Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Jan 18;82(3):571–578. doi: 10.1054/bjoc.1999.0966

Loss of DCC gene expression during ovarian tumorigenesis: relation to tumour differentiation and progression

M Saegusa 1, D Machida 1, I Okayasu 1
PMCID: PMC2363327  PMID: 10682668

Abstract

To clarify the possible role of DCC gene alteration in ovarian neoplasias, we immunohistochemically investigated 124 carcinomas, as well as 55 cystadenomas and 41 low malignant potential (LMP) tumours and compared the results with those for p53 protein expression, clinicopathological factors and survival. A combination of the reverse transcription polymerase chain reaction (RT-PCR) and Southern blot hybridization (SBH) for DCC mRNA levels was also carried out on 26 malignant, five LMP, eight benign and seven normal ovarian samples. Significantly decreased levels of overall DCC values in carcinomas compared with benign and LMP lesions were revealed by both immunohistochemical and RT-PCR/SBH assays. Similar findings were also noted when subdivision was into serous and mucinous categories. In carcinomas, reduction or loss of DCC expression was significantly related to the serous phenotype (serous vs non-serous, P< 0.0001), a high histological grade (grade 1 vs 2 or 3, P< 0.02) and a more advanced stage (FIGO stage I vs II/III/IV, P = 0.0083), while no association was noted with survival. Although p53 immunopositivity demonstrated significant stepwise increase from benign through to malignant lesions, there was no clear association with DCC score values. The results indicated that impaired DCC expression may play an important role in ovarian tumorigenesis. In ovarian carcinomas, the altered expression is closely linked with tumour differentiation and progression. © 2000 Cancer Research Campaign

