Identification of 5 novel genes methylated in breast and other epithelial cancers

Molecular Cancer

Research

Timothy Dobbins¹  Robyn L Ward¹  Stella Tommasi²  Gerd P Pfeifer²  Victoria K Hill³  Dean Gentle³  Eammon R Maher³  Farida Latif³  Ashraf Dallol³  Luke B Hesson⁴  Cheryl Lewis⁵  David Euhus⁵  John Minna⁶  Reinhard Dammann⁷  Temuujin Dansranjavin⁷  Ivan Bieche⁸  Sophie Vacher⁸ 

[1] Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, NSW2052, Australia;Beckman Research Institute, City of Hope, 1500 E Duarte Road, 91010, Duarte, CA, USA;Department of Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, Birmingham, UK;Department of Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, Birmingham, UK;Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, NSW2052, Australia;Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA;Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA;Institute for Genetics, Justus Liebig University Giessen, Heinrich-Buff-Ring 58-62, D-35392, Giessen, Germany;Oncogenetic Laboratory, INSERM U 735, Centre René Huguenin, Saint Cloud, France;

关键词: Breast Cancer;    Breast Cancer Cell Line;    Primary Breast Tumour;    Frequent Methylation;    Mammary Epithelial Cell Line;   

DOI  :  10.1186/1476-4598-9-51

 received in 2009-08-24, accepted in 2010-03-05,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundThere are several high throughput approaches to identify methylated genes in cancer. We utilized one such recently developed approach, MIRA (methylated-CpG island recovery assay) combined with CpG island arrays to identify novel genes that are epigenetically inactivated in breast cancer.ResultsUsing this approach we identified numerous CpG islands that demonstrated aberrant DNA methylation in breast cancer cell lines. Using a combination of COBRA and sequencing of bisulphite modified DNA, we confirmed 5 novel genes frequently methylated in breast tumours; EMILIN2, SALL1, DBC1, FBLN2 and CIDE-A. Methylation frequencies ranged from between 25% and 63% in primary breast tumours, whilst matched normal breast tissue DNA was either unmethylated or demonstrated a much lower frequency of methylation compared to malignant breast tissue DNA. Furthermore expression of the above 5 genes was shown to be restored following treatment with a demethylating agent in methylated breast cancer cell lines. We have expanded this analysis across three other common epithelial cancers (lung, colorectal, prostate). We demonstrate that the above genes show varying levels of methylation in these cancers. Lastly and most importantly methylation of EMILIN2 was associated with poorer clinical outcome in breast cancer and was strongly associated with estrogen receptor as well as progesterone receptor positive breast cancers.ConclusionThe combination of the MIRA assay with CpG island arrays is a very useful technique for identifying epigenetically inactivated genes in cancer genomes and can provide molecular markers for early cancer diagnosis, prognosis and epigenetic therapy.

【 授权许可】

Unknown   
© Hill et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.