Expression of Fragile Sites Triggers Intrachromosomal Mammalian Gene Amplification and Sets Boundaries to Early Amplicons

Coquelle, Arnaud; Pipiras, Eva; Toledo, Franck; Buttin, Gérard; Debatisse, Michèlle

doi:10.1016/s0092-8674(00)80201-9

Cited by 365 publications

(313 citation statements)

References 60 publications

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“…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.…”

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

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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.

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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

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“…Gene amplification is proposed to initiate through the Breakage-Fusion-Bridge (BFB) cycle, in which a telomeric fragile site initiates amplification and a centromeric fragile site defines the size of amplicons (Coquelle et al, 1997). Asymmetrical distributions of amplified genes during the cell cycle confer growth advantage and contribute to the establishment of gene amplification.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the Breakage-Fusion-Bridge theory of gene amplification (Coquelle et al, 1997), FRA11A together with other downstream fragile sequences may contribute to the establishment of the CoAA amplicon boundaries. Together, the data confirm that CoAA has its own amplicon excluding CCND1.…”

Section: Coaa Gene Amplification In Human Cancersmentioning

confidence: 99%

Gene amplification and associated loss of 5′ regulatory sequences of CoAA in human cancers

et al. 2006

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“…This might suggest that cyclin D1 overexpression targets itself for genetic instability, perhaps along with other early replicating genes (possibly more transcriptionally active). Whether this targeted instability is due to upregulation of fragile sites in the chromosome regions (Kuo et al, 1994;Coquelle et al, 1997) or is due to the increased accessibility of transcriptionally active regions to carcinogen attack (Bohr, 1988) remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated cyclin D1 expression early in head and neck tumorigenesis: in vivo evidence for an association with subsequent gene amplification

et al. 1998

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Cyclin D1 proto-oncogene is a key regulator of the mammalian cell-cycle acting at the restriction point in late G1. Ampli®cation of the cyclin D1 locus, located on chromosome 11q13, as well as cyclin D1 protein overexpression have been reported in several human malignancies. The purpose of this study was to evaluate cyclin D1 gene copy status and protein expression during the multistep process of head and neck tumorigenesis, using a combination of¯uorescence in situ hybridization and immunohistochemistry techniques. From 29 selected patients presenting with head and neck squamous carcinoma and whose tumor cytospins had been previously screened for presence (16 cases) or absence (13 cases) of ampli®cation at the 11q13 band, we analysed 46 para n-embedded tissue specimens that demonstrated, besides the primary tumor, the presence of contiguous adjacent normal tissue and/or premalignant lesions. Of the 16 ampli®ed cases, nine demonstrated a continuous progression from premalignant to invasive carcinoma and seven (77.7%) of these cases showed cyclin D1 gene ampli®cation in premalignant lesions prior to development of invasive carcinoma. Increased cyclin D1 protein expression was observed in all 16 ampli®ed tumors and ®ve of the 13 (38.4%) nonampli®ed tumors. Interestingly, dysregulated cyclin D1 expression was also found in the premalignant lesions adjacent to all 16 ampli®ed tumors, and it appeared to precede cyclin D1 gene ampli®cation. In contrast no dysregulated expression was detected in the premalignant lesions of the non-ampli®ed tumors. In conclusion, these ®ndings provide strong evidence for early dysregulation of cyclin D1 expression during the tumorigenesis process and suggest that dysregulated increased expression precedes and possibly enables gene ampli®cation.

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Expression of Fragile Sites Triggers Intrachromosomal Mammalian Gene Amplification and Sets Boundaries to Early Amplicons

Cited by 365 publications

References 60 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

Gene amplification and associated loss of 5′ regulatory sequences of CoAA in human cancers

Dysregulated cyclin D1 expression early in head and neck tumorigenesis: in vivo evidence for an association with subsequent gene amplification

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