Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer |
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Authors: | Ito Yoko Koessler Thibaud Ibrahim Ashraf E K Rai Sushma Vowler Sarah L Abu-Amero Sayeda Silva Ana-Luisa Maia Ana-Teresa Huddleston Joanna E Uribe-Lewis Santiago Woodfine Kathryn Jagodic Maja Nativio Raffaella Dunning Alison Moore Gudrun Klenova Elena Bingham Sheila Pharoah Paul D P Brenton James D Beck Stephan Sandhu Manjinder S Murrell Adele |
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Institution: | Department of Oncology, University of Cambridge, CRUK Cambridge Research Institute, Li Ka- Shing Centre, Robinson Way, Cambridge CB2 0RE, UK. |
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Abstract: | 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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