Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1996 Sep;87(9):923–929. doi: 10.1111/j.1349-7006.1996.tb02121.x

Clonal Heterogeneity in Human Esophageal Squamous Cell Carcinomas on DNA Analysis

Hikaru Hori 1, Satoshi Miyake 1, Yoshimitsu Akiyama 2, Mitsuo Endo 1, Yasuhito Yuasa 2,✉
PMCID: PMC5921211  PMID: 8878454

Abstract

Cancers are thought to arise through multistep accumulation of somatic mutations in the progeny of a single cell. Multiple mutations may induce molecular intratumor heterogeneity. Therefore, we examined molecular clonal heterogeneity in esophageal squamous cell carcinomas. Twenty‐four esophageal squamous cell carcinomas and associated lymph node metastases were examined for microsatellite alterations, and abnormalities of the p53 and transforming growth factor‐β type II receptor (TGF‐β RII) genes. There were eight cases (33%) showing different patterns of loss of heterozygosity in primary tumors and metastatic lymph nodes with microsatellite markers. On the other hand, the abnormalities of p53 were identical in all these cases. No mutation was detected in the simple repeated sequences of the TGF‐β RII gene. These results indicate that molecular clonal heterogeneity exists in esophageal squamous cell carcinomas. Therefore, care is necessary in preoperative genetic diagnosis using biopsy samples.

Keywords: Clonal heterogeneity, Esophageal squamous cell carcinoma, Microsatellite alteration, p53, TGF‐β, type II receptor

Full Text

The Full Text of this article is available as a PDF (452.0 KB).

