ERCC1 Gen-Polymorphismus zur Responseund Prognoseprädiktion einer neoadjuvanten Radiochemotherapie beim Adenocarcinom des Ösophagus

Abstract

Introduction: Neoadjuvant radiochemotherapy (RT/CTx) regimens were primarily designed for treatment of squamous cell carcinoma (SCC) of the esophagus. Own results demonstrate that also patients with locally advanced adenocarcinoma (AC) of the esophagus may achieve a major response in 30 % with a 3 year survival rate of 80 %. To identify these patients, ERCC1 (rs11615) gene polymorphisms were analyzed. ERCC1 is a key enzyme of the nucleotide excision and repair (NER) complex to prevent DNA inter- and intrastrand crosslinks. Methods: Genomic DNA from 144 patients with adenocarcinoma of the esophagus was extracted from paraffin-embedded tissues. For analysis of ERCC1 single nucleotide polymorphisms (SNPs) allelic discrimination was performed by quantitative realtime PCR. Two allele-specific TaqMan probes in competition were used for amplification of ERCC1 (rs11615). Allelic genotyping was correlated with histomorphologic tumor regression and survival after neoadjuvant RT/CTx. Major response (MaHR) was defined as ≤ 10 % vital residual tumor cells. Results: Analysis of tumor regression revealed a MaHR in 49/144 (34 %) patients with a 5-year survival rate (5-YSR) of 72 % (p = 0.0001). ERCC1 gene polymorphisms for all patients showed the following expression pattern: ERCC1 polymorphism (rs11615) CC: n = 13 (9 %), TT: n = 74 (51 %), CT: n = 57 (40 %). ERCC1 polymorphism CT was identified as a predictor for response to the neoadjuvant RT/CTx (p < 0.001). The 5-YSR for patients with CT genotype was 53 %. Contrary to this, the 5-YSR for the group of patients with a CC/TT-polymorphism decreased to 33 %. Conclusion: Analysis of ERCC1 (rs11615) gene polymorphisms reveals a significant (p < 0.001) correlation with response and survival in patients with adenocarcinoma of the esophagus treated with a neoadjuvant radiochemotherapy (CDDP, 5-FU, 36Gy). Single nucleotide polymorphisms of ERCC1 (rs11615) could therefore be applied to further individualize therapy in esophageal cancer.