: a population-based study in Japan. Helicobacter. 2015;20:133–8.CrossRefPubMed
26.
Yamamoto Y, Fujisaki J, Omae M, Hirasawa T, Igarashi M. Helicobacter pylori-negative gastric cancer: characteristics and endoscopic findings. Dig Endosc. 2015;27:551–61.CrossRefPubMed
27.
Horiuchi Y, Fujisaki J, Ishizuka N, Omae M, Ishiyama A, Yoshio T, et al. Study on clinical factors involved in Helicobacter pylori-uninfected, undifferentiated-type early gastric cancer. Digestion. 2017;96:213–9.CrossRefPubMed
Metadata
Title
Genetic analysis of a case of Helicobacter pylori-uninfected intramucosal gastric cancer in a family with hereditary diffuse gastric cancer
Authors
Taro Funakoshi
Shin’ichi Miyamoto
Nobuyuki Kakiuchi
Mitsuhiro Nikaido
Takeshi Setoyama
Akira Yokoyama
Takahiro Horimatsu
Atsushi Yamada
Masako Torishima
Shinji Kosugi
Hidetaka Yamada
Haruhiko Sugimura
Hironori Haga
Yoshiharu Sakai
Seishi Ogawa
Hiroshi Seno
Manabu Muto
Tsutomu Chiba
Publication date
01-07-2019
Publisher
Springer Singapore
Published in
Gastric Cancer / Issue 4/2019
Print ISSN: 1436-3291
Electronic ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-018-00912-w

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