Interphase chromosomal abnormalities and mitotic missegregation of hypomethylated sequences in ICF syndrome cells

Gisselsson, David; Shao, Chunbo; Tuck‐Muller, Cathy M.; Sogorovic, Suzana; Pålsson, Eva; Smeets, Dominique; Ehrlich, Melanie

doi:10.1007/s00412-005-0343-7

Cited by 52 publications

(52 citation statements)

References 39 publications

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“…Abnormalities of the chromosome 1, 9, and 16 centromeres (containing a satellite DNA) and qh regions (containing satellite 2 and 3 sequences) are also common in ICF syndrome (28), a disorder with immunodeficiency, centromere region instability, and abnormal facies. Breakage and rejoining of homologous satellite sequences appear to mediate these centromeric alterations (29). Similar centromeric instability has been hypothesized to underlie many of the whole-arm translocations observed in solid tumors (27).…”

Section: Discussionmentioning

confidence: 82%

A t(1;19)(q10;p10) Mediates the Combined Deletions of 1p and 19q and Predicts a Better Prognosis of Patients with Oligodendroglioma

et al. 2006

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Combined deletion of chromosomes 1p and 19q is associated with improved prognosis and responsiveness to therapy in patients with anaplastic oligodendroglioma. The deletions usually involve whole chromosome arms, suggesting a t(1;19)(q10;p10). Using stem cell medium, we cultured a few tumors. Paraffin-embedded tissue was obtained from 21 Mayo Clinic patients and 98 patients enrolled in 2 North Central Cancer Treatment Group (NCCTG) low-grade glioma trials. Interphase fusion of CEP1 and 19p12 probes detected the t(1;19). 1p/19q deletions were evaluated by fluorescence in situ hybridization. Upon culture, one oligodendroglioma contained an unbalanced 45,XX,t(1;19)(q10;p10). CEP1/19p12 fusion was observed in all metaphases and 74% of interphase nuclei. Among Mayo Clinic oligodendrogliomas, the prevalence of fusion was 81%. Among NCCTG patients, CEP1/19p12 fusion prevalence was 55%, 47%, and 0% among the oligodendrogliomas, mixed oligoastrocytomas, and astrocytomas, respectively. Ninety-one percent of NCCTG gliomas with 1p/19q deletion and 12% without 1p/19q deletion had CEP1/ 19p12 fusion (P < 0.001, C 2 test). The median overall survival (OS) for all patients was 8.1 years without fusion and 11.9 years with fusion (P = 0.003). The median OS for patients with low-grade oligodendroglioma was 9.1 years without fusion and 13.0 years with fusion (P = 0.01). Similar significant median OS differences were observed for patients with combined 1p/19q deletions. The absence of alterations was associated with a significantly shorter OS for patients who received higher doses of radiotherapy. Our results strongly suggest that a t(1;19)(q10;p10) mediates the combined 1p/19q deletion in human gliomas. Like combined 1p/19q deletion, the 1;19 translocation is associated with superior OS and progression-free survival in low-grade glioma patients.

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Section: Discussionmentioning

confidence: 82%

A t(1;19)(q10;p10) Mediates the Combined Deletions of 1p and 19q and Predicts a Better Prognosis of Patients with Oligodendroglioma

et al. 2006

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“…Informed consent was given by all patients or unlinked samples were used. The LCLs were described previously (45)(46)(47) or available from the Coriell Institute (Camden, NJ; GM17900, AG14836, AG14953, and AG15022). Control somatic tissues were autopsy specimens of trauma victims (individuals A, B, and C, all males of 56, 19, and 68 years, respectively).…”

Section: Patients and Dna Samplesmentioning

confidence: 99%

Both Hypomethylation and Hypermethylation in a 0.2-kb Region of a DNA Repeat in Cancer

Nishiyama

Lacey

et al. 2005

Molecular Cancer Research

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NBL2 is a tandem 1.4-kb DNA repeat, whose hypomethylation in hepatocellular carcinomas was shown previously to be an independent predictor of disease progression. Here, we examined methylation of all cytosine residues in a 0.2-kb subregion of NBL2 in ovarian carcinomas, Wilms' tumors, and diverse control tissues by hairpin-bisulfite PCR. This new genomic sequencing method detects 5-methylcytosine on covalently linked complementary strands of a DNA fragment. All DNA clones from normal somatic tissues displayed symmetrical methylation at seven CpG positions and no methylation or only hemimethylation at two others. Unexpectedly, 56% of cancer DNA clones had decreased methylation at some normally methylated CpG sites as well as increased methylation at one or both of the normally unmethylated sites. All 146 DNA clones from 10 cancers could be distinguished from all 91 somatic control clones by assessing methylation changes at three of these CpG sites. The special involvement of DNA methyltransferase 3B in NBL2 methylation was indicated by analysis of cells from immunodeficiency, centromeric region instability, and facial anomalies syndrome patients who have mutations in the gene encoding DNA methyltransferase 3B. Blot hybridization of 33 cancer DNAs digested with CpG methylation-sensitive enzymes confirmed that NBL2 arrays are unusually susceptible to cancer-linked hypermethylation and hypomethylation, consistent with our novel genomic sequencing findings. The combined Southern blot and genomic sequencing data indicate that some of the cancer-linked alterations in CpG methylation are occurring with considerable sequence specificity. NBL2 is an attractive candidate for an epigenetic cancer marker and for elucidating the nature of epigenetic changes in cancer. (Mol Cancer Res 2005;3(11):617 -26)

