Alternative mechanisms of gene amplification in human cancers

Kuwahara, Yoshitaka; Tanabe, Chikako; Ikeuchi, Tatsuro; Aoyagi, Kazuhiko; Nishigaki, Michiko; Sanada, Hiromi; Hoshinaga, Kiyotaka; Yoshida, Teruhiko; Sasaki, Hiroki; Terada, Masaaki

doi:10.1002/gcc.20075

Cited by 32 publications

(28 citation statements)

References 28 publications

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“…Any increase in parts of genome containing oncogenes, such as HER-2/neu, would play a key role in the onset and development of tumors (16,17). Overexpression of HER-2/neu gene has been reported in 92-95% of gastric cancer cases (18,19).…”

Section: Discussionmentioning

confidence: 99%

HER-2/neu gene amplification in gastric adenocarcinoma and its relationship with clinical and pathological findings

Azarhoosh

Ebneghasem

Besharat

2017

J. Gastrointest. Oncol.

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Background: Amplification of the HER-2/neu oncogene influences the progression of gastric cancer, its prognosis, and therapy. A precise examination of HER-2/neu-amplified tumor tissue is essential for managing disease and prescribing the appropriate treatment. This study aimed to investigate the status of HER-2/neu gene in the gastric cancer samples and its relationship with clinical and pathological information. Methods: In this study on 80 paraffin-embedded tissue samples from patients with gastric adenocarcinoma [2006][2007][2008][2009][2010][2011], DNA was extracted to quantify the gene expression levels of HER-2 using a polymerase chain reaction (PCR) method. Data were statistically analyzed by chi-square test using SPSS16.0 software. Results: PCR results indicated that HER-2/neu gene amplifications occurred in 58 of the 80 samples (72.5%). HER-2/neu gene expression was not significantly related to age and sex, but the larger tumor size and the more advanced stage were significantly associated with HER-2/neu overexpression. Conclusions:The data show the HER-2/neu gene is more amplified in stage 4 of gastric cancer with a larger size of mass. Older age and male sex also appear to be more associated with HER-2/neu gene expression.

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Section: Discussionmentioning

confidence: 99%

HER-2/neu gene amplification in gastric adenocarcinoma and its relationship with clinical and pathological findings

Azarhoosh

Ebneghasem

Besharat

2017

J. Gastrointest. Oncol.

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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%

“…1,2 Chromosomal abnormalities associated with DNA amplification can be organized as extrachromosomal copies, called double minutes (dmins); in tandem arrays as head-to-tail or inverted repeats within a chromosome, often forming a cytologically visible, homogeneously staining region (HSR); or distributed at various locations in the genome (distributed insertions). 1,3,4 The most frequently amplified genes in cancers are MYCN, ERBB2 and EGFR. 4 The epidermal growth factor receptor (EGFR) is a cell membrane receptor with intrinsic protein tyrosine kinase activity, which has been the subject of rigorous investigation due to its involvement in several human cancers and its potential as a target of therapy.…”

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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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“…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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Alternative mechanisms of gene amplification in human cancers

Cited by 32 publications

References 28 publications

HER-2/neu gene amplification in gastric adenocarcinoma and its relationship with clinical and pathological findings

HER-2/neu gene amplification in gastric adenocarcinoma and its relationship with clinical and pathological findings

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

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

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