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

Victoria K. Hill, Luke B. Hesson, Temuujin Dansranjavin, Ashraf Dallol, Ivan Bieche, Sophie Vacher, Stella Tommasi, Timothy Dobbins, Dean Gentle, David Euhus, Cheryl Lewis, Reinhard Dammann, Robyn L. Ward, John Minna, Eammon R. Maher, Gerd P. Pfeifer, Farida Latif

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Abstract

Background: There 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.Results: Using 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.Conclusion: The 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.

Original languageEnglish (US)
Article number51
JournalMolecular Cancer
Volume9
DOIs
StatePublished - Mar 5 2010

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ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

Cite this

Hill, V. K., Hesson, L. B., Dansranjavin, T., Dallol, A., Bieche, I., Vacher, S., Tommasi, S., Dobbins, T., Gentle, D., Euhus, D., Lewis, C., Dammann, R., Ward, R. L., Minna, J., Maher, E. R., Pfeifer, G. P., & Latif, F. (2010). Identification of 5 novel genes methylated in breast and other epithelial cancers. Molecular Cancer, 9, [51]. https://doi.org/10.1186/1476-4598-9-51