When, where and how the bridge breaks: anaphase bridge breakage plays a crucial role in gene amplification and HSR generation

Shimizu, Noriaki; Shingaki, Kenta; Kaneko-Sasaguri, Yukiko; Hashizume, Toshihiko; Kanda, Teru

doi:10.1016/j.yexcr.2004.09.001

Cited by 144 publications

(155 citation statements)

References 45 publications

Supporting

Mentioning

144

Contrasting

Unclassified

Order By: Relevance

“…1,3,4 According to the breakage-fusion-bridge model of amplification, the initiating event in HSR formation is double chromatid breakage at a fragile site or telomere erosion, 2,26,27 fused sister chromatids and breaking of the anaphase bridges. 28 Breakage-fusion-bridge cycles could then result in inverted amplified structures, 29 and the mutated sister chromatids are distributed to the daughter cells giving rise to intra-tumor heterogeneity. 30 Gene amplifications are also acquired by selection and unequal segregation of circular extrachromosomal chromatin (dmin and episomes).…”

Section: Discussionmentioning

confidence: 99%

New pattern of EGFR amplification in glioblastoma and the relationship of gene copy number with gene expression profile

et al. 2010

View full text Add to dashboard Cite

Gene amplification is a process that is characterized by an increase in the copy number of a restricted region in a chromosome arm, and is frequently associated with an overexpression of the corresponding amplified gene. Amplified DNA can be organized either as extrachromosomal elements, repeated units at a single locus or scattered throughout the genome. The amplification of the gene for epidermal growth factor receptor (EGFR) is a common finding in glioblastomas and the amplified gene copies appears as double minutes. The aim of this study was to investigate the different patterns of EGFR amplification in 40 cases of glioblastoma using FISH analysis in metaphases and paraffin sections, and to investigate the relationship of gene copy number with gene expression profile. The analysis of copy number alterations of EGFR was validated by quantitative PCR and SNP microarrays. We observed that in 42% of the cases, the type of amplification of EGFR was as double minute chromosomes. In addition, we detected another type of amplification, with extra copies of EGFR inserted in different loci of chromosome 7, present in 28% of cases. In this form of amplification, the number of copies is small, and the percentage of cells with EGFR amplification is rarely more than 15%. This model of amplification could correspond to a variant of the insertion mechanism, or a consequence of a process of duplication. Our results suggest that this mechanism could represent an early stage of amplification in glioblastomas. Overall, we found a close correlation between EGFR gene copy-number alterations and the level of EGFR protein expression. However, all cases with a high level of mRNA exhibited strong expression for the EGFR protein, and most cases with a low level of mRNA showed no overexpression of EGFR protein.

show abstract

Section: Discussionmentioning

confidence: 99%

New pattern of EGFR amplification in glioblastoma and the relationship of gene copy number with gene expression profile

et al. 2010

View full text Add to dashboard Cite

show abstract

“…1-5) [3][4][5][6][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] . This method is now also used to measure NPBs, a biomarker of dicentric chromosomes resulting from telomere end-fusions or DNA misrepair, and to measure NBUDs, a biomarker of gene amplification [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] . The significance of these developments and the concept of the CBMN assay as a ''cytome'' assay of chromosomal instability are explained in the following sections.…”

Section: Introductionmentioning

confidence: 99%

“…The formation of anaphase bridges and NPBs has been observed in models of rodent and human intestinal cancer in vivo and shown to correlate with telomere length, indicating that NPB formation may also be used as a surrogate measure of critically short telomeres 25 . Real-time in vitro studies showed that anaphase bridges may be broken in more than one region during late anaphase, leading to the formation of acentric chromosome fragments and eventually MNi 26,27 . Therefore, some MNi may also originate from broken anaphase bridges although whether this actually happens in cytokinesisblocked cells remains unclear.…”

Section: Introductionmentioning

confidence: 99%

“…This process has been observed in cultures grown under strong selective conditions that induce gene amplification as well as under moderate folic acid deficiency [27][28][29][30][31][32][33][34][35][36][37] . Shimizu et al 31,32 showed, using in vitro experiments with mammalian cells, that amplified DNA is selectively localized to specific sites at the periphery of the nucleus and eliminated via nuclear budding to form MNi during S phase of mitosis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cytokinesis-block micronucleus cytome assay

2007

View full text Add to dashboard Cite

“…In our study, the marked presence of MNi and NBUDs without any stimulus demonstrates evident traces of mitotic errors and reinforces the CIN phenotype in both cell lines evaluated. The MNi are the result of lagging or broken chromosomes (double strand breaks), chromatid cohesion defects, telomere fusions or fragmentation of anaphase bridges (NBUDs) (Shimizu et al 2005;Fenech 2007). Although we did not find differences in MNi quantity between the cell lines, we found that UW473 showed significantly more NPBs and BUDs than UW402 cells, important biomarkers of a chromosomally instable phenotype (Gisselsson et al 2000;Gisselsson 2008).…”

Section: Discussionmentioning

confidence: 99%

Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

et al. 2013

View full text Add to dashboard Cite

Chromosomal heterogeneity is a hallmark of most tumors and it can drive critical events as growth advantages, survival advantages, progression and karyotypic evolution. Medulloblastoma (MB) is the most common malignant central nervous system tumor in children. This work attempted to investigate chromosomal heterogeneity and instability profiles of two MB pediatric cell lines and their relationship with cell phenotype. We performed GTG-banding and cytokinesis-block micronucleus cytome assays, as well as morphological characterization, cell population doubling time, colony-forming efficiency, and chemo-sensitivity assays in two pediatric MB cell lines (UW402 and UW473). Both MB cells showed a high chromosomal heterogeneity. UW473 cells showed *2 fold higher both clonal-and non-clonal chromosomal alterations than UW402 cells. Besides, UW473 showed two clonal-groups well-differentiated by ploidy level (\2n[and\4n[) and also presented a significantly higher number of chromosomal instability biomarkers. These results were associated with high morphological heterogeneity and survival advantages for UW473 and proliferation advantages for UW402 cells. Moreover, UW473 was significantly more sensitive to methotrexate, temozolomide and cisplatin while UW402 cells were more sensitive to doxorubicin. These data suggest that distinct different degrees of karyotypic heterogeneity and instability may affect neoplasic phenotype of MB cells. These findings bring new insights into cell and tumor biology.

show abstract

When, where and how the bridge breaks: anaphase bridge breakage plays a crucial role in gene amplification and HSR generation

Cited by 144 publications

References 45 publications

New pattern of EGFR amplification in glioblastoma and the relationship of gene copy number with gene expression profile

New pattern of EGFR amplification in glioblastoma and the relationship of gene copy number with gene expression profile

Cytokinesis-block micronucleus cytome assay

Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

Contact Info

Product

Resources

About