Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer

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.

Intragenic ATM Methylation in Peripheral Blood DNA as a Biomarker of Breast Cancer Risk

“…Previous studies investigating peripheral blood methylation variability in relation to cancer risk have focused mainly on rare epimutations or genome-wide methylation levels (25,39). Only a few studies have investigated gene-specific DMRs and all of these have been carried out in small retrospective studies or used nonquantitative methods (26)(27)(28)(29).…”

“…Previous reports of WBC DNA methylation and cancer risk include studies of global DNA methylation levels in repeat regions across the genome (e.g., LINE1, Alu) or 5-mC content in genomic DNA (16)(17)(18)(19)(20); studies of genespecific DNA methylation levels in candidate genes (14,(21)(22)(23)(24)(25)(26)(27)(28)(29), and genome-wide DNA methylation microarray studies (15,(30)(31)(32). Although these studies provide enticing findings, most included relatively small study populations and/or used samples collected after diagnosis, thus raising concerns about reverse causality and the potential confounding influences of active disease or treatment on DNA methylation in blood (25). Most research on DNA methylation in cancer has focused on gene promoter CpG islands (CGI).…”

Association of genomic instability, and the methylation status of imprinted genes and mismatch-repair genes, with neural tube defects

“…One study indicates that IGF2 DMR0 hypo-methylation occurs as an acquired tissue-specific somatic event, rather than a constitutive innate epimutation in tumor tissues. 40 It should be important to further explore the mechanisms that regulate the imprinting of the IGF2/H19 in the NTDs.…”

Recurrent epimutations activate gene body promoters in primary glioblastoma

“…The CG genes SOHLH2, SSX2, SSX4B, SSX8, SSX9, and PAGE5 are also recurrently hypomethylated in GBM (Wu et al 2010). Promoter hypomethylation is associated with transcriptional activation at other single-copy genes, for example IGF2/H19 (associated with loss of imprinting) (Cui et al 2002;Ito et al 2008), CA9 (Cho et al 2001), and SRPX2 (Oster et al 2013). As ;98% of 59 promoter CpG islands (CGIs) are unmethylated in brain (Maunakea et al 2010), they are more frequently targets of aberrant hypermethylation in cancer (Costello et al 2000;Zardo et al 2002).…”