Preferential induction of chromosome 1 multibranched figures and whole-arm deletions in a human pro-B cell line treated with 5-azacytidine or 5-azadeoxycytidine

Abstract

5-Azacytidine (azaCR) causes genomic demethylation and decondensation of juxtacentromeric heterochromatin in chromosomes 1, 9, and 16. We determined the karyotypes of a pro-B cell line (FLEB14) treated with azaCR or its deoxynucleoside analog (azaCdR). About 80% of the induced rearrangements were in chromosome 1, and almost 90% of these involved its pericentromeric region. Multibranched figures with up to seven chromosome 1 arms, as well as whole-arm deletions of this chromosome, were the predominant anomalies, often with one normal homolog of chromosome 1 present. Isochromosomes 1 and fusions in the pericentromeric regions of chromosomes 1 and 16 or chromosomes 1 and 9 were also seen. The overlap of the spectrum of chromosomal rearrangements in azaCR- or azaCdR-treated FLEB14 cells and in mitogen-stimulated lymphocytes from patients with a rare genetic disease (ICF) associated with localized DNA hypomethylation supports the hypothesis that the DNA demethyiating activity of azaCR is essential for the induction of these pericentromeric rearrangements. These studies may help elucidate the overrepresentation of chromosome 1 pericentromeric rearrangements in many types of cancer cells.

DNA hypomethylation is prevalent even in low-grade breast cancers

“…10,11,[15][16][17] Studies of ICF lymphoid cells and normal cells treated with DNA methylation inhibitors suggest that DNA hypomethylation can favor pericentromeric rearrangements, including the formation of unstable multiradial chromosomes that may give rise to stable, unbalanced cancer-like DNA rearrangements. 15,16,18,19 This is consistent with a comparative genomic hybridization study showing a significant association between 1qh gain and Chr1 Sat2 hypomethylation in hepatocellular carcinomas. 20 Because pericentromeric rearrangements of Chr1 and Chr16 are overrepresented in diverse cancers and often lead to 1qh gain and 16qh loss, 21 they could participate in tumorigenesis or tumor progression.…”

“…20 Moreover, in normal lymphoid cells, the DNA methylation inhibitors 5-azacytidine or 5-azadeoxycytidine specifically induce pericentromeric rearrangements especially in the longest region of Sat2, which is at 1qh. 18 Comparison of global DNA hypomethylation, tumor grade, and axillary lymph node involvement in breast adenocarcinomas. Global DNA methylation levels for breast cancers were determined by HPLC of DNA digested to mononucleosides.…”

Quantitative analysis of associations between DNA hypermethylation, hypomethylation, and DNMT RNA levels in ovarian tumors

“…Cancer-linked DNA hypomethylation may have an important role in increasing cancer-predisposing chromosome rearrangements (Kokalj-Vokac et al, 1993;Hernandez et al, 1997;Eden et al, 2003), although the frequency of this hypomethylation in satellite DNA is much greater than that of satellite DNA rearrangements and is not related to aneuploidy . Satellite DNA hypomethylation might have an indirect effect on gene expression that favors tumorigenesis, for example, by influencing the sequestration of DNA-binding proteins in highly repeated DNA regions.…”

DNA methylation, chromatin inheritance, and cancer

“…Increased genomic instability seen in the hypomethylated genome of embryonic stem cells lacking Dnmt1 provides evidence for a genome protective capacity for methylation (Chen et al, 1998). Furthermore, the pericentromeric areas of many chromosomes are particularly heavily methylated in the constitutive heterochromatin and loss of this pericentromeric methylation both in a genetic disorder, immunode®ciency-centromeric instability-facial anomalies (ICF) syndrome, and through treatment with the demethylating agent 5-aza-2'-deoxycytidine (5aza-dC) is associated with increased chromosome translocations (Ji et al, 1997;Hernandez et al, 1997;Tuck-Muller et al, 2000). In ICF syndrome, patients harbor mutations in DNMT3B (Keshet et al, 1986;Xu et al, 1999;Hansen et al, 1999;Okano et al, 1999).…”