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Emergence of genetic instability in children treated for leukemia (2000)

B. A. Finette ; A. C. Homans ; R. J. Albertini

American Association for the Advancement of Science (AAAS)

In: Science. 288(5465): 514-7.

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Publication Date: 2000-04-25

Description: T cells from patients who had received chemotherapy for B-lineage acute lymphocytic leukemia were studied to determine whether genetic instability, a principal characteristic of cancer cells, can also occur in nonmalignant cells. Consistent with expectations for a genetic instability phenotype, multiple mutations were detected in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) reporter gene in independently isolated mutant T cells expressing identical rearranged T cell receptor beta (TCRbeta) gene hypervariable regions. These results indicate that cancer treatment can lead to genetic instability in nonmalignant cells in some individuals. They also suggest a mechanistic paradigm for the induction of second malignancies and drug resistance.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Finette, B A -- Homans, A C -- Albertini, R J -- 1K01CA77737/CA/NCI NIH HHS/ -- 1R29HD35309/HD/NICHD NIH HHS/ -- P30CA22435/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2000 Apr 21;288(5465):514-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics, Vermont Cancer Center, University of Vermont, Medical Alumni Building, Burlington, VT 05405, USA. finette@salus.med.uvm.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10775110" target="_blank"〉PubMed〈/a〉

Keywords: Adolescent ; Adult ; Alleles ; Antineoplastic Agents/*therapeutic use ; Burkitt Lymphoma/blood/*drug therapy/*genetics ; Cell Lineage ; Cell Transformation, Neoplastic ; Child ; Child, Preschool ; Clone Cells ; Drug Resistance, Neoplasm ; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor ; Genes, Reporter ; *Genes, T-Cell Receptor ; Humans ; Hypoxanthine Phosphoribosyltransferase/genetics ; Infant ; *Mutation ; Neoplasms, Second Primary/etiology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood/drug therapy/*genetics ; Recurrence ; *T-Lymphocytes

Print ISSN: 0036-8075

Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

Published by American Association for the Advancement of Science (AAAS)

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T cells responsive to myelin basic protein in patients with multiple sclerosis (1990)

M. Allegretta ; J. A. Nicklas ; S. Sriram ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 247(4943): 718-21.

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Publication Date: 1990-02-09

Description: Gene mutation in vivo in human T lymphocytes appears to occur preferentially in dividing cells. Individuals with multiple sclerosis (MS) are assumed to have one or more populations of diving T cells that are being stimulated by autoantigens. Mutant T cell clones from MS patients were isolated and tested for reactivity to myelin basic protein, an antigen that is thought to participate in the induction of the disease. The hypoxanthine guanine phosphoribosyltransferase (hprt) clonal assay was used to determine mutant frequency values in MS patients with chronic progressive disease. Eleven of 258 thioguanine-resistant (hprt-) T cell clones from five of the six MS patients who were tested proliferated in response to human myelin basic protein without prior in vitro exposure to this antigen. No wild-type clones from these patients, nor any hprt- or wild-type clones from three healthy individuals responded to myelin basic protein. Thus, T cell clones that react with myelin basic protein can be isolated from the peripheral blood of MS patients.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Allegretta, M -- Nicklas, J A -- Sriram, S -- Albertini, R J -- CA30688-07/CA/NCI NIH HHS/ -- NS00849/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 1990 Feb 9;247(4943):718-21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genetics Laboratory, University of Vermont, Burlington 05401.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/1689076" target="_blank"〉PubMed〈/a〉

Keywords: Adult ; Autoantigens/immunology ; Cell Division ; Clone Cells/immunology ; Female ; Humans ; Hypoxanthine Phosphoribosyltransferase/genetics ; Male ; Middle Aged ; Multiple Sclerosis/genetics/*immunology ; Mutation ; Myelin Basic Protein/*immunology ; T-Lymphocytes/drug effects/*immunology ; Thioguanine/pharmacology ; X Chromosome

Print ISSN: 0036-8075

Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

Published by American Association for the Advancement of Science (AAAS)

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Electronic Resource

In Vivo Somatic Mutations in Humans: Measurement and Analysis (1990)

Albertini, R J ; Nicklas, J A ; O'Neill, J P ; [et al.]

