Human Molecular Genetics Advance Access published online on June 9, 2008
Human Molecular Genetics, 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 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 WC1 N 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
* Corresponding author amm207{at}cam.ac.uk Tel 01223 404520
Received April 9, 2008; Revised May 21, 2008; Accepted May 23, 2008
The imprinted Insulin-like growth factor 2 gene (IGF2) 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 two to five 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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