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Nat Commun. 2017 Sep 7;8(1):467. doi: 10.1038/s41467-017-00639-9.

Copy number rather than epigenetic alterations are the major dictator of imprinted methylation in tumors.

Author information

1
Imprinting and Cancer group, Cancer Epigenetic and Biology Program (PEBC), Institut d'Investigació Biomedica de Bellvitge (IDIBELL), Avinguda Granvia, L'Hospitalet de Llobregat, 08907, Barcelona, Spain.
2
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
3
Universitat Pompeu Fabra (UPF), Barcelona, Spain Universitat Pompeu Fabra (UPF), 08003, Barcelona, Spain.
4
Cancer Epigenetics group, Cancer Epigenetic and Biology Program (PEBC), Institut d'Investigació Biomedica de Bellvitge (IDIBELL), Avinguda Granvia, L'Hospitalet de Llobregat, 08907, Barcelona, Spain.
5
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028, Barcelona, Spain.
6
Genetics Laboratory, UDIAT- Diagnostic Centre, Corporació Sanitària Parc Taulí, 08208, Sabadell, Spain.
7
Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, 08907, Catalonia, Spain.
8
Institucio Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Spain.
9
Imprinting and Cancer group, Cancer Epigenetic and Biology Program (PEBC), Institut d'Investigació Biomedica de Bellvitge (IDIBELL), Avinguda Granvia, L'Hospitalet de Llobregat, 08907, Barcelona, Spain. dmonk@idibell.cat.

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.Altered genomic imprinting is frequently reported in cancer. Here, the authors analyze copy number and methylation in cancer cell lines and primary tumors to show that imprinted methylation profiles represent the accumulation of copy number alteration, rather than epigenetic alterations.

PMID:
28883545
PMCID:
PMC5589900
DOI:
10.1038/s41467-017-00639-9
[Indexed for MEDLINE]
Free PMC Article

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