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Evaluation of Different Biomarkers to Predict Individual Radiosensitivity in an Inter-Laboratory Comparison–Lessons for Future Studies

Identifieur interne : 004327 ( Main/Exploration ); précédent : 004326; suivant : 004328

Evaluation of Different Biomarkers to Predict Individual Radiosensitivity in an Inter-Laboratory Comparison–Lessons for Future Studies

Auteurs : Burkhard Greve [Allemagne] ; Tobias Bölling [Allemagne] ; Susanne Amler [Allemagne] ; Ute Rössler [Allemagne] ; Maria Gomolka [Allemagne] ; Claudia Mayer [Allemagne] ; Odilia Popanda [Allemagne] ; Kristin Dreffke [Allemagne] ; Astrid Rickinger [Allemagne] ; Eberhard Fritz [Allemagne] ; Friederike Eckardt-Schupp [Allemagne] ; Christina Sauerland [Allemagne] ; Herbert Braselmann [Allemagne] ; Wiebke Sauter [Allemagne] ; Thomas Illig [Allemagne] ; Dorothea Riesenbeck [Allemagne] ; Stefan Könemann [Allemagne] ; Normann Willich [Allemagne] ; Simone Mörtl [Allemagne] ; Hans Theodor Eich [Allemagne] ; Peter Schmezer [Allemagne]

Source :

RBID : PMC:3479094

Abstract

Radiotherapy is a powerful cure for several types of solid tumours, but its application is often limited because of severe side effects in individual patients. With the aim to find biomarkers capable of predicting normal tissue side reactions we analysed the radiation responses of cells from individual head and neck tumour and breast cancer patients of different clinical radiosensitivity in a multicentric study. Multiple parameters of cellular radiosensitivity were analysed in coded samples of peripheral blood lymphocytes (PBLs) and derived lymphoblastoid cell lines (LCLs) from 15 clinical radio-hypersensitive tumour patients and compared to age- and sex-matched non-radiosensitive patient controls and 15 lymphoblastoid cell lines from age- and sex- matched healthy controls of the KORA study. Experimental parameters included ionizing radiation (IR)-induced cell death (AnnexinV), induction and repair of DNA strand breaks (Comet assay), induction of yH2AX foci (as a result of DNA double strand breaks), and whole genome expression analyses. Considerable inter-individual differences in IR-induced DNA strand breaks and their repair and/or cell death could be detected in primary and immortalised cells with the applied assays. The group of clinically radiosensitive patients was not unequivocally distinguishable from normal responding patients nor were individual overreacting patients in the test system unambiguously identified by two different laboratories. Thus, the in vitro test systems investigated here seem not to be appropriate for a general prediction of clinical reactions during or after radiotherapy due to the experimental variability compared to the small effect of radiation sensitivity. Genome-wide expression analysis however revealed a set of 67 marker genes which were differentially induced 6 h after in vitro-irradiation in lymphocytes from radio-hypersensitive and non-radiosensitive patients. These results warrant future validation in larger cohorts in order to determine parameters potentially predictive for clinical radiosensitivity.


Url:
DOI: 10.1371/journal.pone.0047185
PubMed: 23110060
PubMed Central: 3479094


Affiliations:


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Le document en format XML

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<addr-line>Division of Epigenomics and Cancer Risk Factors, German Cancer Research Centre (DKFZ), Heidelberg, Germany</addr-line>
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<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Division of Epigenomics and Cancer Risk Factors, German Cancer Research Centre (DKFZ), Heidelberg</wicri:regionArea>
<placeName>
<region type="land" nuts="1">Bade-Wurtemberg</region>
<region type="district" nuts="2">District de Karlsruhe</region>
<settlement type="city">Heidelberg</settlement>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Dreffke, Kristin" sort="Dreffke, Kristin" uniqKey="Dreffke K" first="Kristin" last="Dreffke">Kristin Dreffke</name>
<affiliation wicri:level="1">
<nlm:aff id="aff2">
<addr-line>Leibniz Institute for Age Research – Fritz Lipmann Institute (FLI), Jena, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Leibniz Institute for Age Research – Fritz Lipmann Institute (FLI), Jena</wicri:regionArea>
<wicri:noRegion>Jena</wicri:noRegion>
<wicri:noRegion>Jena</wicri:noRegion>
<wicri:noRegion>Jena</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Rickinger, Astrid" sort="Rickinger, Astrid" uniqKey="Rickinger A" first="Astrid" last="Rickinger">Astrid Rickinger</name>
<affiliation wicri:level="1">
<nlm:aff id="aff3">
<addr-line>Institute of Radiation Biology, Helmholtz Centre Munich – German Research Centre for Environmental Health, Neuherberg, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Radiation Biology, Helmholtz Centre Munich – German Research Centre for Environmental Health, Neuherberg</wicri:regionArea>
<wicri:noRegion>Neuherberg</wicri:noRegion>
<wicri:noRegion>Neuherberg</wicri:noRegion>
<wicri:noRegion>Neuherberg</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Fritz, Eberhard" sort="Fritz, Eberhard" uniqKey="Fritz E" first="Eberhard" last="Fritz">Eberhard Fritz</name>
<affiliation wicri:level="1">
<nlm:aff id="aff2">
<addr-line>Leibniz Institute for Age Research – Fritz Lipmann Institute (FLI), Jena, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Leibniz Institute for Age Research – Fritz Lipmann Institute (FLI), Jena</wicri:regionArea>
<wicri:noRegion>Jena</wicri:noRegion>
<wicri:noRegion>Jena</wicri:noRegion>
<wicri:noRegion>Jena</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Eckardt Schupp, Friederike" sort="Eckardt Schupp, Friederike" uniqKey="Eckardt Schupp F" first="Friederike" last="Eckardt-Schupp">Friederike Eckardt-Schupp</name>
<affiliation wicri:level="1">
<nlm:aff id="aff3">
<addr-line>Institute of Radiation Biology, Helmholtz Centre Munich – German Research Centre for Environmental Health, Neuherberg, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Radiation Biology, Helmholtz Centre Munich – German Research Centre for Environmental Health, Neuherberg</wicri:regionArea>
<wicri:noRegion>Neuherberg</wicri:noRegion>
<wicri:noRegion>Neuherberg</wicri:noRegion>
<wicri:noRegion>Neuherberg</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Sauerland, Christina" sort="Sauerland, Christina" uniqKey="Sauerland C" first="Christina" last="Sauerland">Christina Sauerland</name>
<affiliation wicri:level="1">
<nlm:aff id="aff4">
<addr-line>Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Biostatistics and Clinical Research, University of Muenster, Muenster</wicri:regionArea>
<wicri:noRegion>Muenster</wicri:noRegion>
<wicri:noRegion>Muenster</wicri:noRegion>
<wicri:noRegion>Muenster</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Braselmann, Herbert" sort="Braselmann, Herbert" uniqKey="Braselmann H" first="Herbert" last="Braselmann">Herbert Braselmann</name>
<affiliation wicri:level="1">
<nlm:aff id="aff5">
<addr-line>Institute of Molecular Radiation Biology, Helmholtz Centre Munich – German Research Centre for Environmental Health, Neuherberg, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Molecular Radiation Biology, Helmholtz Centre Munich – German Research Centre for Environmental Health, Neuherberg</wicri:regionArea>
<wicri:noRegion>Neuherberg</wicri:noRegion>
<wicri:noRegion>Neuherberg</wicri:noRegion>
<wicri:noRegion>Neuherberg</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Sauter, Wiebke" sort="Sauter, Wiebke" uniqKey="Sauter W" first="Wiebke" last="Sauter">Wiebke Sauter</name>
<affiliation wicri:level="1">
<nlm:aff id="aff6">
<addr-line>Institute of Epidemiology, Helmholtz Centre Munich – German Research Centre for Environmental Health, Neuherberg, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Epidemiology, Helmholtz Centre Munich – German Research Centre for Environmental Health, Neuherberg</wicri:regionArea>
<wicri:noRegion>Neuherberg</wicri:noRegion>
<wicri:noRegion>Neuherberg</wicri:noRegion>
<wicri:noRegion>Neuherberg</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Illig, Thomas" sort="Illig, Thomas" uniqKey="Illig T" first="Thomas" last="Illig">Thomas Illig</name>
<affiliation wicri:level="1">
<nlm:aff id="aff6">
<addr-line>Institute of Epidemiology, Helmholtz Centre Munich – German Research Centre for Environmental Health, Neuherberg, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Epidemiology, Helmholtz Centre Munich – German Research Centre for Environmental Health, Neuherberg</wicri:regionArea>
<wicri:noRegion>Neuherberg</wicri:noRegion>
<wicri:noRegion>Neuherberg</wicri:noRegion>
<wicri:noRegion>Neuherberg</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Riesenbeck, Dorothea" sort="Riesenbeck, Dorothea" uniqKey="Riesenbeck D" first="Dorothea" last="Riesenbeck">Dorothea Riesenbeck</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">
<addr-line>Department of Radiotherapy, University Hospital of Muenster, Muenster, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Radiotherapy, University Hospital of Muenster, Muenster</wicri:regionArea>
<wicri:noRegion>Muenster</wicri:noRegion>
<wicri:noRegion>Muenster</wicri:noRegion>
<wicri:noRegion>Muenster</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Konemann, Stefan" sort="Konemann, Stefan" uniqKey="Konemann S" first="Stefan" last="Könemann">Stefan Könemann</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">
<addr-line>Department of Radiotherapy, University Hospital of Muenster, Muenster, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Radiotherapy, University Hospital of Muenster, Muenster</wicri:regionArea>
<wicri:noRegion>Muenster</wicri:noRegion>
<wicri:noRegion>Muenster</wicri:noRegion>
<wicri:noRegion>Muenster</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Willich, Normann" sort="Willich, Normann" uniqKey="Willich N" first="Normann" last="Willich">Normann Willich</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">
<addr-line>Department of Radiotherapy, University Hospital of Muenster, Muenster, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Radiotherapy, University Hospital of Muenster, Muenster</wicri:regionArea>
<wicri:noRegion>Muenster</wicri:noRegion>
<wicri:noRegion>Muenster</wicri:noRegion>
<wicri:noRegion>Muenster</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Mortl, Simone" sort="Mortl, Simone" uniqKey="Mortl S" first="Simone" last="Mörtl">Simone Mörtl</name>
<affiliation wicri:level="1">
<nlm:aff id="aff3">
<addr-line>Institute of Radiation Biology, Helmholtz Centre Munich – German Research Centre for Environmental Health, Neuherberg, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Radiation Biology, Helmholtz Centre Munich – German Research Centre for Environmental Health, Neuherberg</wicri:regionArea>
<wicri:noRegion>Neuherberg</wicri:noRegion>
<wicri:noRegion>Neuherberg</wicri:noRegion>
<wicri:noRegion>Neuherberg</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Eich, Hans Theodor" sort="Eich, Hans Theodor" uniqKey="Eich H" first="Hans Theodor" last="Eich">Hans Theodor Eich</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">
<addr-line>Department of Radiotherapy, University Hospital of Muenster, Muenster, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Radiotherapy, University Hospital of Muenster, Muenster</wicri:regionArea>
<wicri:noRegion>Muenster</wicri:noRegion>
<wicri:noRegion>Muenster</wicri:noRegion>
<wicri:noRegion>Muenster</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Schmezer, Peter" sort="Schmezer, Peter" uniqKey="Schmezer P" first="Peter" last="Schmezer">Peter Schmezer</name>
<affiliation wicri:level="3">
<nlm:aff id="aff7">
<addr-line>Division of Epigenomics and Cancer Risk Factors, German Cancer Research Centre (DKFZ), Heidelberg, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Division of Epigenomics and Cancer Risk Factors, German Cancer Research Centre (DKFZ), Heidelberg</wicri:regionArea>
<placeName>
<region type="land" nuts="1">Bade-Wurtemberg</region>
<region type="district" nuts="2">District de Karlsruhe</region>
<settlement type="city">Heidelberg</settlement>
</placeName>
</affiliation>
</author>
</analytic>
<series>
<title level="j">PLoS ONE</title>
<idno type="eISSN">1932-6203</idno>
<imprint>
<date when="2012">2012</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<p>Radiotherapy is a powerful cure for several types of solid tumours, but its application is often limited because of severe side effects in individual patients. With the aim to find biomarkers capable of predicting normal tissue side reactions we analysed the radiation responses of cells from individual head and neck tumour and breast cancer patients of different clinical radiosensitivity in a multicentric study. Multiple parameters of cellular radiosensitivity were analysed in coded samples of peripheral blood lymphocytes (PBLs) and derived lymphoblastoid cell lines (LCLs) from 15 clinical radio-hypersensitive tumour patients and compared to age- and sex-matched non-radiosensitive patient controls and 15 lymphoblastoid cell lines from age- and sex- matched healthy controls of the KORA study. Experimental parameters included ionizing radiation (IR)-induced cell death (AnnexinV), induction and repair of DNA strand breaks (Comet assay), induction of yH2AX foci (as a result of DNA double strand breaks), and whole genome expression analyses. Considerable inter-individual differences in IR-induced DNA strand breaks and their repair and/or cell death could be detected in primary and immortalised cells with the applied assays. The group of clinically radiosensitive patients was not unequivocally distinguishable from normal responding patients nor were individual overreacting patients in the test system unambiguously identified by two different laboratories. Thus, the
<italic>in vitro</italic>
test systems investigated here seem not to be appropriate for a general prediction of clinical reactions during or after radiotherapy due to the experimental variability compared to the small effect of radiation sensitivity. Genome-wide expression analysis however revealed a set of 67 marker genes which were differentially induced 6 h after in vitro-irradiation in lymphocytes from radio-hypersensitive and non-radiosensitive patients. These results warrant future validation in larger cohorts in order to determine parameters potentially predictive for clinical radiosensitivity.</p>
</div>
</front>
<back>
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<li>Bade-Wurtemberg</li>
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