Amplification of the N-myc gene in human neuroblastomas: tandemly repeated amplicons within homogeneously staining regions on different chromosomes with the retention of single copy gene at the resident site

Amler, Lukas C.; Shibasaki, Y.; Savelyeva, Larisa; Schwab, Manfred

doi:10.1016/0165-1110(92)90015-2

Cited by 21 publications

(11 citation statements)

References 13 publications

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“…This suggests that the amplified sequences have not been present on extrachromosomal particles during earlier stages of tumor development, since reintegration of such particles usually occurs at various different locations in the genome (Carroll et al, 1988). Although targeted integration of extrachromosomal amplicons containing the dihydrofolate reductase gene has been proposed to occur in hamster cells (Windle et al, 1991), in human cells they frequently integrate at non-native sites (Alitalo et al, 1983;Amler et al, 1992) or they remain extrachromo-soma1 (Pauletti et al, 1990). 2) All apparently complete chromosomes 11 show hybridization with the IN72 probe.…”

Section: The Mechanism Of Sptcific Gene Amplificationmentioning

confidence: 99%

Amplification of the 11q13 region in human carcinoma cell lines: A mechanistic view

Roelofs

Schuuring

Wiegant

et al. 1993

Genes Chromosomes & Cancer

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We previously proposed that a local duplication, not the loss of the subsequently amplified marker from its original site, might be the first step in gene amplification in human cells. It is important to investigate this issue in naturally occurring amplification and when copy numbers are relatively low. We have examined the location of single-copy and amplified 11q13 sequences in cell lines from human breast cancers and squamous cell carcinomas using fluorescence in situ hybridization both with a probe specific for the 11q13 amplifying region and with a chromosome 11-specific library. We show that in most cell lines the 11q13 amplicons are physically linked to chromosome 11 or to a chromosome derived from chromosome 11 by various rearrangements near the 11q13 region. In none of the cell lines were interstitial deletions of 11q13 detected. These results indicate that 11q13 amplification in human tumor cells generally does not involve deletion as the initial step. One cell line with chromosomally located amplified 11q13 sequences contained double minutes that harbored the MYC gene but no 11q13 sequences. This suggests that the genetic outcome and the mechanism of gene amplification are probably dependent on specific DNA sequences rather than on the origin of the cells.

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Section: The Mechanism Of Sptcific Gene Amplificationmentioning

confidence: 99%

Amplification of the 11q13 region in human carcinoma cell lines: A mechanistic view

Roelofs

Schuuring

Wiegant

et al. 1993

Genes Chromosomes & Cancer

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“…The majority of metaphases showed only one amplified locus on one of the two chromosomes 1 (Fig. 7C through E).…”

Section: Materuils and Methodsmentioning

confidence: 99%

“…FISH using cosDR6 as a probe revealed that more than 80% of the cells in the resistant populations exhibited cytogenetic localizations of amplified P-gp DNA distal to the single-copy locus on chromosome 1 (Fig. 7B through F, arrows), whereas in most cases, the single-copy sequence remained in its residential locus (Fig.…”

Section: Materuils and Methodsmentioning

confidence: 99%

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Chromosome breakage at a major fragile site associated with P-glycoprotein gene amplification in multidrug-resistant CHO cells.

Kuo¹,

Vyas²,

Jiang³

et al. 1994

Mol. Cell. Biol.

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Recent studies of several drug-resistant Chinese hamster cell lines suggested that a breakage-fusion-bridge mechanism is frequently involved in the amplification of drug resistance genes. These observations underscore the importance of chromosome breakage in the initiation of DNA amplification in mammalian cells. However, the mechanism of this breakage is unknown. Here, we propose that the site of chromosome breakage consistent with the initial event of P-glycoprotein (P-gp) gene amplification via the breakage-fusion-bridge cycle in three independently established multidrug-resistant CHO cells was located at 1q31. This site is a major chromosome fragile site that can be induced by methotrexate and aphidicolin treatments. Pretreatments of CHO cells with methotrexate or aphidicolin enhanced the frequencies of resistance to vinca alkaloid and amplification of the P-gp gene. These observations suggest that chromosome fragile sites play a pivotal role in DNA amplification in mammalian cells. Our data are also consistent with the hypothesis that gene amplification can be initiated by stress-induced chromosome breakage that is independent of modes of action of cytotoxic agents. Drug-resistant variants may arise by their growth advantage due to overproduction of cellular target molecules via gene amplification.

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“…Fluorescent in situ hybridization (FISH) and other studies have shown that amplicons may be composed of DNA from multiple different parts of the genome (Guan et al 1994;Muleris et al 1995;Volik et al 2003Volik et al , 2006Lim et al 2005;Van Roy et al 2006). Where the amplified DNA is from the same genomic region, both inverted orientation of amplified repeat units (Hellman et al 2002;Herrick et al 2005) and noninverted (tandem) orientation (Amler et al 1992;Kuwahara et al 2004;Vogt et al 2004;Herrick et al 2005) have been reported. Each of these patterns may reflect different pathogenetic processes.…”

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confidence: 99%

Architectures of somatic genomic rearrangement in human cancer amplicons at sequence-level resolution

Bignell¹,

Santarius²,

Pole³

et al. 2007

Genome Res.

186

177

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For decades, cytogenetic studies have demonstrated that somatically acquired structural rearrangements of the genome are a common feature of most classes of human cancer. However, the characteristics of these rearrangements at sequence-level resolution have thus far been subject to very limited description. One process that is dependent upon somatic genome rearrangement is gene amplification, a mechanism often exploited by cancer cells to increase copy number and hence expression of dominantly acting cancer genes. The mechanisms underlying gene amplification are complex but must involve chromosome breakage and rejoining. We sequenced 133 different genomic rearrangements identified within four cancer amplicons involving the frequently amplified cancer genes MYC, MYCN, and ERBB2. The observed architectures of rearrangement were diverse and highly distinctive, with evidence for sister chromatid breakage-fusion-bridge cycles, formation and reinsertion of double minutes, and the presence of bizarre clusters of small genomic fragments. There were characteristic features of sequences at the breakage-fusion junctions, indicating roles for nonhomologous end joining and homologous recombination-mediated repair mechanisms together with nontemplated DNA synthesis. Evidence was also found for sequence-dependent variation in susceptibility of the genome to somatic rearrangement. The results therefore provide insights into the DNA breakage and repair processes operative in somatic genome rearrangement and illustrate how the evolutionary histories of individual cancers can be reconstructed from large-scale cancer genome sequencing.

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Amplification of the N-myc gene in human neuroblastomas: tandemly repeated amplicons within homogeneously staining regions on different chromosomes with the retention of single copy gene at the resident site

Cited by 21 publications

References 13 publications

Amplification of the 11q13 region in human carcinoma cell lines: A mechanistic view

Amplification of the 11q13 region in human carcinoma cell lines: A mechanistic view

Chromosome breakage at a major fragile site associated with P-glycoprotein gene amplification in multidrug-resistant CHO cells.

Architectures of somatic genomic rearrangement in human cancer amplicons at sequence-level resolution

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