Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer.

TitleSomatically acquired hypomethylation of IGF2 in breast and colorectal cancer.
Publication TypeJournal Article
Year of Publication2008
AuthorsIto, Y, Koessler, T, Ibrahim, AEK, Rai, S, Vowler, SL, Abu-Amero, S, Silva, A-L, Maia, A-T, Huddleston, JE, Uribe-Lewis, S, Woodfine, K, Jagodic, M, Nativio, R, Dunning, A, Moore, G, Klenova, E, Bingham, S, Pharoah, PDP, Brenton, JD, Beck, S, Sandhu, MS, Murrell, A
JournalHum Mol Genet
Volume17
Issue17
Pagination2633-43
Date Published2008 Sep 01
ISSN1460-2083
KeywordsBreast Neoplasms, Case-Control Studies, Colorectal Neoplasms, DNA Methylation, Female, Gene Expression Regulation, Neoplastic, Genomic Imprinting, Humans, Insulin-Like Growth Factor II
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.

DOI10.1093/hmg/ddn163
Alternate JournalHum. Mol. Genet.
Citation Key10.1093/hmg/ddn163
PubMed ID18541649
PubMed Central IDPMC2515372
Grant ListG0401088 / / Medical Research Council / United Kingdom
/ / British Heart Foundation / United Kingdom
/ / Wellcome Trust / United Kingdom
/ / Cancer Research UK / United Kingdom