title: Variable maternal methylation overlapping the nc886/vtRNA2-1 locus is locked between hypermethylated repeats and is frequently altered in cancer.
abstract: Cancer is as much an epigenetic disease as a genetic one; however, the interplay between these two processes is unclear. Recently, it has been shown that a large proportion of DNA methylation variability can be explained by allele-specific methylation (ASM), either at classical imprinted loci or those regulated by underlying genetic variants. During a recent screen for imprinted differentially methylated regions, we identified the genomic interval overlapping the non-coding nc886 RNA (previously known as vtRNA2-1) as an atypical ASM that shows variable levels of methylation, predominantly on the maternal allele in many tissues. Here we show that the nc886 interval is the first example of a polymorphic imprinted DMR in humans. Further analysis of the region suggests that the interval subjected to ASM is approximately 2 kb in size and somatically acquired. An in depth analysis of this region in primary cancer samples with matching normal adjacent tissue from the Cancer Genome Atlas revealed that aberrant methylation in bladder, breast, colon and lung tumors occurred in approximately 27% of cases. Hypermethylation occurred more frequently than hypomethylation. Using additional normal-tumor paired samples we show that on rare occasions the aberrant methylation profile is due to loss-of-heterozygosity. This work therefore suggests that the nc886 locus is subject to variable allelic methylation that undergoes cancer-associated epigenetic changes in solid tumors.
authors.affiliation: Imprinting and Cancer Group; Cancer Epigenetic and Biology Program; Institut d'Investigació Biomedica de Bellvitge; Hospital Duran i Reynals; Barcelona, Spain.
authors.forename: Valeria
authors.initials: V
authors.lastname: Romanelli
authors.affiliation: Department of Maternal-Fetal Biology and Department of Molecular Endocrinology; National Research Institute for Child Health and Development; Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakabayashi
authors.affiliation: Cancer Epigenetics Group; Cancer Epigenetic and Biology Program; Institut d'Investigació Biomedica de Bellvitge; Hospital Duran i Reynals; Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Vizoso
authors.affiliation: Cancer Epigenetics Group; Cancer Epigenetic and Biology Program; Institut d'Investigació Biomedica de Bellvitge; Hospital Duran i Reynals; Barcelona, Spain.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Moran
authors.affiliation: Servicio de Neonatología; Hospital Sant Joan de Déu; Fundació Sant Joan de Déu; Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Iglesias-Platas
authors.affiliation: Department of Maternal-Fetal Biology and Department of Molecular Endocrinology; National Research Institute for Child Health and Development; Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Sugahara
authors.affiliation: Fundación IVI; Instituto Universitario IVI; Universidad de Valencia; INCLIVA; Valencia, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Simón
authors.affiliation: Department of Maternal-Fetal Biology and Department of Molecular Endocrinology; National Research Institute for Child Health and Development; Tokyo, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Hata
authors.affiliation: Cancer Epigenetics Group; Cancer Epigenetic and Biology Program; Institut d'Investigació Biomedica de Bellvitge; Hospital Duran i Reynals; Barcelona, Spain; Department of Physiological Sciences II; School of Medicine; University of Barcelona; Barcelona, Spain; Institucio Catalana de Recerca i Estudis Avançats (ICREA); Barcelona, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Imprinting and Cancer Group; Cancer Epigenetic and Biology Program; Institut d'Investigació Biomedica de Bellvitge; Hospital Duran i Reynals; Barcelona, Spain.
authors.forename: Franck
authors.initials: F
authors.lastname: Court
authors.affiliation: Imprinting and Cancer Group; Cancer Epigenetic and Biology Program; Institut d'Investigació Biomedica de Bellvitge; Hospital Duran i Reynals; Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Monk
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D056426:Genetic Loci; D018392:Genomic Imprinting; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D022661:RNA, Untranslated / Q000235:genetics*; D020080:Tandem Repeat Sequences; D001749:Urinary Bladder Neoplasms / Q000235:genetics; D055815:Young Adult
chemical_list: D022661:RNA, Untranslated
keywords: DNA methylation; imprinting; miRNAs; nc886; vault RNAs; vtRNA2-1