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“…Mutations in the DNA methyltransferase DNMT3B in immunodeficiency centromeric instability facial anomalies (ICF) syndrome patients (14) lead to loss of DNA methylation at specific genomic sites (15,16). Prominent sites of hypomethylation in ICF are satellite DNAs in the juxtacentromeric heterochromatin at chromosome regions 1qh, 16qh, and 9qh, and aberrant association of the satellite II-rich 1qh and 16qh regions has been seen in nuclei of ICF cells (17). Sites on the female inactive X chromosome (Xi), especially CpG islands, are also hypomethylated in ICF syndrome.…”

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confidence: 99%

Chromosome territory reorganization in a human disease with altered DNA methylation

Matarazzo

Boyle

D’Esposito

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Chromosome territory (CT) organization and chromatin condensation have been linked to gene expression. Although individual genes can be transcribed from inside CTs, some regions that have constitutively high expression or are coordinately activated loop out from CTs and decondense. The relationship between epigenetic marks, such as DNA methylation, and higher-order chromatin structures is largely unexplored. DNMT3B mutations in immunodeficiency centromeric instability facial anomalies (ICF) syndrome result in loss of DNA methylation at particular sites, including CpG islands on the inactive X chromosome (Xi). This allows the specific effects of DNA methylation on CTs to be examined. Using fluorescence in situ hybridization, we reveal a differential organization of the human pseudoautosomal region (PAR)2 between the CTs of the X and Y in normal males and the active X (Xa) and the Xi in females. There is also a more condensed chromatin structure on Xi compared with Xa in this region. PAR2 genes are relocalized toward the outside of the Y and Xi CTs in ICF, and on the Xi, we show that this can extend to genes distant from the site of DNA hypomethylation itself. This reorganization is not simply a reflection of the transcriptional activation of the relocalized genes. This report of altered CT organization in a human genetic disease illustrates that DNA hypomethylation at restricted sites in the genome can lead to more extensive changes in nuclear organization away from the original site of epigenetic change. X inactivation ͉ Y chromosomeT o fully understand the orchestration of gene expression, it is necessary to understand how chromatin is spatially organized within the cell nucleus. In particular, the position of a gene with respect to its chromosome territory (CT) and the chromatin condensation of its genomic region have been linked to gene activation and repression (1). Although individual genes can be transcribed from inside of CTs (2), some regions that have constitutively high gene expression (3,4) or are subject to coordinate gene activation during development (5, 6) or differentiation (7) or in response to physiological stimuli (8) locate at the edge or outside of their CT. This level of nuclear reorganization is often accompanied by a visible level of chromatin decondensation (5, 6, 9). The precise function, if any, of repositioning toward the outside of CTs remains unclear (1), but it may allow for genes to access a nuclear environment enriched in the components of the transcription (10) and/or mRNAprocessing machinery (4,11,12) and so enhance the efficiency of transcription.The interplay between this level of higher-order chromatin organization and epigenetic mechanisms that act at primary levels of chromatin structure, such as DNA methylation, is a little-explored area. In plants, changes in the architecture of CTs can be induced by treatment with inhibitors of DNA methylation (13). However, the genome-wide demethylation that follows 5-azacytidine treatment or genetic deficiency in DNA methyltransferase...

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Interphase chromosomal abnormalities and mitotic missegregation of hypomethylated sequences in ICF syndrome cells

Cited by 52 publications

References 39 publications

A t(1;19)(q10;p10) Mediates the Combined Deletions of 1p and 19q and Predicts a Better Prognosis of Patients with Oligodendroglioma

A t(1;19)(q10;p10) Mediates the Combined Deletions of 1p and 19q and Predicts a Better Prognosis of Patients with Oligodendroglioma

Both Hypomethylation and Hypermethylation in a 0.2-kb Region of a DNA Repeat in Cancer

Chromosome territory reorganization in a human disease with altered DNA methylation

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