Keywords: DCC, p53, ovarian carcinoma, RT-PCR

Full Text

The Full Text of this article is available as a PDF (294.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baas I. O., Mulder J. W., Offerhaus G. J., Vogelstein B., Hamilton S. R. An evaluation of six antibodies for immunohistochemistry of mutant p53 gene product in archival colorectal neoplasms. J Pathol. 1994 Jan;172(1):5–12. doi: 10.1002/path.1711720104. [DOI] [PubMed] [Google Scholar]
  2. Bell D. A., Scully R. E. Early de novo ovarian carcinoma. A study of fourteen cases. Cancer. 1994 Apr 1;73(7):1859–1864. doi: 10.1002/1097-0142(19940401)73:7<1859::aid-cncr2820730714>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  3. Cho K. R., Oliner J. D., Simons J. W., Hedrick L., Fearon E. R., Preisinger A. C., Hedge P., Silverman G. A., Vogelstein B. The DCC gene: structural analysis and mutations in colorectal carcinomas. Genomics. 1994 Feb;19(3):525–531. doi: 10.1006/geno.1994.1102. [DOI] [PubMed] [Google Scholar]
  4. Chuong C. M., Jiang T. X., Yin E., Widelitz R. B. cDCC (chicken homologue to a gene deleted in colorectal carcinoma) is an epithelial adhesion molecule expressed in the basal cells and involved in epithelial-mesenchymal interaction. Dev Biol. 1994 Aug;164(2):383–397. doi: 10.1006/dbio.1994.1208. [DOI] [PubMed] [Google Scholar]
  5. Ekstrand B. C., Mansfield T. A., Bigner S. H., Fearon E. R. DCC expression is altered by multiple mechanisms in brain tumours. Oncogene. 1995 Dec 7;11(11):2393–2402. [PubMed] [Google Scholar]
  6. Eltabbakh G. H., Belinson J. L., Kennedy A. W., Biscotti C. V., Casey G., Tubbs R. R., Blumenson L. E. p53 overexpression is not an independent prognostic factor for patients with primary ovarian epithelial cancer. Cancer. 1997 Sep 1;80(5):892–898. [PubMed] [Google Scholar]
  7. Enomoto T., Fujita M., Cheng C., Nakashima R., Ozaki M., Inoue M., Nomura T. Loss of expression and loss of heterozygosity in the DCC gene in neoplasms of the human female reproductive tract. Br J Cancer. 1995 Mar;71(3):462–467. doi: 10.1038/bjc.1995.94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. 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. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 1990 Jan 5;247(4938):49–56. doi: 10.1126/science.2294591. [DOI] [PubMed] [Google Scholar]
  9. Gao X., Honn K. V., Grignon D., Sakr W., Chen Y. Q. Frequent loss of expression and loss of heterozygosity of the putative tumor suppressor gene DCC in prostatic carcinomas. Cancer Res. 1993 Jun 15;53(12):2723–2727. [PubMed] [Google Scholar]
  10. Goi T., Yamaguchi A., Nakagawara G., Urano T., Shiku H., Furukawa K. Reduced expression of deleted colorectal carcinoma (DCC) protein in established colon cancers. Br J Cancer. 1998;77(3):466–471. doi: 10.1038/bjc.1998.74. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hedrick L., Cho K. R., Fearon E. R., Wu T. C., Kinzler K. W., Vogelstein B. The DCC gene product in cellular differentiation and colorectal tumorigenesis. Genes Dev. 1994 May 15;8(10):1174–1183. doi: 10.1101/gad.8.10.1174. [DOI] [PubMed] [Google Scholar]
  12. Herod J. J., Eliopoulos A. G., Warwick J., Niedobitek G., Young L. S., Kerr D. J. The prognostic significance of Bcl-2 and p53 expression in ovarian carcinoma. Cancer Res. 1996 May 1;56(9):2178–2184. [PubMed] [Google Scholar]
  13. Horstmann M. A., Pösl M., Scholz R. B., Anderegg B., Simon P., Baumgaertl K., Delling G., Kabisch H. Frequent reduction or loss of DCC gene expression in human osteosarcoma. Br J Cancer. 1997;75(9):1309–1317. doi: 10.1038/bjc.1997.222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Huang Y., Boynton R. F., Blount P. L., Silverstein R. J., Yin J., Tong Y., McDaniel T. K., Newkirk C., Resau J. H., Sridhara R. Loss of heterozygosity involves multiple tumor suppressor genes in human esophageal cancers. Cancer Res. 1992 Dec 1;52(23):6525–6530. [PubMed] [Google Scholar]
  15. Inoue M., Fujita M., Enomoto T., Morimoto H., Monden T., Shimano T., Tanizawa O. Immunohistochemical analysis of p53 in gynecologic tumors. Am J Clin Pathol. 1994 Nov;102(5):665–670. doi: 10.1093/ajcp/102.5.665. [DOI] [PubMed] [Google Scholar]
  16. Keino-Masu K., Masu M., Hinck L., Leonardo E. D., Chan S. S., Culotti J. G., Tessier-Lavigne M. Deleted in Colorectal Cancer (DCC) encodes a netrin receptor. Cell. 1996 Oct 18;87(2):175–185. doi: 10.1016/s0092-8674(00)81336-7. [DOI] [PubMed] [Google Scholar]
  17. Kikuchi-Yanoshita R., Konishi M., Fukunari H., Tanaka K., Miyaki M. Loss of expression of the DCC gene during progression of colorectal carcinomas in familial adenomatous polyposis and non-familial adenomatous polyposis patients. Cancer Res. 1992 Jul 1;52(13):3801–3803. [PubMed] [Google Scholar]
