Inherited and inducible chromosomal instability: a fragile bridge between genome integrity mechanisms and tumourigenesis

Wright, Esmond

doi:10.1002/(sici)1096-9896(199901)187:1<19::aid-path233>3.0.co;2-1

Cited by 61 publications

(33 citation statements)

References 99 publications

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“…Moreover, carcinogens, particularly radiations and mutagenic chemical carcinogens, induce aneuploidy without delay, and thus long before cancer [170][171][172][173][174], as postulated by the chromosomal theory. Most importantly, our own studies have shown that among the many effects that carcinogens have on cells [40], aneuploidy is the one that consistently segregates with subsequent carcinogenesis [84,170].…”

Section: Carcinogens Function As Aneuploidogensmentioning

confidence: 99%

“…A series of recent studies, aiming at the definition of mutations that might 'initiate' carcinogenesis, have instead all pointed to chromosomal initiation [67,73,174]. Based on the dosage of a carcinogen delivered to cell cultures, the percentages of 'initiated' cells were found to be Ͼ1,000-fold larger than expected for the target gene [73].…”

Section: Carcinogens Function As Aneuploidogensmentioning

confidence: 99%

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Aneuploidy and Cancer: From Correlation to Causation

Duesberg

Fabarius³

et al. 2006

Infection and Inflammation: Impacts on Oncogenesis

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Conventional genetic theories have failed to explain why cancer (1) is not found in newborns and thus not heritable; (2) develops only years to decades after 'initiation' by carcinogens; (3) is caused by non-mutagenic carcinogens; (4) is chromosomally and phenotypically 'unstable'; (5) carries cancer-specific aneuploidies; (6) evolves polygenic phenotypes; (7) nonselective phenotypes such as multidrug resistance, metastasis or affinity for non-native sites and 'immortality' that is not necessary for tumorigenesis; (8) contains no carcinogenic mutations. We propose instead that cancer is a chromosomal disease: Accordingly, carcinogens initiate chromosomal evolutions via unspecific aneuploidies. By unbalancing thousands of genes aneuploidy corrupts teams of proteins that segregate, synthesize and repair chromosomes. Aneuploidy is thus a steady source of karyotypic-phenotypic variations from which, in classical Darwinian terms, selection of cancer-specific aneuploidies encourages the evolution and subsequent malignant 'progressions' of cancer cells. The rates of these variations are proportional to the degrees of aneuploidy, and can exceed conventional mutation by 4-7 orders of magnitude. This makes cancer cells new cell 'species' with distinct, but unstable karyotypes, rather than mutant cells. The cancer-specific aneuploidies generate complex, malignant phenotypes, through the abnormal dosages of the thousands of genes, just as trisomy 21 generates Down syndrome. Thus cancer is a chromosomal rather than a genetic disease. The chromosomal theory explains (1) nonheritability of cancer, because aneuploidy is not heritable; (2) long 'neoplastic latencies' by the low probability of evolving competitive new species; (3) nonselective phenotypes via genes hitchhiking on selective chromosomes, and (4) 'immortality', because chromosomal variations neutralize negative mutations and adapt to inhibitory conditions much faster than conventional mutation. Based on this article a similar one, entitled 'The chromosomal basis of cancer', has since been published by us in Cellular Oncology 2005;27:293-318. Copyright © 2006 S. Karger AG, Basel Despite over 100 years of cancer research, the cause of cancer is still a matter of debate . We propose here that the problem of cancer is still

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Section: Carcinogens Function As Aneuploidogensmentioning

confidence: 99%

Section: Carcinogens Function As Aneuploidogensmentioning

confidence: 99%

Aneuploidy and Cancer: From Correlation to Causation

Duesberg

Fabarius³

et al. 2006

Infection and Inflammation: Impacts on Oncogenesis

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“…Chromosomal rearrangements including aneuploidy, chromosomal translocations and duplications, and ampli®cation of selected genes are common in tumor cells (reviewed by Wright, 1999). Loss of p53 function frequently leads to deregulated cell cycle control and chromosomal instability, which favors tumor growth (reviewed by Prives and Hall, 1999).…”

Section: Molecular Characterization Of Tumors From Wnt-1 Tg Animalsmentioning

confidence: 99%

Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer

2000

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Wnt-1 was ®rst identi®ed as a protooncogene activated by viral insertion in mouse mammary tumors. Transgenic expression of this gene using a mouse mammary tumor virus LTR enhancer causes extensive ductal hyperplasia early in life and mammary adenocarcinomas in approximately 50% of the female transgenic (TG) mice by 6 months of age. Metastasis to the lung and proximal lymph nodes is rare at the time tumors are detected but frequent after the removal of the primary neoplasm. The potent mitogenic e ect mediated by Wnt-1 expression does not require estrogen stimulation; tumors form after an increased latency in estrogen receptor a-null mice. Several genetic lesions, including inactivation of p53 and over-expression of Fgf-3, collaborate with Wnt-1 in leading to mammary tumors, but loss of Sky and inactivation of one allele of Rb do not a ect the rate of tumor formation in Wnt-1 TG mice.

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“…50 Fanconi Anemia is an autosomal recessive disease associated with skeletal birth defects, anemia, hypogonadism, reduced fertility and cancer (leukemia and squamous cell carcinoma). Fanconi anemia is a genetic heterogeneous disease with at least eight proposed complementation groups based on cell fusion studies.…”

Section: Discussionmentioning

confidence: 99%

An expression of interest

Bonetta¹

2006

Nature

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Bax is a Bcl-2 family member that promotes apoptosis but has paradoxical effects on lymphoma development in p53-deficient mice. To better understand the mechanism of Baxinduced lymphoma development, the effect of Bax levels, p53 status and Bcl-2 coexpression on lymphoma development were determined. In addition, DNA content and cytogenetics were performed on young (premalignant) Lck-Bax mice as measures of genetic instability. Bax promoted lymphoma development in p53-deficient mice in a dose-dependent manner. Bax expression also led to lymphoma development in both p53 +/À and +/+ animals. Ploidy analysis in mice prior to the onset of overt thymic lymphomas demonstrated that Lck-Bax transgenic mice were more likely to be aneuploid and demonstrate increased chromosome instability. With tumor progression, aneuploidy increased and Bax expression was maintained. Importantly, coexpression of Bcl-2 delayed lymphoma development in Lck-Bax transgenic mice. These data support a model in which increased sensitivity to apoptosis leads directly to chromosome instability in developing T cells and may explain a number of paradoxical observations regarding Bcl-2 family members and the regulation of cancer.

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Inherited and inducible chromosomal instability: a fragile bridge between genome integrity mechanisms and tumourigenesis

Cited by 61 publications

References 99 publications

Aneuploidy and Cancer: From Correlation to Causation

Aneuploidy and Cancer: From Correlation to Causation

Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer

An expression of interest

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