Karyotype evolution and tumor development

Yosida, Tosihide H.

doi:10.1016/0165-4608(83)90047-x

Cited by 27 publications

(7 citation statements)

References 71 publications

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“…However, it also predicts three reasons why such karyotypes will be difficult to identify: (i) The karyotypes of aneuploid cells are moving targets that change autocatalytically at rates that are directly proportional to the degree of aneuploidy, i.e., 2% per generation in highly aneuploid cells (see above) (45); (ii) due to the relative large numbers of chromosomes of animal cells and the randomness of aneuploidy-catalyzed chromosome reassortments, a drug-specific chromosome constellation will be masked by a great variety of nonspecific collateral variations; and (iii) because there are often several alternative pathways to generate the same phenotype, e.g., resistance to a specific drug (6,9,72) or loss of differentiated function, there are probably also several different phenotype-specific karyotypes. In agreement with both of these predictions, all cytogenetic studies of drug resistance have observed nonparental, but as yet no drug-specific, karyotypes (10,55,(68)(69)(70)(73)(74)(75)(76).…”

Section: Chromosome Reassortments Vs Gene Mutation As Causes Of Drugsupporting

confidence: 55%

Origin of multidrug resistance in cells with and without multidrug resistance genes: Chromosome reassortments catalyzed by aneuploidy

Duesberg

Stindl

Hehlmann

2001

Proc. Natl. Acad. Sci. U.S.A.

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Cancer cells and aneuploid cell lines can acquire resistance against multiple unrelated chemotherapeutic drugs that are over 3,000-fold those of normal levels and display spontaneous resistances up to 20-fold of normal levels. Two different mechanisms were proposed for this phenotype: (i) classical mutation of drug metabolizing genes or (ii) chromosome reassortments, catalyzed by cancer-and cell line-specific aneuploidy, which generate, via new gene dosage combinations, a plethora of cancer phenotypes, including drug resistance. To distinguish between these mechanisms, we have asked whether three mouse cell lines can become drug resistant, from which two or three genes have been deleted, and on which multidrug resistance is thought to depend: Mdr1a, Mdr1b, and Mrp1. Because all three lines could acquire multidrug resistance and were aneuploid, whereas diploid mouse cells could not, we conclude that aneuploid cells become drug resistant via specific chromosome assortments, independent of putative resistance genes. We have asked further whether aneuploid drug-resistant Chinese hamster cells revert spontaneously to drug sensitivity in the absence of cytotoxic drugs at the high rates that are typical of chromosome reassortments catalyzed by aneuploidy or at the very low or zero rates (i.e., deletion) of gene mutation. We found that four drug-resistant hamster cell lines reverted to drug sensitivity at rates of about 2-3% per generation, whereas two closely related lines remained resistant under our conditions. Thus, the karyotypic instability generated by aneuploidy emerges as the common source of the various levels of drug resistance of cancer cells: minor spontaneous resistances reflect accidental chromosome assortments, the high selected resistances reflect complex specific assortments, and multidrug resistance reflects new combinations of unselected genes located on the same chromosomes as selected genes.

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Section: Chromosome Reassortments Vs Gene Mutation As Causes Of Drugsupporting

confidence: 55%

Origin of multidrug resistance in cells with and without multidrug resistance genes: Chromosome reassortments catalyzed by aneuploidy

Duesberg

Stindl

Hehlmann

2001

Proc. Natl. Acad. Sci. U.S.A.

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“…Based on their different origins and ranges of action, aneuploidy and gene mutation make very different, testable predictions. For example, nature uses gene mutation for minor adjustments within a species, but reserves mutation of chromosome numbers for major, discontinuous alterations such as the generation of new species [Shapiro, 1983;Yosida, 1983;O'Brien et al, 1999]. In view of this aneuploidy appears to be a more plausible cause for the complex phenotypes of cancer than gene mutation.…”

Section: Introductionmentioning

confidence: 99%

Aneuploidy, the somatic mutation that makes cancer a species of its own

Duesberg

Rasnick

2000

Cell Motil. Cytoskeleton

207

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“…Karyotypic individuality is apparently the rule for the over 57,000 human cancers listed in the NCIMitelman database, 4 as well as for all animal cancers that have been tested. 6,11,38,65,66 All of these are defined by individual clonal karyotypes with individual chromosome copy numbers and typically also with individual marker or rearranged chromosomes.…”

Section: -14mentioning

confidence: 99%