Palo Alto, Calif. : Annual Reviews

Annual Review of Genetics 24 (1990), S. 305-326

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ISSN: 0066-4197

Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff

Topics: Biology

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1146/annurev.ge.24.120190.001513

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Addressing Nonlinearity in the Exposure-Response Relationship for a Genotoxic Carcinogen: Cancer Potency Estimates for Ethylene Oxide (2004)

Kirman, C. R. ; Sweeney, L. M. ; Teta, M. J. ; [et al.]

350 Main Street , Malden , MA 02148 , USA , and 9600 Garsington Road , Oxford OX4 2DQ , UK . : Blackwell Publishing, Inc.

Risk analysis 24 (2004), S. 0

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ISSN: 1539-6924

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Energy, Environment Protection, Nuclear Power Engineering

Notes: Ethylene oxide (EO) has been identified as a carcinogen in laboratory animals. Although the precise mechanism of action is not known, tumors in animals exposed to EO are presumed to result from its genotoxicity. The overall weight of evidence for carcinogenicity from a large body of epidemiological data in the published literature remains limited. There is some evidence for an association between EO exposure and lympho/hematopoietic cancer mortality. Of these cancers, the evidence provided by two large cohorts with the longest follow-up is most consistent for leukemia. Together with what is known about human leukemia and EO at the molecular level, there is a body of evidence that supports a plausible mode of action for EO as a potential leukemogen. Based on a consideration of the mode of action, the events leading from EO exposure to the development of leukemia (and therefore risk) are expected to be proportional to the square of the dose. In support of this hypothesis, a quadratic dose-response model provided the best overall fit to the epidemiology data in the range of observation. Cancer dose-response assessments based on human and animal data are presented using three different assumptions for extrapolating to low doses: (1) risk is linearly proportionate to dose; (2) there is no appreciable risk at low doses (margin-of-exposure or reference dose approach); and (3) risk below the point of departure continues to be proportionate to the square of the dose. The weight of evidence for EO supports the use of a nonlinear assessment. Therefore, exposures to concentrations below 37 μg/m3 are not likely to pose an appreciable risk of leukemia in human populations. However, if quantitative estimates of risk at low doses are desired and the mode of action for EO is considered, these risks are best quantified using the quadratic estimates of cancer potency, which are approximately 3.2- to 32-fold lower, using alternative points of departure, than the linear estimates of cancer potency for EO. An approach is described for linking the selection of an appropriate point of departure to the confidence in the proposed mode of action. Despite high confidence in the proposed mode of action, a small linear component for the dose-response relationship at low concentrations cannot be ruled out conclusively. Accordingly, a unit risk value of 4.5 × 10−8 (μg/m3)−1 was derived for EO, with a range of unit risk values of 1.4 × 10−8 to 1.4 × 10−7 (μg/m3)−1 reflecting the uncertainty associated with a theoretical linear term at low concentrations.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1111/j.0272-4332.2004.00517.x

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Electronic Resource

Germinal HPRT splice donor site mutation results in multiple RNA splicing products in T-lymphocyte cultures (1996)

Hunter, T. C. ; Melancon, S. B. ; Dallaire, L. ; [et al.]

Springer

Somatic cell and molecular genetics 22 (1996), S. 145-150

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ISSN: 1572-9931

Source: Springer Online Journal Archives 1860-2000

Topics: Biology , Medicine

Notes: Abstract We have used peripheral blood T-lymphocyte cultures to analyze the hprt mutation in two Lesch-Nyhan syndrome males who are cousins and to confirm the carrier status of female members of the family. Both cDNA and genomic DNA sequencing studies show that this patient carries a hitherto undescribed single base deletion in the exon 5 donor splice site sequence (15:+1, δG, base number 31635). The largest cDNA product contained all nine hprt exons plus an insertion of 66 bases of intron 5, consistent with the use of a cryptic splice site in intron 5 (aag67/gtaagc). This splicing error would result in a chain terminating codon immediately after exon 5 (15:2–4, taa) and predicts a polypeptide of 133 amino acids. This loss of the normal splice donor site also results in multiple hprt mRNA species, combining the use of the cryptic splice site in intron 5 and splicing errors involving exons 2–6. In addition to defining a new Lesch-Nyhan mutation (hprtHenryville), these results provide insight into aberrant splicing of hprt mRNA in T-lymphocytes.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF02369904

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