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Purpose: The basal transcription of heme oxygenase-1 (HO-1) regulation is dependent upon a GTn repeat polymorphism (GTn) in the promoter of the heme oxygenase-1 gene (HMOX-1). Here, we evaluate the role of GTn in only surgically resected esophageal cancer (EC) patients without neoadjuvant or adjuvant treatment. Patients and Methods: Genomic DNA was extracted from peripheral blood of 297 patients. To determine the number of the GTn repeats DNA was amplified by PCR and sequenced. The results were correlated with clinicopathological parameters, disseminated tumor cells (DTC) and clinical outcome. Results: Three genotypes (SS, SL and LL) were defined based on cut-off points for short allele (SGTn) with GTn repeats <25 and ≥25 as long allele (LGTn). Throughout all analyses a contrary role of GTn was evident in squamous cell carcinoma (SCC) and adenocarcinoma (AC) patients. In SCC patients the SS genotype patients presented with less aggressive tumors in terms of tumor size, presence of regional and non-regional lymph-node metastases, DTC and lower relapse rate compared to SL and LL genotype patients. In contrast, in AC patients the SS genotype patients displayed more aggressive tumor biology with bigger tumors, higher rate of lymph-node metastasis and DTC and tumor recurrence rate compared to LL and SL genotype patients. The disease-free (DFS) and overall survival (OS) in SCC patients was markedly reduced in LL genotypes compared to SL and SS genotypes. In parallel, in AC the SS genotype patients displayed the worst DFS and OS. GTn was identified as an independent prognostic factor with contrary prognostic value for tumor recurrence and death in SCC and AC.Conclusion: GTn is a strong prognostic marker in EC that allows to stratify patients with different histology to different risk profiles.