Human Molecular Genetics Advance Access originally published online on June 9, 2008
Human Molecular Genetics 2008 17(17):2633-2643; doi:10.1093/hmg/ddn163
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Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer
1 Department of Oncology, University of Cambridge, CRUK Cambridge Research Institute, Li Ka- Shing Centre, Robinson Way, Cambridge CB2 0RE, UK 2 Strangeways Research Laboratory, Cancer Research UK Department of Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, UK 3 CRUK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK 4 Department of Biological Sciences, University of Essex, Colchester CQ4 3SQ, Essex, UK 5 Department of Clinical & Molecular Genetics, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK 6 Medical Research Council Dunn Human Nutrition Unit, University of Cambridge, CB2 0XY 7 UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street, London, WC1E 6BT, UK 8 MRC Centre for Nutrition in Cancer Epidemiology Prevention and Survival, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
* To whom correspondence should be addressed. Tel +44 01223 404520. Email: amm207{at}cam.ac.uk
Received April 9, 2008; Accepted May 23, 2008
The imprinted insulin-like growth factor 2 (IGF2) gene is expressed predominantly from the paternal allele. Loss of imprinting (LOI) associated with hypomethylation at the promoter proximal sequence (DMR0) of the IGF2 gene was proposed as a predisposing constitutive risk biomarker for colorectal cancer. We used pyrosequencing to assess whether IGF2 DMR0 methylation is either present constitutively prior to cancer or whether it is acquired tissue-specifically after the onset of cancer. DNA samples from tumour tissues and matched non-tumour tissues from 22 breast and 42 colorectal cancer patients as well as peripheral blood samples obtained from colorectal cancer patients [SEARCH (n=case 192, controls 96)], breast cancer patients [ABC (n=case 364, controls 96)] and the European Prospective Investigation of Cancer [EPIC-Norfolk (n=breast 228, colorectal 225, controls 895)] were analysed. The EPIC samples were collected 2–5 years prior to diagnosis of breast or colorectal cancer. IGF2 DMR0 methylation levels in tumours were lower than matched non-tumour tissue. Hypomethylation of DMR0 was detected in breast (33%) and colorectal (80%) tumour tissues with a higher frequency than LOI indicating that methylation levels are a better indicator of cancer than LOI. In the EPIC population, the prevalence of IGF2 DMR0 hypomethylation was 9.5% and this correlated with increased age not cancer risk. Thus, IGF2 DMR0 hypomethylation occurs as an acquired tissue-specific somatic event rather than a constitutive innate epimutation. These results indicate that IGF2 DMR0 hypomethylation has diagnostic potential for colon cancer rather than value as a surrogate biomarker for constitutive LOI.
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