2000
DOI: 10.1073/pnas.97.26.14295
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Explaining the high mutation rates of cancer cells to drug and multidrug resistance by chromosome reassortments that are catalyzed by aneuploidy

Abstract: The mutation rates of cancer cells to drug and multidrug resistance are paradoxically high, i.e., 10 ؊3 to 10 ؊6 , compared with those altering phenotypes of recessive genes in normal diploid cells of about 10 ؊12 . Here the hypothesis was investigated that these mutations are due to chromosome reassortments that are catalyzed by aneuploidy. Aneuploidy, an abnormal number of chromosomes, is the most common genetic abnormality of cancer cells and is known to change phenotypes (e.g., Down's syndrome). Moreover, … Show more

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Cited by 157 publications
(128 citation statements)
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“…Chromosome missegregation may promote an evolutionary benefit within the solid tumour mass by altering gene dosage across the tumour population as evidenced by the transcriptional changes induced by single-cell chromosome transfer experiments (Upender et al, 2004). A compelling hypothesis generated from these observations is that the selection of a drug resistance gene encoded on a missegregated chromosome after chemotherapy exposure is associated with 'multiple unselected phenotypes' induced by genes encoded on the same chromosome that may promote resistance to unrelated drug compounds (Duesberg et al, 2000).…”
Section: Chromosomal Instability Classifies Solid Tumours Into a Poormentioning
confidence: 99%
See 1 more Smart Citation
“…Chromosome missegregation may promote an evolutionary benefit within the solid tumour mass by altering gene dosage across the tumour population as evidenced by the transcriptional changes induced by single-cell chromosome transfer experiments (Upender et al, 2004). A compelling hypothesis generated from these observations is that the selection of a drug resistance gene encoded on a missegregated chromosome after chemotherapy exposure is associated with 'multiple unselected phenotypes' induced by genes encoded on the same chromosome that may promote resistance to unrelated drug compounds (Duesberg et al, 2000).…”
Section: Chromosomal Instability Classifies Solid Tumours Into a Poormentioning
confidence: 99%
“…Aneuploid cells acquire multidrug resistance at a higher rate than diploid cells that may be catalysed by chromosome reassortments at each mitosis (Duesberg et al, 2000). Chromosome missegregation may promote an evolutionary benefit within the solid tumour mass by altering gene dosage across the tumour population as evidenced by the transcriptional changes induced by single-cell chromosome transfer experiments (Upender et al, 2004).…”
Section: Chromosomal Instability Classifies Solid Tumours Into a Poormentioning
confidence: 99%
“…2) and change phenotypes at rates that far exceed those at which genotypes and phenotypes are changed by conventional mutation [53][54][55]. For example, highly aneuploid cancer cells become drug resistant at rates of up to 10 Ϫ3 per cell generation [53,54,[56][57][58] or become metastatic at 'high rates' [59,60].…”
Section: Karyotype-phenotype Variations At Rates That Are Orders Highmentioning
confidence: 99%
“…The mutation hypothesis has to assume mutation rates of up to 10 Ϫ3 per cell generation to explain the frequent, spontaneous variation of phenotypes in highly aneuploid cancer cells. Examples are the 'high rates', compared to mutation, at which some cancers generate metastatic cells [59,60], or generate drug-resistant variants [53,54,56,58]. But the mutation rates of most cancers are not higher than those of normal cells [6,19,20,47,66,[70][71][72][73][74].…”
Section: Appendixmentioning
confidence: 99%
“…Robust checkpoints operate during mammalian spermatogenesis to eliminate most chromosomally imbalanced sperm [16]. Surprisingly, human oocytes and embryos, especially those derived from older individuals, fail to implement discriminating cell cycle checkpoints [18] and as a result allow for the propagation of aneuploid cells with both potential beneficial and deleterious effects to the somatic organism [19].…”
Section: Chromosomal Disorders and Dna Repair Mechanisms In Human Eggsmentioning
confidence: 99%