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Hypermethylation at 9q32-33 tumour suppressor region is age-related in normal urothelium and an early and frequent alteration in bladder cancer

Oncogene volume 20, pages 531–537 (2001)Cite this article

Abstract

Transcriptional silencing by CpG island hypermethylation of gene regulatory regions is one mechanism for inactivation of tumour suppressor genes. Chromosome 9q deletion is frequently found in transitional cell carcinoma (TCC) of the bladder and upper urinary tract and one of the putative tumour suppressor loci has been mapped to 9q32-33. A gene designated as DBCCR1 was identified in the candidate region and its mRNA expression is thought to be suppressed by hypermethylation. To understand the role of hypermethylation in TCC, we evaluated the methylation status of 20 CpG sites of the DBCCR1 5′-CpG island region in a total of 69 tumours from 45 patients, 21 normal urothelial specimens, and six bladder cancer cell lines. Aberrant hypermethylation levels were found in 36 (52%) of 69 tumours without any association with tumour grade or stage. Methylation was weakly detected in the normal urothelium in association with ageing. Although recurrent tumours tended to have higher methylation levels than the initial tumours, the methylation pattern was mostly maintained between multifocal TCCs in individual patients. The results suggest that hypermethylation of the DBCCR1 region is one of the earliest alterations in the development of TCCs and there may be an age-related hypermethylation-based field defect in normal urothelium. Methylator or methylation-resistant phenotype seems to be maintained during multifocal development or recurrence of most TCCs.

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Acknowledgements

This work is supported by Grants-in-Aid (B12470327, B10470331, B10470330, B09557129, B10470336) from the Ministry of Education, Science, Sports and Culture of Japan.

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Authors and Affiliations

  1. Department of Urology, Akita University School of Medicine, Akita, Japan

    Tomonori Habuchi, Hideaki Kakinuma, Lizhong Wang, Norihiko Tsuchiya, Shigeru Satoh, Toshiya Akao, Kazunari Sato & Tetsuro Kato

  2. Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Takeshi Takahashi & Osamu Ogawa

  3. ICRF Cancer Medicine Unit, St. James's University Hospital, Leeds, UK

    Margaret A Knowles

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  1. Tomonori Habuchi
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Habuchi, T., Takahashi, T., Kakinuma, H. et al. Hypermethylation at 9q32-33 tumour suppressor region is age-related in normal urothelium and an early and frequent alteration in bladder cancer. Oncogene 20, 531–537 (2001). https://doi.org/10.1038/sj.onc.1204122

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