Abstract
The short arm of the chromosome 11, known to harbour a number of putative and established tumour-suppressor genes, is frequently hypermethylated in various human neoplasms. We subjected the promoter regions of two genes residing at 11p, namely the tumour-suppressor gene WT1 (Wilms' tumour gene) (11p13) and the calcitonin gene (11p15.5), to methylation analysis in human sporadic colorectal cancer using genomic sequencing. Both genes showed significant hypermethylation of CpG sites within their promoter regions in adenomas and carcinomas compared with normal colonic mucosa. Although the WT1 promoter region was significantly hypermethylated, two CpG sites located in Sp1 motifs were unmethylated in the majority of cases (68-74% of carcinomas). The expression of WT1 gene, as revealed by in situ hybridization, showed no differences between normal colonic mucosa and malignant carcinoma. Together with earlier observations, our present results support the view that the short arm of human chromosome 11 is subjected to widespread regional hypermethylation in various human malignancies.
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- Cunningham C., Dunlop M. G. Genetics of colorectal cancer. Br Med Bull. 1994 Jul;50(3):640–655. doi: 10.1093/oxfordjournals.bmb.a072914. [DOI] [PubMed] [Google Scholar]
- Feinberg A. P., Gehrke C. W., Kuo K. C., Ehrlich M. Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res. 1988 Mar 1;48(5):1159–1161. [PubMed] [Google Scholar]
- Fraizer G. C., Wu Y. J., Hewitt S. M., Maity T., Ton C. C., Huff V., Saunders G. F. Transcriptional regulation of the human Wilms' tumor gene (WT1). Cell type-specific enhancer and promiscuous promoter. J Biol Chem. 1994 Mar 25;269(12):8892–8900. [PubMed] [Google Scholar]
- Hewitt S. M., Fraizer G. C., Saunders G. F. Transcriptional silencer of the Wilms' tumor gene WT1 contains an Alu repeat. J Biol Chem. 1995 Jul 28;270(30):17908–17912. doi: 10.1074/jbc.270.30.17908. [DOI] [PubMed] [Google Scholar]
- Ichikawa T., Ichikawa Y., Dong J., Hawkins A. L., Griffin C. A., Isaacs W. B., Oshimura M., Barrett J. C., Isaacs J. T. Localization of metastasis suppressor gene(s) for prostatic cancer to the short arm of human chromosome 11. Cancer Res. 1992 Jun 15;52(12):3486–3490. [PubMed] [Google Scholar]
- Issa J. P., Ottaviano Y. L., Celano P., Hamilton S. R., Davidson N. E., Baylin S. B. Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet. 1994 Aug;7(4):536–540. doi: 10.1038/ng0894-536. [DOI] [PubMed] [Google Scholar]
- Issa J. P., Vertino P. M., Wu J., Sazawal S., Celano P., Nelkin B. D., Hamilton S. R., Baylin S. B. Increased cytosine DNA-methyltransferase activity during colon cancer progression. J Natl Cancer Inst. 1993 Aug 4;85(15):1235–1240. doi: 10.1093/jnci/85.15.1235. [DOI] [PubMed] [Google Scholar]
- Jones P. A. DNA methylation errors and cancer. Cancer Res. 1996 Jun 1;56(11):2463–2467. [PubMed] [Google Scholar]
- Laird P. W., Jaenisch R. DNA methylation and cancer. Hum Mol Genet. 1994;3(Spec No):1487–1495. doi: 10.1093/hmg/3.suppl_1.1487. [DOI] [PubMed] [Google Scholar]
- Lichy J. H., Modi W. S., Seuanez H. N., Howley P. M. Identification of a human chromosome 11 gene which is differentially regulated in tumorigenic and nontumorigenic somatic cell hybrids of HeLa cells. Cell Growth Differ. 1992 Aug;3(8):541–548. [PubMed] [Google Scholar]
- Loh W. E., Jr, Scrable H. J., Livanos E., Arboleda M. J., Cavenee W. K., Oshimura M., Weissman B. E. Human chromosome 11 contains two different growth suppressor genes for embryonal rhabdomyosarcoma. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1755–1759. doi: 10.1073/pnas.89.5.1755. [DOI] [PMC free article] [PubMed] [Google Scholar]
- MacLeod A. R., Szyf M. Expression of antisense to DNA methyltransferase mRNA induces DNA demethylation and inhibits tumorigenesis. J Biol Chem. 1995 Apr 7;270(14):8037–8043. doi: 10.1074/jbc.270.14.8037. [DOI] [PubMed] [Google Scholar]
- Malik K. T., Wallace J. I., Ivins S. M., Brown K. W. Identification of an antisense WT1 promoter in intron 1: implications for WT1 gene regulation. Oncogene. 1995 Oct 19;11(8):1589–1595. [PubMed] [Google Scholar]
- Myöhänen S., Wahlfors J., Jänne J. Automated fluorescent genomic sequencing as applied to the methylation analysis of the human ornithine decarboxylase gene. DNA Seq. 1994;5(1):1–8. doi: 10.3109/10425179409039698. [DOI] [PubMed] [Google Scholar]
- Rauscher F. J., 3rd, Morris J. F., Tournay O. E., Cook D. M., Curran T. Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence. Science. 1990 Nov 30;250(4985):1259–1262. doi: 10.1126/science.2244209. [DOI] [PubMed] [Google Scholar]
- Schalling M., Dagerlind A., Brené S., Hallman H., Djurfeldt M., Persson H., Terenius L., Goldstein M., Schlesinger D., Hökfelt T. Coexistence and gene expression of phenylethanolamine N-methyltransferase, tyrosine hydroxylase, and neuropeptide tyrosine in the rat and bovine adrenal gland: effects of reserpine. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8306–8310. doi: 10.1073/pnas.85.21.8306. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sharrard R. M., Royds J. A., Rogers S., Shorthouse A. J. Patterns of methylation of the c-myc gene in human colorectal cancer progression. Br J Cancer. 1992 May;65(5):667–672. doi: 10.1038/bjc.1992.142. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Silverman A. L., Park J. G., Hamilton S. R., Gazdar A. F., Luk G. D., Baylin S. B. Abnormal methylation of the calcitonin gene in human colonic neoplasms. Cancer Res. 1989 Jul 1;49(13):3468–3473. [PubMed] [Google Scholar]
- Strohmeyer T. Nephroblastom (Wilms' Tumor): Zytogenetische und molekularbiologische Grundlagen. Klin Padiatr. 1993 May-Jun;205(3):135–139. doi: 10.1055/s-2007-1025214. [DOI] [PubMed] [Google Scholar]
- Tornaletti S., Pfeifer G. P. Complete and tissue-independent methylation of CpG sites in the p53 gene: implications for mutations in human cancers. Oncogene. 1995 Apr 20;10(8):1493–1499. [PubMed] [Google Scholar]
- de Bustros A., Nelkin B. D., Silverman A., Ehrlich G., Poiesz B., Baylin S. B. The short arm of chromosome 11 is a "hot spot" for hypermethylation in human neoplasia. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5693–5697. doi: 10.1073/pnas.85.15.5693. [DOI] [PMC free article] [PubMed] [Google Scholar]