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  • Original Paper
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CpG island promoter hypermethylation of a novel Ras-effector gene RASSF2A is an early event in colon carcinogenesis and correlates inversely with K-ras mutations

Oncogene volume 24, pages 3987–3994 (2005)Cite this article

Abstract

We report in silico identification and characterisation of a novel member of the ras association domain family 1 (RASSF1)/NORE1 family, namely, RASSF2, located at chromosomal region 20p13. It has three isoforms, all contain a ras association domain in the C-terminus. The longest isoform RASSF2A contains a 5′ CpG island. RASSF2A was cloned from a brain cDNA library and directly sequenced, confirming the genomic gene structure. In previous reports, we and others have demonstrated that RASSF1A is epigenetically inactivated in a variety of cancers, including sporadic colorectal cancer (CRC). In the present report, we analysed the methylation status of RASSF2A promoter region CpG island in sporadic CRC and compared it to K-ras mutation status. RASSF2A promoter region CpG island was hypermethylated in a majority of colorectal tumour cell lines (89%) and in primary colorectal tumours (70%), while DNA from matched normal mucosa was found to be unmethylated (tumour-specific methylation). RASSF2A expression was reactivated in methylated tumour cell lines after treatment with 5-aza 2-deoxycytidine. RASSF2A methylation is an early event, detectable in 7/8 colon adenomas. Furthermore, 75% of colorectal tumours with RASSF2A methylation had no K-ras mutations (codons, 12 and 13) (P=0.048), Fisher's exact test). Our data demonstrate that RASSF2A is frequently inactivated in CRCs by CpG island promoter hypermethylation, and that epigenetic (RASSF2A) and genetic (K-ras) changes are mutually exclusive and provide alternative pathways for affecting Ras signalling.

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Authors and Affiliations

  1. Section of Medical and Molecular Genetics, Division of Reproductive and Child Health, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    Luke B Hesson, Robin Wilson, Eamonn R Maher & Farida Latif

  2. Department of Surgery, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    Dion Morton, Clare Adams & Mike Walker

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  1. Luke B Hesson
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Correspondence to Farida Latif.

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Hesson, L., Wilson, R., Morton, D. et al. CpG island promoter hypermethylation of a novel Ras-effector gene RASSF2A is an early event in colon carcinogenesis and correlates inversely with K-ras mutations. Oncogene 24, 3987–3994 (2005). https://doi.org/10.1038/sj.onc.1208566

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