Carcinogenesis Advance Access published online on March 10, 2008
Carcinogenesis, doi:10.1093/carcin/bgn067
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
A distinct ERCC1 haplotype is associated with mRNA expression levels in prostate cancer patients
1 Department of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
2 Department of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3 Department of Radiology, University Hospital, Heidelberg, Germany
* Correspondence to: O. Popanda, Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; E-mail: o.popanda{at}dkfz.de
Both genetic variants and 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 PCR after reverse transcription, and ERCC1 rs11615 T>C, ERCC1 rs3212986 C>A, MDM2 rs2279744 T>G and TP53 rs17878362 (p53PIN3) polymorphisms were determined. Considerable inter-individual differences in mRNA expression were found (coefficients of variation: ERCC1, 45%; MDM2, 43%; 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.
Received November 21, 2007; revised February 29, 2008; accepted March 2, 2008.