No statistical association between common fragile sites and nonrandom chromosome breakpoints in cancer cells

Sutherland, Grant R.; Simmers, R N

doi:10.1016/0165-4608(88)90004-0

Cited by 53 publications

(16 citation statements)

References 22 publications

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“…Chromosomal rearrangements involving fragile sites occur in these cancer cells at frequencies greater than expected by chance (18). The role of fragile-site expression in initiating malignancy is a subject of debate (51,53,54), with evidence both for and against a causative role (53).…”

Section: Discussionmentioning

confidence: 99%

Cytogenetic damage induced by folate deficiency in mice is enhanced by caffeine.

MacGregor

Schlegel

Wehr

et al. 1990

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

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Folate deficiency in Swiss mice increased the incidence of micronuclei in peripheral blood erythrocytes, indicating increased chromosomal damage in nucleated erythrocyte precursors. Caffeine enhanced the incidence of micronuclei in blood and bone marrow by up to 5-fold in folatedeficient mice at doses that did not significantly alter the micronucleus frequency in the presence of adequate dietary folate. The lower dose of caffeine used in this study (75 mg/kg) approaches doses received by humans who consume large amounts of caffeinated beverages. Since folate deficiency and caffeine consumption are highly prevalent in the human population, the potential for a similar interaction in man should be evaluated.The occurrence of micronuclei in peripheral blood and bone marrow erythrocytes has been used as an indicator of cytogenetic damage in laboratory animals and man (1-3). Two recent studies indicate that folate deficiency and caffeinatedbeverage consumption may elevate the frequency of micronucleated erythrocytes in man. Caffeinated-coffee consumption was associated with an elevated frequency of micronucleated erythrocytes in a cross-sectional study of genotoxic risk factors (4), and folate supplementation lowered micronucleus frequency to normal in an individual with a marginal folate deficiency and an abnormally high micronucleus frequency (5). These studies suggest that folate status and caffeinated-beverage consumption may be risk factors for cytogenetic damage in man.Mild-to-moderate folate deficiency (6-9) and caffeinatedbeverage consumption (10) are both highly prevalent in the general population. Folate deficiency affects up to 60% of low-income and elderly persons (8,11) and is also common in subpopulations, such as alcoholics (12) Folate deficiency in pregnant women has been reported to range from 2% to 50%, depending on the population studied (25). Folate deficiency during pregnancy is associated with an elevated incidence of birth defects (26).Severe folate deficiency induced by antifolate drugs has been shown to increase the frequency of micronuclei in mouse bone marrow erythrocytes (27, 28), but we are not aware of previous reports of increased micronucleus frequencies induced by dietary folate deficiency in laboratory animals.Fragile-site expression induced in vitro by conditions of limiting folate is known to be strongly enhanced by caffeine, leading to micronucleus formation and increased frequencies of chromosome breaks (18,29). Under these conditions, caffeine increases folate-related breakage events, often by more than an order of magnitude. There appear to be no data indicating whether a similar interaction occurs in mammals in vivo. Although earlier studies of caffeine effects in animals and man have failed to demonstrate significant genotoxic effects in vivo at doses near those that would result from the consumption of caffeinated beverages (30-33), the recent report by Chen et al. (34) that chromosomal fragility in human lymphocytes cultured under low-folate conditions is linearly ...

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Section: Discussionmentioning

confidence: 99%

Cytogenetic damage induced by folate deficiency in mice is enhanced by caffeine.

MacGregor

Schlegel

Wehr

et al. 1990

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

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“…There is an ongoing debate on the role of heritable c-fra in human leukemia susceptibility (15)(16)(17) and also on the role of interstitial TLR sequence arrays in chromosomal fragility (3,9). In this context, the data presented here would be most simply explained if the murine D-type TLR sequence polymorphism directly generated a heritable c-fra associated with leukemogenesis.…”

Section: Discussionmentioning

confidence: 99%

Telomere-like DNA polymorphisms associated with genetic predisposition to acute myeloid leukemia in irradiated CBA mice.

Silver¹,

Cox²

1993

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

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There is evidence that interstitial telomere (TTAGGG)n-like sequences at chromosome 2 fragile sites play an important role in the somatic events that characterize the earliest phases of radiation-induced acute myeloid leukemia in the CBA/H mouse. Here we show that the highly inbred CBA/H colony unexpectedly contains four genotypic variants for telomere-like sequence arrays and that almost all induced myeloid leukemias derive from one of the variant subpopulations that constitutes approximately 20% of the colony. Preliminary evidence on the irregular inheritance patterns for these variant sequences is discussed together with the proposal that one form of these telomere sequence arrays either represents or is closely linked to a locus that influences chromosome 2 breakage patterns in hemopoietic cells following irradiation and, through this, susceptibility to induced myeloid leukemia.

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“…Three of these, 2E5-F, 5B, and 13D2, coincide approximately with recurring lesions detected here. The evidence from the literature concerning fragile sites in human chromosomes indicates they are not the sites of tumorigenic lesions (Sutherland and Simmers, 1988). Nevertheless, the drug-induction data presented here suggest strongly at least that a common mechanism is involved.…”

Section: Variants Are Induced By Drugs That Affect Fragile Sitesmentioning

confidence: 79%

Tumor‐associated karyotypic lesions coselected with in vitro macrophage differentiation

Alexander

Berger²,

Day

et al. 1992

Genes Chromosomes & Cancer

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Several cytogenetic lesions in chromosomes 2, 5, 12, and 16 have been repeatedly coselected with in vitro macrophage differentiation in a clonal murine thymic tumor cell line. Parental-type subclones, which show an extremely immature hemopoietic phenotype, do not carry the aberrations. The frequency of the stable differentiated variants is elevated by 5-azacytidine and bromodeoxyuridine, consistent with chromosome breakage being responsible for the phenotype. The frequency is also raised by dexamethasone. Since variants are 300-3,000-fold more resistant to dexamethasone than parental clones, we interpret this to be largely due to selection. Three of the lesions, on chromosome 2, match those previously described as associated specifically with in vivo-generated murine myeloid tumors, induced by X irradiation and corticosteroid treatment. Several implications follow from these observations. (1) In vitro differentiation in clonal tumor cell lines can be used to select for tumor-associated lesions. This should allow genetic and molecular analysis of the chromosome 2 lesions and of others that may pinpoint genes critical to macrophage differentiation and transformation. (2) Myeloid and lymphoid tumors that occur in response to X irradiation may diverge from a common initiating tumor. (3) The hemopoietic lineage switch phenomenon, previously described by several authors, may be caused by similar or identical chromosome aberrations.

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No statistical association between common fragile sites and nonrandom chromosome breakpoints in cancer cells

Cited by 53 publications

References 22 publications

Cytogenetic damage induced by folate deficiency in mice is enhanced by caffeine.

Cytogenetic damage induced by folate deficiency in mice is enhanced by caffeine.

Telomere-like DNA polymorphisms associated with genetic predisposition to acute myeloid leukemia in irradiated CBA mice.

Tumor‐associated karyotypic lesions coselected with in vitro macrophage differentiation

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