REFERENCE

  • 1.Wainscoat , J. S. and Fey , M. F.Assessment of clonality in human tumors: a review . Cancer Res ., 50 , 1355 – 1360 ( 1990. ). [PubMed] [Google Scholar]
  • 2.Vogelstein , B. , Fearon , E. R. , Hamilton , S. R. , Kern , S. E. , Preisinger , A. C. , Leppert , M. , Nakamura , Y. , White , R. , Smith , A. M. M. and Bos , J. L.Genetic alterations during colorectal‐tumour development . N. Engl. J. Med ., 319 , 525 – 532 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 3.Fey , M. F. , Zimmermann , A. , Borisch , B. and Tobler , A.Studying clonal heterogeneity in human cancers . Cancer Res ., 53 , 921 ( 1993. ). [PubMed] [Google Scholar]
  • 4.Oda , T. , Tsuda , H. , Sakamoto , M. and Hirohashi , S.Different mutations of the p53 gene in nodule‐in‐nodule hepatocellular carcinoma as evidence for multistage progression . Cancer Lett ., 83 , 197 – 200 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 5.Sakr , W. A. , Macoska , J. A. , Benson , P. , Grignon , D. J. , Wolman , S. R. , Pontes , J. E. and Crissman , J. D.Allelic loss in locally metastatic, multisampled prostate cancer . Cancer Res ., 54 , 3273 – 3277 ( 1994. ). [PubMed] [Google Scholar]
  • 6.Strickler , J. G. , Zheng , J. , Shu , Q. , Burgart , L. J. , Alberts , S. R. and Shibata , D.p53 mutations and microsatellite instability in sporadic gastric cancer: when guardians fail . Cancer Res ., 54 , 4750 – 4755 ( 1994. ). [PubMed] [Google Scholar]
  • 7.Nagel , S. , Borisch , B. , Thein , S. L. , Oestreicher , M. , Nothiger , F. , Birrer , S. , Tobler , A. and Fey , M. F.Somatic mutations detected by mini‐ and microsatellite DNA markers reveal clonal intratumor heterogeneity in gastrointestinal cancers . Cancer Res ., 55 , 2866 – 2870 ( 1995. ). [PubMed] [Google Scholar]
  • 8.Boring , C. C. , Squires , T. S. and Tong , T.Cancer statistics, 1991 . CA-Cancer J. Clin ., 41 , 19 – 36 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 9.Weissenbach , J. , Gyapay , G. , Dib , C. , Vingal , A. , Morissette , J. , Milasseau , P. , Veisseix , G. and Lathrop , M.A second‐generation linkage map of the human genome . Nature , 359 , 794 – 801 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 10.Maestro , R. , Gasparotto , D. , Vukosavljevic , T. , Barzan , L. , Sulfaro , S. and Boiocchi , M.Three discrete regions of deletion at 3p in head and neck cancers . Cancer Res ., 54 , 5775 – 5779 ( 1993. ). [PubMed] [Google Scholar]
  • 11.Jones , M. H. and Nakamura , Y.Deletion mapping of chromosome 3p in female genital tract malignancies using microsatellite polymorphisms . Oncogene , 7 , 1631 – 1634 ( 1992. ). [PubMed] [Google Scholar]
  • 12.Horio , Y. , Takahashi , T. , Kuroishi , T. , Hibi , K. , Suyama , M. , Niimi , T. , Shimokata , K. , Yamakawa , K. , Nakamura , Y. , Ueda , R. and Takahashi , T.Prognostic significance of p53 mutations and 3p deletions in primary resected non‐small cell lung cancer . Cancer Res ., 53 , 1 – 4 ( 1993. ). [PubMed] [Google Scholar]
  • 13.Latif , F. , Fivash , M. , Glenn , G. , Tory , K. , Orcutt , M. L. , Hampsch , K. , Delisio , J. , Lerman , M. , Cowan , J. , Beckett , M. and Weichselbaum , M.Chromosome 3p deletions in head and neck carcinomas: statistical ascertainment of allelic loss . Cancer Res ., 52 , 1451 – 1456 ( 1992. ). [PubMed] [Google Scholar]
  • 14.Yokota , J. , Tsukada , Y. , Nakajima , T. , Gotoh , M. , Shimosato , Y. , Mori , N. , Tsunokawa , Y. , Sugimura , T. and Terada , M.Loss of heterozygosity on the short arm of chromosome 3 in carcinoma of the uterine cervix . Cancer Res ., 49 , 3598 – 3601 ( 1989. ). [PubMed] [Google Scholar]
  • 15.Brauch , H. , Johnson , B. , Hovis , J. , Yano , T. , Gazdar , A. , Pettengill , O. S. , Graziano , S. , Sorenson , G. D. , Poiesz , B. J. , Minna , J. , Linehan , M. and Zbar , B.Molecular analysis of the short arm of chromosome 3 in small‐cell carcinoma and non‐small‐cell carcinoma of the lung . N. Engl. J. Med ., 317 , 1109 – 1113 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 16.Ogasawara , S. , Maesawa , C. , Tamura , G. and Satodate , R.Frequent microsatellite alterations on chromosome 3p in esophageal squamous cell carcinoma . Cancer Res ., 55 , 891 – 894 ( 1995. ). [PubMed] [Google Scholar]
  • 17.Aaltonen , L. A. , Peltomaki , P. , Leach , F. S. , Sistonen , P. , Pylkkanen , L. , Mecklin , J.‐P. , Jarvinen , H. , Powell , S. M. , Jen , J. , Hamilton , S. R. , Petersen , G. M. , Kinzler , K. W. , Vogelstein , B. and de la Chapelle , A.Clues to the pathogenesis of familial colorectal cancer . Science , 260 , 812 – 816 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 18.Peltomaki , P. , Lothe , R. A. , Aaltonen , L. A. , Pylkkanen , L. , Nystrom‐Lahti , M. , Seruca , R. , David , L. , Holm , R. , Ryberg , D. , Haugen , A. , Brogger , A. , Borresen , A.‐L. and de la Chapelle , A.Microsatellite instability is associated with tumors that characterize the hereditary non‐polyposis colorectal carcinoma syndrome . Cancer Res ., 53 , 5853 – 5855 ( 1993. ). [PubMed] [Google Scholar]
  • 19.Wu , C. , Akiyama , Y. , Imai , K. , Miyake , S. , Nagasaki , H. , Oto , M. , Okabe , S. , Iwama , T. , Mitamura , K. , Masumitsu , H. , Nomizu , T. , Baba , S. , Maruyama , K. and Yuasa , Y.DNA alterations in cells from hereditary non‐polyposis colorectal cancer patients . Oncogene , 9 , 991 – 994 ( 1994. ). [PubMed] [Google Scholar]
  • 20.Han , H.‐J. , Yanagisawa , A. , Kato , Y. , Park , J.‐G. and Nakamura , Y.Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer . Cancer Res ., 53 , 5087 – 5089 ( 1993. ). [PubMed] [Google Scholar]
  • 21.Rhyu , M. G. , Park , W. S. and Meltzer , S. J.Microsatellite instability occurs frequently in human gastric carcinoma . Oncogene , 9 , 29 – 32 ( 1994. ). [PubMed] [Google Scholar]
  • 22.Fishel , R. , Lescoe , M. K. , Rao , M. R. S. , Copeland , N. G. , Jenkins , N. A. , Garber , J. , Kane , M. and Kolodner , R.The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer . Cell , 75 , 1027 – 1038 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 23.Leach , F. S. , Nicolaides , N. C. , Papadopoulos , N. , Liu , B. , Jen , J. , Parsons , R. , Peltomaki , P. , Sistonen , P. , Aaltonen , L. A. , Nystrom‐Lahti , M. , Guan , X.‐Y. , Zhang , J. , Meltzer , P. S. , Yu , J.‐W. , Kao , F.‐T. , Chen , D. J. , Cerosaletti , K. M. , Fournier , R. E. K. , Todd , S. , Lewis , T. , Leach , R. J. , Naylor , S. L. , Weissenbach , J. , Mecklin , J.‐P. , Jarvinen , H. , Petersen , G. M. , Hamilton , S. R. , Green , J. , Jass , J. , Watson , P. , Lynch , H. T. , Trent , J. M. , de la Chapelle , A. , Kinzler , K. W. and Vogelstein , B.Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer . Cell , 75 , 1215 – 1225 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 24.Bronner , C. E. , Baker , S. M. , Morrison , P. T. , Warren , G. , Smith , L. G. , Lescoe , M. K. , Kane , M. , Earabino , C. , Lipford , J. , Lindblom , A. , Tannergard , P. , Bollag , R. J. , Godwin , A. R. , Ward , D. C. , Nordenskjold , M. , Fishel , R. , Kolodner , R. and Liskay , R. M.Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non‐polyposis colon cancer . Nature , 368 , 258 – 261 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 25.Papadopoulos , N. , Nicolaides , N. C. , Wei , Y.‐F. , Ruben , S. M. , Carter , K. C. , Rosen , C. A. , Haseltine , W. A. , Fleischmann , R. D. , Fraser , C. M. , Adams , M. D. , Venter , J. C. , Hamilton , S. R. , Petersen , G. M. , Watson , P. , Lynch , H. T. , Peltomaki , P. , Mecklin , J.‐P. , de la Chapelle , A. , Kinzler , K. W. and Vogelstein , B.Mutation of a mutL homolog in hereditary colon cancer . Science , 263 , 1625 – 1629 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 26.Nicolaides , N. C. , Papadopoulos , N. , Liu , B. , Wei , Y.‐F. , Carter , K. C. , Ruben , S. M. , Rosen , C. A. , Haseltine , W. A. , Fleischmann , R. D. , Fraser , C. M. , Adams , M. D. , Venter , J. C. , Dunlop , M. G. , Hamilton , S. R. , Petersen , G. M. , de la Chapelle , A. , Vogelstein , B. and Kinzler , K. W.Mutations of two PMS homologues in hereditary nonpolyposis colon cancer . Nature , 371 , 75 – 80 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 27.Papadopoulos , N. , Nicolaides , N. C. , Liu , B. , Parsons , R. , Lengauer , C. , Palombo , F. , D'Arrigo , A. , Markowitz , S. , Willson , J. K. V. , Kinzler , K. W. , Jiricny , J. and Vogelstein , B.Mutations of GTBP in genetically unstable cells . Science , 268 , 1915 – 1917 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 28.Meltzer , S. J. , Yin , J. , Manin , B. , Rhyu , M.‐G. , Cottrell , J. , Hudson , E. , Redd , J. L. , Krasna , M. J. , Abraham , J. M. and Reid , B. J.Microsatellite instability occurs frequently and in both diploid and aneuploid cell populations of Barrett's‐associated esophageal adenocarcinomas . Cancer Res ., 54 , 3379 – 3382 ( 1994. ). [PubMed] [Google Scholar]
  • 29.Markowitz , S. , Wang , J. , Myeroff , L. , Parsons , R. , Sun , L. , Lutterbaugh , J. , Fan , R. S. , Zborowska , E. , Kinzler , K. W. , Vogelstein , B. , Brattain , M. and Willson , J. K. V.Inactivation of the type II TGF‐beta receptor in colon cancer cells with microsatellite instability . Science , 268 , 1336 – 1338 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 30.Lu , S.‐L. , Akiyama , Y. , Nagasaki , H. , Saitoh , K. and Yuasa , Y.Mutations of the transforming growth factor‐β type II receptor gene and genomic instability in hereditary nonpolyposis colorectal cancer . Biochem. Biophys. Res. Commun ., 216 , 452 – 457 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 31.Parsons , R. , Myeroff , L. L. , Liu , B. , Willson , J. K. V. , Markowitz , S. D. , Kinzler , K. W. and Vogelstein , B.Microsatellite instability and mutations of the transforming growth factor β type II receptor gene in colorectal cancer . Cancer Res ., 55 , 5548 – 5550 ( 1995. ). [PubMed] [Google Scholar]
  • 32.Hollstein , M. , Sidransky , D. , Vogelstein , B. and Harris , C. C.p53 mutations in human cancers . Science , 253 , 49 – 53 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 33.Levine , A. J. , Momand , J. and Finlay , C. A.The p53 tumour suppressor gene . Nature , 351 , 453 – 456 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 34.Harris , C. C.The p53 tumor suppressor gene: at the crossroads of molecular carcinogenesis, molecular epidemiology and cancer risk assessment . Science , 262 , 1980 – 1981 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 35.Maniatis , T. , Fritsch , J. and Sambrook , J. “ Molecular Cloning: A Laboratory Manual ” ( 1989. ). Cold Spring Harbor Laboratory; , Cold Spring Harbor , New York . [Google Scholar]
  • 36.Hemminki , A. , Peltomaki , P. , Mecklin , J.‐P. , Jarvinen , H. , Salovaara , R. , Nystrom‐Lahti , M. , de la Chapelle , A. and Aaltonen , L. A.Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer . Nat. Genet ., 8 , 405 – 410 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 37.Mashiyama , S. , Murakami , S. , Yoshimoto , T. , Sekiya , T. and Hayashi , K.Detection of p53 gene mutations in human brain tumors by single‐strand conformation polymorphism analysis of polymerase chain reaction products . Oncogene , 6 , 1313 – 1318 ( 1991. ). [PubMed] [Google Scholar]
  • 38.Huang , Y. , Boynton , R. F. , Blount , P. L. , Silverstein , R. J. , Yin , Y. , Tong , Y. , McDaniel , T. K. , Newkirk , C. , Resau , J. H. , Sridhara , R. , Reid , B. J. and Meltzer , S. J.Loss of heterozygosity involves multiple tumor suppressor genes in human esophageal cancers . Cancer Res ., 52 , 6525 – 6530 ( 1992. ). [PubMed] [Google Scholar]
  • 39.Oto , M. , Miyake , S. and Yuasa , Y.Optimization of nonradioactive single strand conformation polymorphism analysis with a conventional minislab gel electrophoresis apparatus . Anal. Biochem ., 213 , 19 – 22 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 40.Greenblatt , M. S. , Bennett , W. P. , Hollstein , M. and Harris , C. C.Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis . Cancer Res ., 54 , 4855 – 4878 ( 1994. ). [PubMed] [Google Scholar]
  • 41.Shimada , M. , Horii , A. , Sasaki , S. , Yanagisawa , A. , Kato , Y. , Yamashita , K. , Okagawa , K. , Yamasaki , K. , Ishiguro , S. , Inoue , M. , Shiozaki , H. and Nakamura , Y.Infrequent replication errors at microsatellite loci in tumors of patients with multiple primary cancers of the esophagus and various other tissues . Jpn. J. Cancer Res ., 86 , 511 – 515 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Fynan , T. and Reiss , M.Resistance to inhibition of cell growth by transforming growth factor‐β and its role in oncogenesis . Crit. Rev. Oncog ., 4 , 493 – 540 ( 1993. ). [PubMed] [Google Scholar]
  • 43.Wrana , J. L. , Attisano , L. , Carcamo , J. , Zentella , A. , Doody , J. , Laiho , M. , Wang , X.‐F. and Massague , J.TGF β signals through a heteromeric protein kinase receptor complex . Cell , 71 , 1003 – 1014 ( 1992. ). [DOI] [PubMed] [Google Scholar]

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

RESOURCES