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  • Original Paper
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RASSF1A promoter region CpG island hypermethylation in phaeochromocytomas and neuroblastoma tumours

Oncogene volume 20, pages 7573–7577 (2001)Cite this article

Abstract

Deletions of chromosome 3p are frequent in many types of neoplasia including neural crest tumours such as neuroblastoma (NB) and phaeochromocytoma. Recently we isolated several candidate tumour suppressor genes (TSGs) from a 120 kb critical interval at 3p21.3 defined by overlapping homozygous deletions in lung and breast tumour lines. Although mutation analysis of candidate TSGs in lung and breast cancers revealed only rare mutations, expression of one of the genes (RASSF1A) was absent in the majority of lung tumour cell lines analysed. Subsequently methylation of a CpG island in the promoter region of RASSF1A was demonstrated in a majority of small cell lung carcinomas and to a lesser extent in non-small cell lung carcinomas. To investigate the role of 3p TSGs in neural crest tumours, we (a) analysed phaeochromocytomas for 3p allele loss (n=41) and RASSF1A methylation (n=23) and (b) investigated 67 neuroblastomas for RASSF1A inactivation. 46% of phaeochromocytomas showed 3p allele loss (38.5% at 3p21.3). RASSF1A promoter region hypermethylation was found in 22% (5/23) of sporadic phaeochromocytomas and in 55% (37/67) of neuroblastomas analysed but RASSF1A mutations were not identified. In two neuroblastoma cell lines, methylation of RASSF1A correlated with loss of RASSF1A expression and RASSF1A expression was restored after treatment with the demethylating agent 5-azacytidine. As frequent methylation of the CASP8 gene has also been reported in neuroblastoma, we investigated whether RASSF1A and CASP8 methylation were independent or related events. CASP8 methylation was detected in 56% of neuroblastomas with RASSF1A methylation and 17% without RASSF1A methylation (P=0.0031). These results indicate that (a) RASSF1A inactivation by hypermethylation is a frequent event in neural crest tumorigenesis, particularly neuroblastoma, and that RASSF1A is a candidate 3p21.3 neuroblastoma TSG and (b) a subset of neuroblastomas may be characterized by a CpG island methylator phenotype.

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Acknowledgements

This work is supported in part by British Heart Foundation, Association for International Cancer Research, and Cancer Research Campaign. S Honorio is supported by Fundacao para a Ciencia e a Technologia. Drs Martinsson and Kogner supported by funds from the Swedish Cancer Society and Swedish Children's Cancer Foundation.

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Author notes

  1. Dewi Astuti and Angelo Agathanggelou: D Astuti and A Agathanggelou contributed equally to this paper

Authors and Affiliations

  1. Department of Paediatrics and Child Health, Section of Medical and Molecular Genetics, University of Birmingham, The Medical School, Edgbaston, Birmingham, B15 2TT, UK

    Dewi Astuti, Angelo Agathanggelou, Sofia Honorio, Ashraf Dallol, Eamonn R Maher & Farida Latif

  2. Department of Clinical Genetics, Gothenburg University, Sahlgrenska University Hospital/Ostra, S-416, Gothenburg, 85, Sweden

    Tommy Martinsson

  3. Department of Woman and Child Health, Childhood Cancer Research Unit, Karolinska Institute, Karolinska Hospital, S-171, Stockholm, 76, Sweden

    Per Kogner

  4. The Birmingham Children's Hospital, Steelhouse Lane, Birmingham, UK

    Carole Cummins

  5. Medizinische Universitätsklinik, Hugstetter Str. 55, Freiburg, D-79106, Germany

    Hartmut PH Neumann

  6. Department of Pediatrics, Kuopio University Hospital, Kuopio, FIN-70211, Finland

    Raimo Voutilainen

  7. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, Massachusetts, USA

    Patricia Dahia

  8. Clinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Center, and the Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA

    Charis Eng

  9. CRC Human Cancer Genetics Research Group, University of Cambridge, Cambridge, UK

    Charis Eng

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  1. Dewi Astuti
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Correspondence to Farida Latif.

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Astuti, D., Agathanggelou, A., Honorio, S. et al. RASSF1A promoter region CpG island hypermethylation in phaeochromocytomas and neuroblastoma tumours. Oncogene 20, 7573–7577 (2001). https://doi.org/10.1038/sj.onc.1204968

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