title: A distinct ERCC1 haplotype is associated with mRNA expression levels in prostate cancer patients.
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 beta-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.
authors.affiliation: Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, DKFZ, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Woelfelschneider
authors.forename: Odilia
authors.initials: O
authors.lastname: Popanda
authors.forename: Carmen
authors.initials: C
authors.lastname: Lilla
authors.forename: Jakob
authors.initials: J
authors.lastname: Linseisen
authors.forename: Claudia
authors.initials: C
authors.lastname: Mayer
authors.forename: Oktay
authors.initials: O
authors.lastname: Celebi
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.forename: Helmut
authors.initials: H
authors.lastname: Bartsch
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.forename: Peter
authors.initials: P
authors.lastname: Schmezer
mesh_terms: D000368:Aged; D000428:Alcohol Drinking; D015992:Body Mass Index; D016644:Canthaxanthin / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D014975:Lutein / Q000097:blood; D008214:Lymphocytes; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D019207:beta Carotene / Q000097:blood
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019207:beta Carotene; D016644:Canthaxanthin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C071447:ERCC1 protein, human; D004720:Endonucleases; D014975:Lutein