  18. Klemi P. J., Pylkkänen L., Kiilholma P., Kurvinen K., Joensuu H. p53 protein detected by immunohistochemistry as a prognostic factor in patients with epithelial ovarian carcinoma. Cancer. 1995 Oct 1;76(7):1201–1208. doi: 10.1002/1097-0142(19951001)76:7<1201::aid-cncr2820760716>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  19. Klemi P. J., Takahashi S., Joensuu H., Kiilholma P., Narimatsu E., Mori M. Immunohistochemical detection of p53 protein in borderline and malignant serous ovarian tumors. Int J Gynecol Pathol. 1994 Jul;13(3):228–233. doi: 10.1097/00004347-199407000-00006. [DOI] [PubMed] [Google Scholar]
  20. Klingelhutz A. J., Hedrick L., Cho K. R., McDougall J. K. The DCC gene suppresses the malignant phenotype of transformed human epithelial cells. Oncogene. 1995 Apr 20;10(8):1581–1586. [PubMed] [Google Scholar]
  21. Kong X. T., Choi S. H., Inoue A., Xu F., Chen T., Takita J., Yokota J., Bessho F., Yanagisawa M., Hanada R. Expression and mutational analysis of the DCC, DPC4, and MADR2/JV18-1 genes in neuroblastoma. Cancer Res. 1997 Sep 1;57(17):3772–3778. [PubMed] [Google Scholar]
  22. Maesawa C., Tamura G., Suzuki Y., Ogasawara S., Sakata K., Kashiwaba M., Satodate R. The sequential accumulation of genetic alterations characteristic of the colorectal adenoma-carcinoma sequence does not occur between gastric adenoma and adenocarcinoma. J Pathol. 1995 Jul;176(3):249–258. doi: 10.1002/path.1711760307. [DOI] [PubMed] [Google Scholar]
  23. Maestro R., Dolcetti R., Gasparotto D., Doglioni C., Pelucchi S., Barzan L., Grandi E., Boiocchi M. High frequency of p53 gene alterations associated with protein overexpression in human squamous cell carcinoma of the larynx. Oncogene. 1992 Jun;7(6):1159–1166. [PubMed] [Google Scholar]
  24. Mandai M., Konishi I., Kuroda H., Komatsu T., Yamamoto S., Nanbu K., Matsushita K., Fukumoto M., Yamabe H., Mori T. Heterogeneous distribution of K-ras-mutated epithelia in mucinous ovarian tumors with special reference to histopathology. Hum Pathol. 1998 Jan;29(1):34–40. doi: 10.1016/s0046-8177(98)90387-2. [DOI] [PubMed] [Google Scholar]
  25. Reale M. A., Hu G., Zafar A. I., Getzenberg R. H., Levine S. M., Fearon E. R. Expression and alternative splicing of the deleted in colorectal cancer (DCC) gene in normal and malignant tissues. Cancer Res. 1994 Aug 15;54(16):4493–4501. [PubMed] [Google Scholar]
  26. Reles A., Schmider A., Press M. F., Schönborn I., Friedmann W., Huber-Schumacher S., Strohmeyer T., Lichtenegger W. Immunostaining of p53 protein in ovarian carcinoma: correlation with histopathological data and clinical outcome. J Cancer Res Clin Oncol. 1996;122(8):489–494. doi: 10.1007/BF01187161. [DOI] [PubMed] [Google Scholar]
  27. Reyes-Mugica M., Rieger-Christ K., Ohgaki H., Ekstrand B. C., Helie M., Kleinman G., Yahanda A., Fearon E. R., Kleihues P., Reale M. A. Loss of DCC expression and glioma progression. Cancer Res. 1997 Feb 1;57(3):382–386. [PubMed] [Google Scholar]
  28. Saegusa M., Kamata Y., Isono M., Okayasu I. Bcl-2 expression is correlated with a low apoptotic index and associated with progesterone receptor immunoreactivity in endometrial carcinomas. J Pathol. 1996 Nov;180(3):275–282. doi: 10.1002/(SICI)1096-9896(199611)180:3<275::AID-PATH660>3.0.CO;2-A. [DOI] [PubMed] [Google Scholar]
  29. Shibata D., Reale M. A., Lavin P., Silverman M., Fearon E. R., Steele G., Jr, Jessup J. M., Loda M., Summerhayes I. C. The DCC protein and prognosis in colorectal cancer. N Engl J Med. 1996 Dec 5;335(23):1727–1732. doi: 10.1056/NEJM199612053352303. [DOI] [PubMed] [Google Scholar]
  30. Sinicrope F. A., Ruan S. B., Cleary K. R., Stephens L. C., Lee J. J., Levin B. bcl-2 and p53 oncoprotein expression during colorectal tumorigenesis. Cancer Res. 1995 Jan 15;55(2):237–241. [PubMed] [Google Scholar]
  31. Slamon D. J., Godolphin W., Jones L. A., Holt J. A., Wong S. G., Keith D. E., Levin W. J., Stuart S. G., Udove J., Ullrich A. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May 12;244(4905):707–712. doi: 10.1126/science.2470152. [DOI] [PubMed] [Google Scholar]
  32. Uchino S., Tsuda H., Noguchi M., Yokota J., Terada M., Saito T., Kobayashi M., Sugimura T., Hirohashi S. Frequent loss of heterozygosity at the DCC locus in gastric cancer. Cancer Res. 1992 Jun 1;52(11):3099–3102. [PubMed] [Google Scholar]
  33. Wynford-Thomas D. P53 in tumour pathology: can we trust immunocytochemistry? J Pathol. 1992 Apr;166(4):329–330. doi: 10.1002/path.1711660402. [DOI] [PubMed] [Google Scholar]
  34. Zeimet A. G., Widschwendter M., Uhl-Steidl M., Müller-Holzner E., Daxenbichler G., Marth C., Dapunt O. High serum levels of soluble CD44 variant isoform v5 are associated with favourable clinical outcome in ovarian cancer. Br J Cancer. 1997;76(12):1646–1651. doi: 10.1038/bjc.1997.611. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES