A distinct ERCC1 haplotype is associated with mRNA expression levels in prostate cancer patients
Identifieur interne : 001602 ( Main/Exploration ); précédent : 001601; suivant : 001603A distinct ERCC1 haplotype is associated with mRNA expression levels in prostate cancer patients
Auteurs : Andreas Woelfelschneider [Allemagne] ; Odilia Popanda [Allemagne] ; Carmen Lilla [Allemagne] ; Jakob Linseisen [Allemagne] ; Claudia Mayer [Allemagne] ; Oktay Celebi [Allemagne] ; Jürgen Debus [Allemagne] ; Helmut Bartsch [Allemagne] ; Jenny Chang-Claude [Allemagne] ; Peter Schmezer [Allemagne]Source :
- Carcinogenesis [ 0143-3334 ] ; 2008.
Abstract
Both genetic variants and messenger RNA (mRNA) expression of DNA repair and tumor suppressor genes have been investigated as molecular markers for therapy outcome. However, the phenotypic impact of genetic variants often remained unclear, thus the rationale of their use in risk prediction may be limited. We therefore analyzed genetic variants together with anthropometric and lifestyle factors to see how these affect mRNA levels of ERCC1, MDM2 and TP53 in primary blood lymphocytes. mRNA expression was measured in 376 prostate cancer patients by quantitative real-time polymerase chain reaction after reverse transcription, and ERCC1 rs11615 T>C, ERCC1 rs3212986 C>A, MDM2 rs2279744 T>G and TP53 rs17878362 (p53PIN3) polymorphisms were determined. Considerable interindividual differences in mRNA expression were found (coefficients of variation: ERCC1, 45%; MDM2, 43% and TP53, 35%). ERCC1 expression was positively correlated with plasma levels of β-carotene (P = 0.03) and negatively correlated with canthaxanthin (P = 0.02) and lutein (P = 0.02). Overall, the polymorphisms affected mRNA expression only weakly. Carriers of a distinct ERCC1 haplotype (CC) showed, however, significantly lower expression values than non-carriers (P = 0.001). Applying logistic regression, we found that CC haplotype carriers had a 1.69-fold increased odds ratio (95% confidence interval: 1.06–2.71) for reduced ERCC1 mRNA levels. This low ERCC1 expression might be associated with reduced DNA repair and better therapy response. In summary, the association we have found between ERCC1 genotype and mRNA expression supports recent clinical observations that genetic variation in ERCC1 can affect treatment outcome and prognosis. Our study further revealed a modulating effect by nutritional factors.
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DOI: 10.1093/carcin/bgn067
Affiliations:
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Tel: +496221 423315, Fax: +49 6221 423359</wicri:regionArea><wicri:noRegion>Fax: +49 6221 423359</wicri:noRegion><wicri:noRegion>Fax: +49 6221 423359</wicri:noRegion></affiliation></author><author><name sortKey="Lilla, Carmen" sort="Lilla, Carmen" uniqKey="Lilla C" first="Carmen" last="Lilla">Carmen Lilla</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 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="Linseisen, Jakob" sort="Linseisen, Jakob" uniqKey="Linseisen J" first="Jakob" last="Linseisen">Jakob Linseisen</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 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="Mayer, Claudia" sort="Mayer, Claudia" uniqKey="Mayer C" first="Claudia" last="Mayer">Claudia Mayer</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 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><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>1Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 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><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>2Department of Radiology, University Hospital Heidelberg, 69120 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="Celebi, Oktay" sort="Celebi, Oktay" uniqKey="Celebi O" first="Oktay" last="Celebi">Oktay Celebi</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Radiology, University Hospital Heidelberg, 69120 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="Debus, Jurgen" sort="Debus, Jurgen" uniqKey="Debus J" first="Jürgen" last="Debus">Jürgen Debus</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Radiology, University Hospital Heidelberg, 69120 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="Bartsch, Helmut" sort="Bartsch, Helmut" uniqKey="Bartsch H" first="Helmut" last="Bartsch">Helmut Bartsch</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 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><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>1Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 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><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>2Department of Radiology, University Hospital Heidelberg, 69120 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="Chang Claude, Jenny" sort="Chang Claude, Jenny" uniqKey="Chang Claude J" first="Jenny" last="Chang-Claude">Jenny Chang-Claude</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 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="Schmezer, Peter" sort="Schmezer, Peter" uniqKey="Schmezer P" first="Peter" last="Schmezer">Peter Schmezer</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 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><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>1Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 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><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>2Department of Radiology, University Hospital Heidelberg, 69120 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><monogr></monogr><series><title level="j" type="main">Carcinogenesis</title><idno type="eISSN">1460-2180</idno><idno type="ISSN">0143-3334</idno><imprint><publisher>Oxford University Press</publisher><date when="2008-09">2008</date><date type="e-published" when="2008-03-10">2008</date><biblScope unit="vol">29</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1758">1758</biblScope><biblScope unit="page" to="1764">1764</biblScope></imprint><idno type="ISSN">0143-3334</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0143-3334</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Both genetic variants and messenger RNA (mRNA) expression of DNA repair and tumor suppressor genes have been investigated as molecular markers for therapy outcome. However, the phenotypic impact of genetic variants often remained unclear, thus the rationale of their use in risk prediction may be limited. We therefore analyzed genetic variants together with anthropometric and lifestyle factors to see how these affect mRNA levels of ERCC1, MDM2 and TP53 in primary blood lymphocytes. mRNA expression was measured in 376 prostate cancer patients by quantitative real-time polymerase chain reaction after reverse transcription, and ERCC1 rs11615 T>C, ERCC1 rs3212986 C>A, MDM2 rs2279744 T>G and TP53 rs17878362 (p53PIN3) polymorphisms were determined. Considerable interindividual differences in mRNA expression were found (coefficients of variation: ERCC1, 45%; MDM2, 43% and TP53, 35%). ERCC1 expression was positively correlated with plasma levels of β-carotene (P = 0.03) and negatively correlated with canthaxanthin (P = 0.02) and lutein (P = 0.02). Overall, the polymorphisms affected mRNA expression only weakly. Carriers of a distinct ERCC1 haplotype (CC) showed, however, significantly lower expression values than non-carriers (P = 0.001). Applying logistic regression, we found that CC haplotype carriers had a 1.69-fold increased odds ratio (95% confidence interval: 1.06–2.71) for reduced ERCC1 mRNA levels. This low ERCC1 expression might be associated with reduced DNA repair and better therapy response. In summary, the association we have found between ERCC1 genotype and mRNA expression supports recent clinical observations that genetic variation in ERCC1 can affect treatment outcome and prognosis. Our study further revealed a modulating effect by nutritional factors.</div></front></TEI><affiliations><list><country><li>Allemagne</li></country><region><li>Bade-Wurtemberg</li><li>District de Karlsruhe</li></region><settlement><li>Heidelberg</li></settlement></list><tree><country name="Allemagne"><region name="Bade-Wurtemberg"><name sortKey="Woelfelschneider, Andreas" sort="Woelfelschneider, Andreas" uniqKey="Woelfelschneider A" first="Andreas" last="Woelfelschneider">Andreas Woelfelschneider</name></region><name sortKey="Bartsch, Helmut" sort="Bartsch, Helmut" uniqKey="Bartsch H" first="Helmut" last="Bartsch">Helmut Bartsch</name><name sortKey="Bartsch, Helmut" sort="Bartsch, Helmut" uniqKey="Bartsch H" first="Helmut" last="Bartsch">Helmut Bartsch</name><name sortKey="Bartsch, Helmut" sort="Bartsch, Helmut" uniqKey="Bartsch H" first="Helmut" last="Bartsch">Helmut Bartsch</name><name sortKey="Celebi, Oktay" sort="Celebi, Oktay" uniqKey="Celebi O" first="Oktay" last="Celebi">Oktay Celebi</name><name sortKey="Chang Claude, Jenny" sort="Chang Claude, Jenny" uniqKey="Chang Claude J" first="Jenny" last="Chang-Claude">Jenny Chang-Claude</name><name sortKey="Debus, Jurgen" sort="Debus, Jurgen" uniqKey="Debus J" first="Jürgen" last="Debus">Jürgen Debus</name><name sortKey="Lilla, Carmen" sort="Lilla, Carmen" uniqKey="Lilla C" first="Carmen" last="Lilla">Carmen Lilla</name><name sortKey="Linseisen, Jakob" sort="Linseisen, Jakob" uniqKey="Linseisen J" first="Jakob" last="Linseisen">Jakob Linseisen</name><name sortKey="Mayer, Claudia" sort="Mayer, Claudia" uniqKey="Mayer C" first="Claudia" last="Mayer">Claudia Mayer</name><name sortKey="Mayer, Claudia" sort="Mayer, Claudia" uniqKey="Mayer C" first="Claudia" last="Mayer">Claudia Mayer</name><name sortKey="Mayer, Claudia" sort="Mayer, Claudia" uniqKey="Mayer C" first="Claudia" last="Mayer">Claudia Mayer</name><name sortKey="Popanda, Odilia" sort="Popanda, Odilia" uniqKey="Popanda O" first="Odilia" last="Popanda">Odilia Popanda</name><name sortKey="Popanda, Odilia" sort="Popanda, Odilia" uniqKey="Popanda O" first="Odilia" last="Popanda">Odilia Popanda</name><name sortKey="Schmezer, Peter" sort="Schmezer, Peter" uniqKey="Schmezer P" first="Peter" last="Schmezer">Peter Schmezer</name><name sortKey="Schmezer, Peter" sort="Schmezer, Peter" uniqKey="Schmezer P" first="Peter" last="Schmezer">Peter Schmezer</name><name sortKey="Schmezer, Peter" sort="Schmezer, Peter" uniqKey="Schmezer P" first="Peter" last="Schmezer">Peter Schmezer</name><name sortKey="Woelfelschneider, Andreas" sort="Woelfelschneider, Andreas" uniqKey="Woelfelschneider A" first="Andreas" last="Woelfelschneider">Andreas Woelfelschneider</name><name sortKey="Woelfelschneider, Andreas" sort="Woelfelschneider, Andreas" uniqKey="Woelfelschneider A" first="Andreas" last="Woelfelschneider">Andreas Woelfelschneider</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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