Abstract
It has been postulated that imprinting aberrations are common in tumors. To understand the role of imprinting in cancer, we have characterized copy-number and methylation in over 280 cancer cell lines and confirm our observations in primary tumors. Imprinted differentially methylated regions (DMRs) regulate parent-of-origin monoallelic expression of neighboring transcripts in cis. Unlike single-copy CpG islands that may be prone to hypermethylation, imprinted DMRs can either loose or gain methylation during tumorigenesis. Here, we show that methylation profiles at imprinted DMRs often not represent genuine epigenetic changes but simply the accumulation of underlying copy-number aberrations (CNAs), which is independent of the genome methylation state inferred from cancer susceptible loci. Our results reveal that CNAs also influence allelic expression as loci with copy-number neutral loss-of-heterozygosity or amplifications may be expressed from the appropriate parental chromosomes, which is indicative of maintained imprinting, although not observed as a single expression foci by RNA FISH.
Highlights
It has been postulated that imprinting aberrations are common in tumors
We have performed an analysis to determine the association between copy-number aberrations (CNAs) and DNA methylation profiles for three cancer cell types originating in the lung, colon and breast which rank among the most frequent solid tumor types, as well as liver, which is a prevalent cause of cancer-associated deaths due to hepatitis B virus infections
In this study we focused on the 661 probes mapping to 37 imprinted differentially methylated regions (DMRs)
Summary
It has been postulated that imprinting aberrations are common in tumors. To understand the role of imprinting in cancer, we have characterized copy-number and methylation in over 280 cancer cell lines and confirm our observations in primary tumors. Genomic imprinting is the parent-of-origin specific monoallelic transcription, regulated in part by allelic difference in DNA methylation established in the male and female germline and maintained throughout somatic development[2]. Deregulated expression, which includes the reactivation of the normally silent allele (commonly referred to as loss-of-imprinting, LOI) or the silencing of the transcribed allele, has been implicated in childhood cancer associated with the classical imprinting disorder Beckwith–Wiedemann syndrome[4] In these cases gains of methylation at the paternally methylated H19 DMR or paternal uniparental disomy (copy-number neutral loss-of-heterozygosity, cnnLOH) result in over-expression of IGF2-miR483 and the concomitant silencing of H19-miR6755. Overall we observe that all four-tumor types show highly aberrant profiles, with a high proportion of aberrant imprinted DMR methylation patterns being associated with cancer-associated CNAs and not somatically acquired epigenetic defects
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