Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1998 Apr;89(4):405–410. doi: 10.1111/j.1349-7006.1998.tb00578.x

Heterogeneity of p53 Mutational Status in Esophageal Squamous Cell Carcinoma

Shirou Kuwabara 1,2,✉, Yoichi Ajioka 1, Hidenobu Watanabe 1, Jiro Hitomi 3, Ken Nishikura 1, Katsuyoshi Hatakeyama 2
PMCID: PMC5921814  PMID: 9617346

Abstract

In esophageal squamous cell carcinoma, p53 gene mutations have been analyzed for inter‐ or intra‐patient heterogeneity but only a few studies have investigated intratumoral heterogeneity. We investigated this question within individual esophageal cancers, and also in their lymph‐node metastases in 8 cases. Analyzing the p53 gene sequence by direct sequencing of polymerase chain reaction products, we found heterogeneity for p53 mutations in the pre‐invasive area in 3 esophageal cancers. In all areas sampled in the invasive portion of each cancer, the p53 mutational status was identical in a given tumor. In heterogeneous tumors, the invasive area showed one of the p53 mutations found in the pre‐invasive area. In nodal metastases, the p53 mutation was identical to that in the invasive area of each primary tumor. These data suggest that the timing of p53 alteration is not as early as might have been expected, indicating that, in regard to p53 gene alteration, some esophageal cancers are composed of various subclones in the pre‐invasive stage with invasiveness developing in one of them, which becomes predominant through clonal selection.

Keywords: Esophageal cancer, p53, Heterogeneity

Full Text

The Full Text of this article is available as a PDF (430.2 KB).

REFERENCES

  • 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. ) Nigro , J. M. , Baker , S. J. , Preisinger , A. C. , Jessup , J. M. , Hostetter , R. , Cleary , K. , Bigner , S. H. , Davidson , N. , Baylin , S. , Devilee , P. , Glover , T. , Collins , F. S. , Weston , A. , Modali , R. , Harris , C. C. and Vogelstein , B.Mutations in the p53 gene occur in diverse human tumour types . Nature , 342 , 705 – 708 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Hollstein , M. , Sidransky , D. , Vogelstein , B. and Harris , C. C.p53 mutations in human cancers . Science , 253 , 49 – 53 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Baker , S. J. , Fearon , E. R. , Nigro , J. M. , Hamilton , S. R. , Preisinger , A. C. , Jessup , J. M. , van Tuinen , P. , Ledbetter , D. H. , Barker , D. F. , Nakamura , Y. , White , R. and Vogelstein , B.Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas . Science , 244 , 217 – 221 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Harris , C. C. and Hollstein , M.Clinical implications of the p53 tumor‐suppressor gene . N. Engl. J. Med. , 329 , 1318 – 1327 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Vogelstein , B. and Kinzler , K. W.p53 function and dysfunction . Cell , 70 , 523 – 526 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Fearon , E. R. and Vogelstein , B.A genetic model for colorectal tumorigenesis . Cell , 61 , 759 – 767 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Shirasawa , S. , Urabe , K. , Yanagawa , Y. , Toshitani , K. , Iwama , T. and Sasazuki , T.p53 gene mutations in colorectal tumors from patients with familial polyposis coli . Cancer Res. , 51 , 2874 – 2878 ( 1991. ). [PubMed] [Google Scholar]
  • 9. ) Ohue , M. , Tomita , N. , Monden , T. , Fujita , M. , Fukunaga , M. , Takami , K. , Yana , I. , Ohnishi , T. , Enomoto , T. , Inoue , M. , Shimano , T. and Mori , T.A frequent alteration of p53 gene in carcinoma in adenoma of colon . Cancer Res. , 54 , 4798 – 4804 ( 1994. ). [PubMed] [Google Scholar]
  • 10. ) Ito , T. , Seyama , T. , Mizuno , T. , Tsuyama , N. , Hayashi , T. , Hayashi , Y. , Dohi , K. , Nakamura , N. and Akiyama , M.Unique association of p53 mutations with undifferentiated but not with differentiated carcinomas of the thyroid gland . Cancer Res. , 52 , 1369 – 1371 ( 1992. ). [PubMed] [Google Scholar]
  • 11. ) Mazars , R. , Pujol , P. , Maudelonde , T. , Jeanteur , P. and Theillet , C.p53 mutations in ovarian cancer: a late event ? Oncogene , 6 , 1685 – 1690 ( 1991. ). [PubMed] [Google Scholar]
  • 12. ) Murakami , Y. , Hayashi , K. , Hirohashi , S. and Sekiya , T.Aberrations of the tumor suppressor p53 and retinoblastoma genes in human hepatocellular carcinomas . Cancer Res. , 51 , 5520 – 5525 ( 1991. ). [PubMed] [Google Scholar]
  • 13. ) Ohgaki , H. , Eibl , R. H. , Schwab , M. , Reichel , M. B. , Mariani , L. , Gehring , M. , Petersen , I. , Holl , T. , Wiestler , O. D. and Kleihues , P.Mutations of the p53 tumor suppressor gene in neoplasms of the human nervous system . Mol. Carcinog. , 8 , 74 – 80 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Ohgaki , H. , Kleihues , P. and Heitz , P. U.p53 mutations in sporadic adrenocortical tumors . Int. J. Cancer , 54 , 408 – 410 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Davidoff , A. M. , Kerns , B. J. , Iglehart , J. D. and Marks , J. R.Maintenance of p53 alterations throughout breast cancer progression . Cancer Res. , 51 , 2605 – 2610 ( 1991. ). [PubMed] [Google Scholar]
  • 16. ) Imazeki , F. , Omata , M. , Nose , H. , Ohto , M. and Isono , K.p53 gene mutations in gastric and esophageal cancers . Gastroenterology , 103 , 892 – 896 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Wagata , T. , Shibagaki , I. , Imamura , M. , Shimada , Y. , Toguchida , J. , Yandell , D. W. , Ikenaga , M. , Tobe , T. and Ishizaki , K.Loss of 17p, mutation of the p53 gene, and overexpression of p53 protein in esophageal squamous cell carcinomas . Cancer Res. , 53 , 846 – 850 ( 1993. ). [PubMed] [Google Scholar]
  • 18. ) Wang , L. D. , Zhou , Q. , Hong , J. Y. , Qiu , S. L. and Yang , C. S.p53 protein accumulation and gene mutations in multifocal esophageal precancerous lesions from symptom free subjects in a high incidence area for esophageal carcinoma in Henan, China . Cancer , 77 , 1244 – 1249 ( 1996. ). [PubMed] [Google Scholar]
  • 19. ) Bennett , W. P. , Hollstein , M. C. , Metcalf , R. A. , Welsh , J. A. , He , A. , Zhu , S. M. , Kusters , I. , Resau , J. H. , Trump , B. F. , Lane , D. P. and Harris , C. C.p53 mutation and protein accumulation during multistage human esophageal carcinogenesis . Cancer Res. , 52 , 6092 – 6097 ( 1992. ). [PubMed] [Google Scholar]
  • 20. ) Gao , H. , Wang , L.‐D. , Zhou , Q. , Hong , J.‐Y. , Huang , T.‐Y. and Yang , C. S.p53 tumor suppressor gene mutation in early esophageal precancerous lesions and carcinoma among high‐risk populations in Henan, China . Cancer Res. , 54 , 4342 – 4346 ( 1994. ). [PubMed] [Google Scholar]
  • 21. ) Parenti , A. R. , Rugge , M. , Frizzera , E. , Ruol , A. , Noventa , F. , Ancona , E. and Ninfo , V.p53 overexpression in the multistep process of esophageal carcinogenesis . Am. J. Surg. Pathol. , 19 , 1418 – 1422 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Japanese Society for Esophageal Diseases . “Guide Line for the Clinical and Pathologic Studies on Carcinoma of the Esophagus ,” 8th Ed. ( 1992. ). Kanehara Co. , Tokyo . [DOI] [PubMed] [Google Scholar]
  • 23. ) Oohashi , Y. , Watanabe , H. , Ajioka , Y. and Hatakeyama , K.p53 immunostaining distinguishes malignant from benign lesions of the gallbladder . Pathol. Intern. , 45 , 58 – 65 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Watanabe , H. , Nakagawa , S. , Endo , Y. , Nishikura , K. and Ajioka , Y.Histological diagnosis of carcinoma in situ and dysplasia of esophageal squamous cell carcimoma . Stomach Intest. , 30 , 407 – 416 ( 1995. ) ( in Japanese ). [Google Scholar]
  • 25. ) Nakagawa , S. , Watanabe , H. , Ajioka , Y. , Nishikura , K. , Hitomi , J. and Hatakeyama , K.Archival analysis of p53 protein overexpression and genetic mutation in esophageal squamous cell carcimona . Acta Med. Biol. , 44 , 63 – 69 ( 1996. ). [Google Scholar]
  • 26. ) Watson , J. D. , Witkowski , J. , Gilman , M. and Zoller , M.“Recombinant DNA ,” 2nd Ed. , p. 92 ( 1992. ). W. H. Freeman and Co. , New York . [Google Scholar]
  • 27. ) Sanger , F. , Nicklen , S. and Coulson , A. R.DNA sequencing with chain‐terminating inhibitors . Proc. Natl. Acad. Sci. USA , 74 , 5463 – 5467 ( 1977. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. ) 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]
  • 29. ) Hori , H. , Miyake , S. , Akiyama , Y. , Endo , M. and Yuasa , Y.Clonal heterogeneity in human esophageal squamous cell carcinomas on DNA analysis . Jpn. J. Cancer. Res. , 87 , 923 – 929 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. ) Mayama , T. , Mori , T. , Abe , K. , Sasano , H. , Nishihira , T. , Satomi , S. and Horii , A.Analysis of the p53 gene mutations in patients with multiple primary cancers of the oesophagus . Eur. J. Surg. Oncol. , 23 , 298 – 303 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Slaughter , D. P. , Southwick , H. W. and Smejkal , W. “ Field cancerization” in oral stratified squamous epithelium . Cancer , 6 , 693 – 698 ( 1953. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) Nees , M. , Homann , N. , Discher , H. , Andl , T. , Enders , C. , Herold‐Mende , C. , Schuhmann , A. and Bosch , F. X.Expression of mutated p53 occurs in tumor‐distant epithelia of head and neck cancer patients: a possible molecular basis for the development of multiple tumors . Cancer Res. , 53 , 4189 – 4196 ( 1993. ). [PubMed] [Google Scholar]
  • 33. ) Chung , K. Y. , Mukhopadhyay , T. , Kim , J. , Casson , A. , Ro , J. Y. , Goepfert , H. , Hong , W. K. and Roth , J. A.Discordant p53 gene mutations in primary head and neck cancers and corresponding second primary cancers of the upper aerodigestive tract . Cancer Res. , 53 , 1676 – 1683 ( 1993. ). [PubMed] [Google Scholar]
  • 34. ) Califano , J. , van der Riet , P. , Westra , W. , Nawroz , H. , Clayman , G. , Piantadosi , S. , Corio , R. , Lee , D. , Greenberg , B. , Koch , W. and Sidransky , D.Genetic progression model for head and neck cancer: implications for field cancerization . Cancer Res. , 56 , 2493 – 2496 ( 1996. ). [PubMed] [Google Scholar]
  • 35. ) Sozzi , G. , Miozzo , M. , Donghi , R. , Pilotti , S. , Cariani , C. T. , Pastorino , U. , Porta , G. D. and Pierotti , M. A.Deletions of 17p and p53 mutations in preneoplastic lesions of the lung . Cancer Res. , 52 , 6079 – 6082 ( 1992. ). [PubMed] [Google Scholar]
  • 36. ) Li , Z.‐H. , Zheng , J. , Weiss , L. M. and Shibata , D.c‐K‐ras and p53 mutations occur very early in adenocarcinoma of the lung . Am. J. Pathol. , 144 , 303 – 309 ( 1994. ). [PMC free article] [PubMed] [Google Scholar]
  • 37. ) Reichel , M. B. , Ohgaki , H. , Petersen , I. and Kleihues , P.p53 mutations in primary human lung tumors and their metastases . Mol. Carcinog. , 9 , 105 – 109 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 38. ) Shibata , D. , Schaeffer , J. , Li , Z. H. , Capella , G. and Perucho , M.Genetic heterogeneity of the c‐K‐ras locus in colorectal adenomas but not in adenocarcinomas . J. Natl. Cancer Inst. , 85 , 1058 – 1063 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 39. ) Baker , S. J. , Markowitz , S. , Fearon , E. R. , Willson , J. K. and Vogelstein , B.Suppression of human colorectal carcinoma cell growth by wild‐type p53 . Science , 249 , 912 – 915 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 40. ) Roth , J. A. , Nguyen , D. , Lawrence , D. D. , Kemp , B. L. , Carrasco , C. H. , Ferson , D. Z. , Hong , W. K. , Komaki , R. , Lee , J. J. , Nesbitt , J. C. , Pisters , K. M. , Putnam , J. B. , Schea , R. , Shin , D. M. , Walsh , G. L. , Dolormente , M. M. , Han , C. I. , Martin , F. D. , Yen , N. , Xu , K. , Stephens , L. C. , McDonnell , T. J. , Mukhopadhyay , T. and Cai , D.Retrovirus‐mediated wild‐type p53 gene transfer to tumors of patients with lung cancer . Nat. Med. , 2 , 985 – 991 ( 1996. ). [DOI] [PubMed] [Google Scholar]

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

RESOURCES