Abstract
Epithelial ovarian carcinoma is often diagnosed at an advanced stage of disease and is the leading cause of death from gynaecological neoplasia. The genetic changes that occur during the development of this carcinoma are poorly understood. It has been proposed that IGFIIR, TGFβ1 and TGFβRII act as a functional unit in the TGFβ growth inhibitory pathway, and that somatic loss-of-function mutations in any one of these genes could lead to disruption of the pathway and subsequent loss of cell cycle control. We have examined these 3 genes in 25 epithelial ovarian carcinomas using single-stranded conformational polymorphism analysis and DNA sequence analysis. A total of 3 somatic missense mutations were found in the TGFβRII gene, but none in IGFRII or TGFβ1. An association was found between TGFβRII mutations and histology, with 2 out of 3 clear cell carcinomas having TGFβRII mutations. This data supports other evidence from mutational analysis of the PTEN and β-catenin genes that there are distinct developmental pathways responsible for the progression of different epithelial ovarian cancer histologic subtypes. © 2001 Cancer Research Campaign http://www.bjcancer.com
Keywords: TGFβ, ovarian cancer, genetic analysis
Full Text
The Full Text of this article is available as a PDF (69.2 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Cardillo M. R., Yap E., Castagna G. Molecular genetic analysis of TGF beta1 in breast cancer. J Exp Clin Cancer Res. 1997 Mar;16(1):57–63. [PubMed] [Google Scholar]
- Cardillo M. R., Yap E., Castagna G. Molecular genetic analysis of TGF-beta1 in ovarian neoplasia. J Exp Clin Cancer Res. 1997 Mar;16(1):49–56. [PubMed] [Google Scholar]
- Cardillo M. R., Yap E. TGF-beta1 in colonic neoplasia: a genetic molecular and immunohistochemical study. J Exp Clin Cancer Res. 1997 Sep;16(3):281–288. [PubMed] [Google Scholar]
- Chen R. H., Derynck R. Homomeric interactions between type II transforming growth factor-beta receptors. J Biol Chem. 1994 Sep 9;269(36):22868–22874. [PubMed] [Google Scholar]
- Chenevix-Trench G., Kerr J., Hurst T., Shih Y. C., Purdie D., Bergman L., Friedlander M., Sanderson B., Zournazi A., Coombs T. Analysis of loss of heterozygosity and KRAS2 mutations in ovarian neoplasms: clinicopathological correlations. Genes Chromosomes Cancer. 1997 Feb;18(2):75–83. doi: 10.1002/(sici)1098-2264(199702)18:2<75::aid-gcc1>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
- Chenevix-Trench G., Leary J., Kerr J., Michel J., Kefford R., Hurst T., Parsons P. G., Friedlander M., Khoo S. K. Frequent loss of heterozygosity on chromosome 18 in ovarian adenocarcinoma which does not always include the DCC locus. Oncogene. 1992 Jun;7(6):1059–1065. [PubMed] [Google Scholar]
- Cooke I. E., Shelling A. N., Le Meuth V. G., Charnock M. L., Ganesan T. S. Allele loss on chromosome arm 6q and fine mapping of the region at 6q27 in epithelial ovarian cancer. Genes Chromosomes Cancer. 1996 Apr;15(4):223–233. doi: 10.1002/(SICI)1098-2264(199604)15:4<223::AID-GCC4>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
- De Souza A. T., Hankins G. R., Washington M. K., Fine R. L., Orton T. C., Jirtle R. L. Frequent loss of heterozygosity on 6q at the mannose 6-phosphate/insulin-like growth factor II receptor locus in human hepatocellular tumors. Oncogene. 1995 May 4;10(9):1725–1729. [PubMed] [Google Scholar]
- De Souza A. T., Hankins G. R., Washington M. K., Orton T. C., Jirtle R. L. M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. Nat Genet. 1995 Dec;11(4):447–449. doi: 10.1038/ng1295-447. [DOI] [PubMed] [Google Scholar]
- Garrigue-Antar L., Muñoz-Antonia T., Antonia S. J., Gesmonde J., Vellucci V. F., Reiss M. Missense mutations of the transforming growth factor beta type II receptor in human head and neck squamous carcinoma cells. Cancer Res. 1995 Sep 15;55(18):3982–3987. [PubMed] [Google Scholar]
- Gerdes M. J., Larsen M., McBride L., Dang T. D., Lu B., Rowley D. R. Localization of transforming growth factor-beta1 and type II receptor in developing normal human prostate and carcinoma tissues. J Histochem Cytochem. 1998 Mar;46(3):379–388. doi: 10.1177/002215549804600312. [DOI] [PubMed] [Google Scholar]
- Goff B. A., Sainz de la Cuesta R., Muntz H. G., Fleischhacker D., Ek M., Rice L. W., Nikrui N., Tamimi H. K., Cain J. M., Greer B. E. Clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy in stage III disease. Gynecol Oncol. 1996 Mar;60(3):412–417. doi: 10.1006/gyno.1996.0065. [DOI] [PubMed] [Google Scholar]
- Guo Y., Kyprianou N. Overexpression of transforming growth factor (TGF) beta1 type II receptor restores TGF-beta1 sensitivity and signaling in human prostate cancer cells. Cell Growth Differ. 1998 Feb;9(2):185–193. [PubMed] [Google Scholar]
- Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
- Jirtle R. L., Hankins G. R., Reisenbichler H., Boyer I. J. Regulation of mannose 6-phosphate/insulin-like growth factor-II receptors and transforming growth factor beta during liver tumor promotion with phenobarbital. Carcinogenesis. 1994 Aug;15(8):1473–1478. doi: 10.1093/carcin/15.8.1473. [DOI] [PubMed] [Google Scholar]
- Landis S. H., Murray T., Bolden S., Wingo P. A. Cancer statistics, 1998. CA Cancer J Clin. 1998 Jan-Feb;48(1):6–29. doi: 10.3322/canjclin.48.1.6. [DOI] [PubMed] [Google Scholar]
- Lynch M. A., Nakashima R., Song H., DeGroff V. L., Wang D., Enomoto T., Weghorst C. M. Mutational analysis of the transforming growth factor beta receptor type II gene in human ovarian carcinoma. Cancer Res. 1998 Oct 1;58(19):4227–4232. [PubMed] [Google Scholar]
- Makar A. P., Baekelandt M., Tropé C. G., Kristensen G. B. The prognostic significance of residual disease, FIGO substage, tumor histology, and grade in patients with FIGO stage III ovarian cancer. Gynecol Oncol. 1995 Feb;56(2):175–180. doi: 10.1006/gyno.1995.1027. [DOI] [PubMed] [Google Scholar]
- Munger J. S., Harpel J. G., Gleizes P. E., Mazzieri R., Nunes I., Rifkin D. B. Latent transforming growth factor-beta: structural features and mechanisms of activation. Kidney Int. 1997 May;51(5):1376–1382. doi: 10.1038/ki.1997.188. [DOI] [PubMed] [Google Scholar]
- Obata K., Morland S. J., Watson R. H., Hitchcock A., Chenevix-Trench G., Thomas E. J., Campbell I. G. Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors. Cancer Res. 1998 May 15;58(10):2095–2097. [PubMed] [Google Scholar]
- Orita M., Iwahana H., Kanazawa H., Hayashi K., Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2766–2770. doi: 10.1073/pnas.86.8.2766. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Polyak K. Negative regulation of cell growth by TGF beta. Biochim Biophys Acta. 1996 Mar 18;1242(3):185–199. doi: 10.1016/0304-419x(95)00009-5. [DOI] [PubMed] [Google Scholar]
- Rich J. N., Zhang M., Datto M. B., Bigner D. D., Wang X. F. Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. J Biol Chem. 1999 Dec 3;274(49):35053–35058. doi: 10.1074/jbc.274.49.35053. [DOI] [PubMed] [Google Scholar]
- Taylor S. S., Knighton D. R., Zheng J., Ten Eyck L. F., Sowadski J. M. Structural framework for the protein kinase family. Annu Rev Cell Biol. 1992;8:429–462. doi: 10.1146/annurev.cb.08.110192.002241. [DOI] [PubMed] [Google Scholar]
- Tsukazaki T., Chiang T. A., Davison A. F., Attisano L., Wrana J. L. SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell. 1998 Dec 11;95(6):779–791. doi: 10.1016/s0092-8674(00)81701-8. [DOI] [PubMed] [Google Scholar]
- Vincent F., Hagiwara K., Ke Y., Stoner G. D., Demetrick D. J., Bennett W. P. Mutation analysis of the transforming growth factor beta type II receptor in sporadic human cancers of the pancreas, liver, and breast. Biochem Biophys Res Commun. 1996 Jun 25;223(3):561–564. doi: 10.1006/bbrc.1996.0934. [DOI] [PubMed] [Google Scholar]
- Wang D., Kanuma T., Mizunuma H., Takama F., Ibuki Y., Wake N., Mogi A., Shitara Y., Takenoshita S. Analysis of specific gene mutations in the transforming growth factor-beta signal transduction pathway in human ovarian cancer. Cancer Res. 2000 Aug 15;60(16):4507–4512. [PubMed] [Google Scholar]
- Wang D., Song H., Evans J. A., Lang J. C., Schuller D. E., Weghorst C. M. Mutation and downregulation of the transforming growth factor beta type II receptor gene in primary squamous cell carcinomas of the head and neck. Carcinogenesis. 1997 Nov;18(11):2285–2290. doi: 10.1093/carcin/18.11.2285. [DOI] [PubMed] [Google Scholar]
- Wright K., Wilson P., Morland S., Campbell I., Walsh M., Hurst T., Ward B., Cummings M., Chenevix-Trench G. beta-catenin mutation and expression analysis in ovarian cancer: exon 3 mutations and nuclear translocation in 16% of endometrioid tumours. Int J Cancer. 1999 Aug 27;82(5):625–629. doi: 10.1002/(sici)1097-0215(19990827)82:5<625::aid-ijc1>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
- Yan Z., Winawer S., Friedman E. Two different signal transduction pathways can be activated by transforming growth factor beta 1 in epithelial cells. J Biol Chem. 1994 May 6;269(18):13231–13237. [PubMed] [Google Scholar]
- Zhang F., Strand A., Robbins D., Cobb M. H., Goldsmith E. J. Atomic structure of the MAP kinase ERK2 at 2.3 A resolution. Nature. 1994 Feb 24;367(6465):704–711. doi: 10.1038/367704a0. [DOI] [PubMed] [Google Scholar]
- ten Dijke P., Heldin C. H. Signal transduction. An anchor for activation. Nature. 1999 Jan 14;397(6715):109–111. doi: 10.1038/16357. [DOI] [PubMed] [Google Scholar]
