Skip to main content
NCBI home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1996 Aug;87(8):843–848. doi: 10.1111/j.1349-7006.1996.tb02109.x

E‐Cadherin Gene Mutations in Signet Ring Cell Carcinoma of the Stomach

Hiromi Muta 1,2,✉, Masayuki Noguchi 1, Yae Kanai 1, Atsushi Ochiai 1, Hajime Nawata 2, Setsuo Hirohashi 1
PMCID: PMC5921174  PMID: 8797891

Abstract

To clarify the significance of E‐cadherin gene alterations in the development of diffuse‐type adenocarcinoma of the stomach, we analyzed mutations of the E‐cadherin gene using the polymerase chain reaction single‐strand conformation polymorphism (PCR‐SSCP) method followed by direct sequencing. Twenty‐two signet ring cell carcinomas of the stomach (10 intramucosal and 12 advanced cancers) were examined. Genomic DNA was extracted separately from cancerous and non‐cancerous tissues and PCR‐SSCP analysis was performed on exons 5 to 9 and the adjacent 30‐ to 40‐base‐pair intron sequences of the E‐cadherin gene. Mobility shifts were found in 2 of the 10 intramucosal cancers. In 2 of the 12 advanced cancers, abnormalities of the E‐cadherin gene were observed in intramucosal lesions as well as in deeply invaded areas. These results indicated that E‐cadherin gene mutations are an early event in the development of signet ring cell carcinoma of the stomach. Direct sequencing revealed that the locations of mutations of the E‐cadherin gene included the branch point sequence in the intron which is responsible for RNA splicing. Reverse transcriptase‐PCR demonstrated aberrant RNA splicing in a case with a branch point mutation, suggesting that branch point mutations play an important role in functional modifications of E‐cadherin in signet ring cell carcinoma of the stomach.

Keywords: E‐Cadherin, Gene mutation, Signet ring cell carcinoma, Stomach cancer

Full Text

The Full Text of this article is available as a PDF (366.7 KB).

REFERENCE

  • 1.Shimoyama , Y. , Hirohashi , S. , Hirano , S. , Noguchi , M. , Shimosato , Y. , Takeichi , M. , Abe , O.Cadherin cell‐adhesion molecules in human epithelial tissues and carcinomas . Cancer Res ., 49 , 2128 – 2133 ( 1989. ). [PubMed] [Google Scholar]
  • 2.Takeichi , M.Cadherin cell adhesion receptors as a morphogenetic regulator . Science , 251 , 1451 – 1455 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 3.Frixen , U. H. , Behrens , J. , Sachs , M. , Eberle , G. , Voss , B. , Warda , A. , Lochner , D. and Birchmeier , W.E‐Cadherinmediated cell‐cell adhesion prevents invasiveness of human carcinoma cells . J. Cell Biol ., 113 , 173 – 185 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Behrens , J. , Mareel , M. M. , van Roy , F. M. and Birchmeier , W.Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin‐mediated cell‐cell adhesion . J. Cell Biol ., 108 , 2435 – 2446 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Vleminckx , K. , Vakaet , L.Jr. , Wareel , M. , Fiers , W. and van Roy , F.Genetic manipulation of E‐cadherin expression by epithelial tumor cells reveals an invasion suppressor role . Cell , 66 , 107 – 119 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 6.Shimoyama , Y. and Hirohashi , S.Expression of E‐ and P‐cadherin in gastric carcinoma . Cancer Res ., 51 , 2185 – 2192 ( 1991. ). [PubMed] [Google Scholar]
  • 7.Oka , H. , Shiozaki , H. , Kobayashi , K. , Tahara , H. , Tamura , S. , Miyata , M. , Doki , Y. , Iihara , K. , Matsuyoshi , N. , Hirano , S. , Takeichi , M. and Mori , T.Immunohistochemical evaluation of E‐cadherin adhesion molecule expression in human gastric cancer . Virchows Arch. A , 421 , 149 – 156 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 8.Mayer , B. , Johnson , J. P. , Leitl , F. , Jauch , K. W. , Heiss , M. M. , Schildberg , F. W. , Birchmier , W. and Funke , I.E‐cadherin expression in primary and metastatic gastric cancer: down‐regulation correlates with cellular dedifferentiation and glandular disintegration . Cancer Res ., 53 , 1690 – 1695 ( 1993. ). [PubMed] [Google Scholar]
  • 9.Yoshiura , K. , Kanai , Y. , Ochiai , A. , Shimoyama , Y. , Sugimura , T. and Hirohashi , S.Silencing of the E‐cadherin invasion‐suppressor gene by CpG methylation in human carcinomas . Proc. Natl. Acad. Sci. USA , 92 , 7416 – 7419 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Oda , T. , Kanai , Y. , Oyama , T. , Yoshiura , K. , Shimoyama , Y. , Birchmeier , W. , Sugimura , T. and Hirohashi , S.E‐Cadherin gene mutations in human gastric carcinoma cell lines . Proc. Natl. Acad. Sci. USA , 91 , 1858 – 1862 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Oda , T. , Kanai , Y. , Shimoyama , Y. , Nagafuchi , A. , Tsukita , S. and Hirohashi , S.Cloning of the human α‐catenin cDNA and its aberrant mRNA in a human cancer cell line . Biochem. Biophys. Res. Commun ., 193 , 897 – 904 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 12.Ochiai , A. , Akimoto , S. , Shimoyama , Y. , Nagafuchi , A. , Tsukita , S. and Hirohashi , S.Frequent loss of α catenin expression in scirrhous carcinomas with scattered cell growth . Jpn. J. Cancer Res ., 85 , 266 – 273 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Shimoyama , Y. , Nagafuchi , A. , Fujita , S. , Gotoh , M. , Takeichi , M. , Tsukita , S. and Hirohashi , S.Cadherin dysfunction in a human cancer cell line: possible involvement of loss of α‐catenin expression in reduced cell‐cell adhesiveness . Cancer Res ., 52 , 5770 – 5774 ( 1992. ). [PubMed] [Google Scholar]
  • 14.Oyama , T. , Kanai , Y. , Ochiai , A. , Akimoto , S. , Oda , T. , Yanagihara , K. , Nagafuchi , A. , Tsukita , S. , Shimabamoto , S. , Ito , F. , Takeichi , M. , Matsuda , H. and Hirohashi , S.A truncated β‐catenin disrupts the interaction between E‐cadherin and α‐catenin: a cause of loss of intercellular adhesiveness in human cancer cell lines . Cancer Res ., 54 , 6282 – 6287 ( 1994. ). [PubMed] [Google Scholar]
  • 15.Matsuyoshi , N. , Hamaguchi , M. , Taniguchi , S. , Nagafuchi , A. , Tsukita , S. and Takeichi , M.Cadherinmediated cell‐cell adhesion is perturbed by v‐src tyrosine phosphorylation in metastatic fibroblasts . J. Cell Biol ., 118 , 703 – 714 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Shibata , T. , Gotoh , M. , Ochiai , A. and Hirohashi , S.Association of plakoglobin with APC, a tumor suppressor gene product, and its regulation by tyrosine phosphorylation . Biochem. Biophys. Res. Commun ., 203 , 519 – 522 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 17.Kanai , Y. , Ochiai , A. , Shibata , T. , Oyama , T. , Ushijima , S. , Akimoto , S. and Hirohashi , S.c‐erbB‐2 gene product directly associates with β‐catenin and plakoglobin . Biochem. Biophys. Res. Commun ., 208 , 1067 – 1072 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 18.Ochiai , A. , Akimoto , S. , Kanai , Y. , Shibata , T. , Oyama , T. and Hirohashi , S.c‐erbB‐2 gene product associates with catenins in human cancer cells . Biochem. Biophys. Res. Commun ., 205 , 73 – 78 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 19.Becker , K. F. , Atkinson , M. J. , Reich , U. , Huang , H. H. , Nekarda , H. , Siewert , J. R. and Hofler , H.Exon skipping in the E‐cadherin gene transcript in metastatic human gastric carcinomas . Hum. Mol. Genet ., 2 , 803 – 804 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 20.Risinger , J. I. , Berchuck , A. , Kohler , M. F. and Boyd , J.Mutations of the E‐cadherin gene in human gynecologic cancers . Nat. Genet ., 7 , 98 – 102 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 21.Becker , K. F. , Atkinson , M. J. , Reich , U. , Becker , I. , Nekarda , H. , Siewert , J. R. and Hofler , H.E‐Cadherin gene mutations provide clues to diffuse type gastric carcinoma . Cancer Res ., 54 , 3845 – 3852 ( 1994. ). [PubMed] [Google Scholar]
  • 22.Kanai , Y. , Oda , T. , Tsuda , H. , Ochiai , A. and Hirohashi , S.Point mutation of the E‐cadherin gene in invasive lobular carcinoma of the breast . Jpn. J. Cancer Res ., 85 , 1035 – 1039 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Lauren , P.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 ( 1965. ). [DOI] [PubMed] [Google Scholar]
  • 24.Sugano , H. , Nakamura , K. and Kato , Y.Pathological studies of human gastric cancer . Acta Pathol. Jpn ., 32 , 329 – 347 ( 1982. ). [PubMed] [Google Scholar]
  • 25.Maehara , Y. , Sakaguchi , Y. , Moriguchi , S. , Orita , H. , Korenaga , D. , Kohnoe , S. and Sugimachi , K.Signet ring cell carcinoma of the stomach . Cancer , 69 , 1645 – 1650 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 26.Jass , J. R. , Sobin , L. H. and Watanabe , H.The World Health Organization's histologic classification of gastrointestinal tumors . Cancer , 66 , 2162 – 2167 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 27.Kim , J. P. , Kim , S. C. and Yang , H. K.Prognostic significance of signet ring cell carcinoma of the stomach . Surg. Oncol ., 3 , 221 – 227 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 28.Sugihara , H. , Hattori , T. , Fukuda , M. and Fujita , S.Cell proliferation and differentiation in intramucosal and advanced signet ring cell carcinomas of the human stomach . Virchows Arch. A , 411 , 117 – 127 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 29.Ichihara , M. , Hara , T. , Takagi , M. , Cho , L. C. , Gorman , D. M. and Miyajima , A.Impaired interleukin‐3 (IL‐3) response of the A/J mouse is caused by a branch point mutation in the IL‐3 receptor . Hum. Mol. Genet ., 2 , 803 – 804 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Reed , R. and Maniatis , T.Intron sequences involved in lariat formation during pre‐mRNA splicing . Cell , 41 , 95 – 105 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 31.Padget , R. A. , Orabowski , P. J. , Konarska , M. M. , Seiler , S. and Sharp , P. A.Splicing of messenger RNA precursors . Annu. Rev. Biochem ., 55 , 1119 – 1150 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 32.Ris‐Stalpers , C. , Verleun‐Mooijman , M. C. T. , de Blaeij , T. J. P. , Degenhart , H. J. , Trapman , J. and Brinkmann , A. O.Differential splicing of human androgen receptor pre‐mRNA in X‐linked Reifenstein syndrome, because of a deletion involving a putative branch site . Am. J. Hum. Genet ., 54 , 609 – 617 ( 1994. ). [PMC free article] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES