Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1998 Jan;89(1):40–46. doi: 10.1111/j.1349-7006.1998.tb00477.x

Alteration of p53 Clonality Accompanying Colorectal Cancer Progression

Akifumi Kuwabara 1,2,✉, Hidenobu Watanabe 1, Yoichi Ajioka 1, Kazuhiro Yasuda 1, Hidetoshi Saito 2, Keiji Matsuda 3, Hiroshi Kijima 4, Katuyoshi Hatakeyama 2
PMCID: PMC5921584  PMID: 9510474

Abstract

The aim of this study was to clarify whether or not the status of gene alteration is heterogeneous in intramucosal carcinoma and homogeneous within invasive carcinoma. We selected 10 colorectal carcinoma cases (1 mucosal, 5 submucosal and 4 advanced carcinomas including 2 cases with lymph node metastasis) and analyzed the p53 gene sequence. Six colorectal cancers in this study showed heterogeneity in p53 mutations in cells from the intramucosal part. In the invasive part of a carcinoma, p53 mutation status was homogeneous intratumorally in all cases. These data indicate that, in regard to p53 gene alterations, colorectal cancers can be composed of various subclones when limited to the mucosa, but clonal selection occurs when one of these subclones commences invasion to the submucosa, generating a monoclonal invasive carcinoma.

Keywords: Colorectal cancer, p53 gene, Clonality, Heterogeneity, Intramucosal carcinoma

Full Text

The Full Text of this article is available as a PDF (908.5 KB).

REFERENCES

  • 1. ) Bishop , J. M.The molecular genetics of cancer . Science , 235 , 305 – 311 ( 1987. ). 3541204 [Google Scholar]
  • 2. ) Fearon , E. R. and Vogelstein , B.A genetic model for colorectal tumorigenesis . Cell , 61 , 759 – 767 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) 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]
  • 4. ) Kinzler , K. W. , Nilbert , M. C. , Su , L.‐K. , Vogelstein , B. , Bryan , T. M. , Levy , D. B. , Smith , K. J. , Preisinger , A. C. , Hedge , P. , McKechnie , D. , Finniear , R. , Markham , A. , Groffen , G. , Boguski , M. S. , Altschul , S. F. , Horii , A. , Ando , H. , Miyoshi , Y. , Miki , Y. , Nishisho , I. and Nakamura , Y.Identification of FAP locus genes from chromosome 5q21 . Science , 253 , 661 – 665 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Fearon , E. R. , Cho , K. R. , Nigro , J. M. , Kern , S. E. , Simons , J. W. , Ruppert , J. M. , Hamilton , S. R. , Preisinger , A. C. , Thomas , G. , Kinzler , K. W. and Vogelstein , B.Identification of a chromosome 18q gene that is altered in colorectal cancers . Science , 247 , 49 – 56 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Forrester , K. , Almoguera , C. , Han , K. , Grizzle , W. E. and Percho , M.Detection of high incidence of K‐ras oncogenes during human colon tumorigenesis . Nature , 327 , 298 – 303 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Baker , S. J. , Preisinger , A. C. , Jessup , J. M. , Paraskeva , C. , Markowitz , S. , Willson , J. K. V. , Hamilton , S. R. and Vogelstein , B.p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis . Cancer Res. , 50 , 7717 – 7722 ( 1990. ). [PubMed] [Google Scholar]
  • 8. ) Kikuchi‐Yanoshita , R. , Konishi , M. , Ito , S. , Seki , M. , Tanaka , K. , Maeda , Y. , Iino , H. , Fukuyama , M. , Koike , M. , Mori , T. , Sakuraba , H. , Fukunari , H. , Iwama , T. and Miyaki , M.Genetic changes of both p53 alleles associated with the conversion from colorectal adenoma to early carcinoma in familial adenomatous polyposis and non‐familial adenomatous polyposis patients . Cancer Res. , 52 , 3965 – 3971 ( 1992. ). [PubMed] [Google Scholar]
  • 9. ) Tahara , E.Genetic alterations in human gastrointestinal cancers. The application to molecular diagnosis . Cancer , 75 , 1411 – 1417 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Japanese Research Society for Cancer of the Colon and Rectum . In“General Rules for Clinical and Pathological Studies on Cancer of Colon, Rectum and Anus ,” 5th Ed. ( 1994. ). Kanehara Co. , Tokyo . [Google Scholar]
  • 11. ) Watanabe , H. , Ajioka , Y. , Yamaguchi , M. , Noda , Y. , Honma , T. and Motoyama , T.Relationship of colorectal adenoma and colorectal carcinoma: based on the authors' diagnosis criteria . Stomach Intest. , 24 , 253 – 259 ( 1989. ) ( in Japanese ). [Google Scholar]
  • 12. ) Kobayashi , M. , Watanabe , H. , Ajioka , Y. , Honma , T. and Asakura , H.Effect of K‐ras mutation on morphogenesis of colorectal adenomas and early cancers: relationship to distribution of proliferating cells . Hum. Pathol. , 27 , 1042 – 1049 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Maeo , S. , Ajioka , Y. , Watanabe , H. , Kobayashi , M. and Kobayashi , M.The proliferating cell nuclear antigen (PCNA) index correlates with the grade of cytologic atypia in well‐differentiated early adenocarcinomas of the large intestine . Pathol. Int. , 45 , 359 – 365 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Oohashi , Y. , Watanabe , H. , Ajioka , Y. and Hatakeyama , K.p53 immunostaining distinguishes malignant from benign lesions of the gall‐bladder . Pathol. Int. , 45 , 58 – 65 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) 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 carcinoma . Acta Med. Biol. , 44 , 63 – 69 ( 1996. ). [Google Scholar]
  • 16. ) Watson , J. D. , Witkowski , J. , Gilman , M. and Zoller , M.“Recombinant DNA ,” 2nd Ed. , p. 92 ( 1992. ). W. H. Freeman and Company; , New York . [Google Scholar]
  • 17. ) Nowell , P. C.The clonal evolution of tumor cell populations . Science , 194 , 23 – 28 ( 1976. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Heppner , G. H.Tumor heterogeneity . Cancer Res. , 44 , 2259 – 2265 ( 1984. ). [PubMed] [Google Scholar]
  • 19. ) Burmer , G. C. and Loeb , L. A.Mutations in the KRAS2 oncogene during progressive stage of human colon carcinoma . Proc. Natl. Acad. Sci. USA , 86 , 2403 – 2407 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. ) Levin , B. and Reichmann , A.Chromosomes and large bowel tumors . Cancer Genet. Cytogenet. , 19 , 159 – 162 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Koha , M. , Brismar , B. and Wikstörm , B.DNA content in primary tumors and lymph node metastases in colorectal adenocarcinoma . APMIS , 100 , 640 – 644 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) 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]
  • 23. ) 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]
  • 24. ) Mirchandani , D. , Zheng , J. , Miller , G. J. , Ghosh , A. K. , Shibata , D. K. , Cote , R. J. and Roy‐Burman , P.Heterogeneity in intratumor distribution of p53 mutations in human prostate cancer . Am. J. Pathol. , 147 , 92 – 101 ( 1995. ). [PMC free article] [PubMed] [Google Scholar]
  • 25. ) Konishi , N. , Hiasa , Y. , Matsuda , H. , Tao , M. , Tsuzuki , T. , Hayashi , I. , Kitahori , Y. , Shirai , T. , Yanani , R. , Shimozaki , J. and Lin , J.‐C.Intratumor cellular heterogeneity and alterations in ras oncogene and p53 tumor suppressor gene in human prostate carcinoma . Am. J. Pathol. , 147 , 1112 – 1122 ( 1995. ). [PMC free article] [PubMed] [Google Scholar]
  • 26. ) Nagel , S. , Borisch , B. , Thein , S. L. , Oestreicher , M. , Nöthiger , F. , Birrer , S. , Tobbler , A. and Fey , 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]
  • 27. ) Lane , D. P.Cancer. p53, guardian of the genome . Nature , 358 , 15 – 16 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) El‐Deiry , W. S. , Harper , J. W. , O'Connor , P. M. , Velculescu , V. E. , Canman , C. E. , Jackman , J. , Pietenpol , J. A. , Burrell , M. , Hill , D. E. , Wang , Y. , Wilman , K. G. , Mercer , W. E. , Kastan , M. B. , Kohn , K. W. , Elledge , S. J. , Kinzler , K. W. and Vogelstein , B.WAF1/CIP1 is induced in p53‐mediated G1 arrest and apoptosis . Cancer Res. , 54 , 1169 – 1174 ( 1994. ). [PubMed] [Google Scholar]
  • 29. ) Shimoda , T. , Ikegami , M. , Fujisaki , J. , Matsui , T. , Aizawa , S. and Ishikawa , E.Early colorectal carcinoma with special reference to its development de novo . Cancer , 64 , 1138 – 1146 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) 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]
  • 31. ) Kanjilal , S. , Strom , S. S. , Clayman , G. L. , Weber , R. S. , El‐Naggar , A. K. , Kapur , V. , Cummings , K. K. , Hill , L. A. , Spitz , M. R. , Kripke , M. L. and Ananthaswamy , H. N.p53 mutations in nonmelanoma skin cancer of the head and neck: molecular evidence for field cancerization . Cancer Res. , 55 , 3604 – 3609 ( 1995. ). [PubMed] [Google Scholar]
  • 32. ) Bedi , G. C. , Westra , W. H. , Gabrielson , E. , Koch , W. and Sidransky , D.Multiple head and neck tumors: evidence for a common clonal origin . Cancer Res. , 56 , 2484 – 2487 ( 1996. ). [PubMed] [Google Scholar]
  • 33. ) Califano , J. , Riet , P. V. D. , 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 , 2488 – 2492 ( 1996. ). [PubMed] [Google Scholar]

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

RESOURCES