Detection of somatic mutations in man: evaluation of the microtitre cloning assay for T-lymphocytes

Henderson, L.M.; Cole, H.S.D.; Cole, Jane; James, Stuart; Green, Michael

doi:10.1093/mutage/1.3.195

Cited by 81 publications

(25 citation statements)

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“…In addition, the variance within multiple samples on the same subject is less than samples between different individuals. These data are consistent with the findings of others (24,25,28). The mean control MF, 4.6 x 10 -6, is also similar to that previously reported (20)(21)(22)(23)(24)(25)(26)28).…”

Section: Somatic Mutation In Controlssupporting

confidence: 93%

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Mutagenesis after cancer therapy.

Kelsey

Casini

Mauch

et al. 1993

Environ Health Perspect

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A subset of Hodgkin's disease (HD) and breast cancer patients have been reported to have elevated hprt mutant frequencies in peripheral blood lymphocytes after cessation of therapy. A subset of these patients are also known to develop second therapy-related malignancies. Therefore, it is clearly important to determine if these elevations in mutant frequency represent true, persistently elevated mutation frequencies. As a follow-up to our study of patients previously treated for HD, we recruited for a prospective study six previously treated HD patients and five patients who had been treated for squamous cell carcinoma of the head and neck. These individuals were studied several times over a 6-7 months. The results confirmed that a subset of patients have persistently high mutant frequencies when compared to 71 previously studied controls. The study was designed to determine if the elevated mutant frequencies of treated patients represented independent mutations or resulted from the in vivo expansion of single mutant cells. We used the polymerase chain reaction to examine DNA single strand conformation polymorphisms at the T-cell receptor-y locus of individual mutant clones. This analysis showed that 20.1% of the mutants from Hodgkin's disease patients and 17.5% of the mutants from squamous cell carcinoma patients were siblings. The sibling mutants generally did not persist over time. However, one patient had one mutant clone that persisted, but slowly decreased in prevalence over a 7 month sampling period. The data demonstrate that treatments for cancer result in persistently elevated mutation frequencies at the hprt locus in some, but not all, patients. In addition, our results confirm previous studies indicating that it is not always appropriate to assume equality between mutant and mutation frequencies when studying individuals exposed to significant doses of known mutagens or carcinogens.

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Section: Somatic Mutation In Controlssupporting

confidence: 93%

“…These data are shown in Table 2. The within individual variation in MF ( (25). Data from these controls, studied throughout a 1.5-year period, indicate that the MF remains stable over time in healthy controls.…”

Section: Somatic Mutation In Controlsmentioning

confidence: 88%

Mutagenesis after cancer therapy.

Kelsey

Casini

Mauch

et al. 1993

Environ Health Perspect

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“…It locus in T lymphocytes has been described in detail elsewhere [Henderson et al, 1986;Cole et al, 1988]. Briefly, for each mutant frequency has also been shown that cells bearing t(14;18) mutation determination, the cells were thawed rapidly, washed in RPMI 1640 share several characteristics with follicular lymphoma medium (Dutch modification, Gibco BRL) supplemented with 10% hucells, including an extended life span, B lymphocyte specman AB serum (kindly supplied by the Regional Blood Transfusion ificity, and mutation spectrum [Liu et al, 1994; Corto-Service) before being cultured overnight in the same medium supplepassi and Liu, 1995].…”

Section: Introductionmentioning

confidence: 99%

Correlated mutagenesis ofbcl2 andhprt loci in blood lymphocytes

Liu

Cortopassi

Steingrimsdottir

et al. 1997

Environ. Mol. Mutagen.

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“…The HPRT and GPA assays have also been applied to individuals and populations suffering from "DNA repair deficiency" syndromes, which are characterized by very high cancer incidences. Thus, HPRT mutation has been found to be spontaneously elevated in homozygotes for the recessive "cancer-prone" disorders Bloom syndrome (Vijayalaxmi et al, 1983), Fanconi anemia (Vijayalaxmi et al, 1985;Sala-Trepat et al, 1993) and ataxia telangiectasia (Henderson et al, 1986;Cole and Arlett, 1994), all associated with deficiencies in resolving DNA double-strand breaks. The GPA assay has demonstrated 10-(ataxia 13 GRANT telangiectasia), 50-(Fanconi anemia) and 100-fold (Bloom syndrome) increases in the frequency of spontaneous somatic mutation in these patients Langlois et al, 1989;Kyoizumi et al, 1989;Sala-Trepat et al, 1990;Mott et al, 1994;Grant et al, 1998;Grant and Auerbach, in preparation).…”

Section: Somatic Mutational Analysismentioning

confidence: 99%

Elevated Levels of Somatic Mutation as a Biomarker of Environmental Effects Contributing to Breast Carcinogenesis

Grant¹

2002

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and AUTHOR(S)Stephen G. Grant, Ph.D. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)8 ABSTRACT (Maximum 200 Words)Risk factors for the development of breast cancer remain largely unknown, especially those associated with the effect of the environment. Despite the known influence of hormonal factors, breast tumorigenesis has been shown to involve an accumulation of serial genetic changes in cancer genes. X-irradiation is a genotoxic exposure that has been identified as a risk factor for breast cancer. If somatic mutation is a major mechanism that drives the process of breast carcinogenesis, we hypothesize that breast cancer should develop preferentially in women with higher frequencies of somatic variation, as measured at a neutral reporter locus. The rate of somatic mutation is determined by exposure to endogenous and exogenous genotoxic agents and by an individual's ability to deal with such exposures through biotransformation of xenobiotics and DNA repair. We are using two established bioassays of in vivo human somatic mutation to study a large population of newly diagnosed primary breast cancer patients. These genetic/environmental interactions can be quantitated simply from observed effect, before we have completely understood the underlying mechanisms. Our primary goal is to provide a rationale for simple laboratory blood tests to be incorporated into the risk estimation equation for breast cancer.14. 3 IntroductionBreast cancer is one of the most common malignancies in the western world, and increases in incidence are being seen worldwide. Risk factors for the development of breast cancer remain largely unknown, with up to 75% of breast cancers occurring in the absence of established risk factors. The three risk factors that have been established are: family history of breast cancer, metabolic factors related to hormone production, and exposure to X-irradiation (Gail and Benichou, 1992;Claus et al., 1994). This study proposes that the last mentioned factor, exposure to ionizing radiation, is actually indicative of a larger involvement of genotoxicity in the etiology of breast cancer. This suggests that exposure to carcinogenic chemicals and susceptibility to mutagenesis and carcinogenesis play a significant role in determining who will develop a tumor of the breast. Indeed, evidence is mounting that the two known breast cancer susceptibility genes, BRCA1 and BRCA2 are actually DNA repair genes that modulate the genotoxi...

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Detection of somatic mutations in man: evaluation of the microtitre cloning assay for T-lymphocytes

Cited by 81 publications

References 0 publications

Mutagenesis after cancer therapy.

Mutagenesis after cancer therapy.

Correlated mutagenesis ofbcl2 andhprt loci in blood lymphocytes

Elevated Levels of Somatic Mutation as a Biomarker of Environmental Effects Contributing to Breast Carcinogenesis

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