Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer

Yoko Ito, Thibaud Koessler, Ashraf E K Ibrahim, Sushma Rai, Sarah L Vowler, Sayeda Abu-Amero, Ana-Luisa Silva, Ana-Teresa Maia, Joanna E Huddleston, Santiago Uribe-Lewis, Kathryn Woodfine, Maja Jagodic, Raffaella Nativio, Alison Dunning, Gudrun Moore, Elena Klenova, Sheila Bingham, Paul D P Pharoah, James D Brenton, Stephan BeckManjinder S Sandhu, Adele Murrell

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106 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)2633-2643
Number of pages11
JournalHuman Molecular Genetics
Volume17
Issue number17
Early online date9 Jun 2008
DOIs
Publication statusPublished - 1 Sep 2008

Keywords

  • Breast Neoplasms
  • Case-Control Studies
  • Colorectal Neoplasms
  • DNA Methylation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genomic Imprinting
  • Humans
  • Insulin-Like Growth Factor II

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    Ito, Y., Koessler, T., Ibrahim, A. E. K., Rai, S., Vowler, S. L., Abu-Amero, S., Silva, A-L., Maia, A-T., Huddleston, J. E., Uribe-Lewis, S., Woodfine, K., Jagodic, M., Nativio, R., Dunning, A., Moore, G., Klenova, E., Bingham, S., Pharoah, P. D. P., Brenton, J. D., ... Murrell, A. (2008). Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer. Human Molecular Genetics, 17(17), 2633-2643. https://doi.org/10.1093/hmg/ddn163