Opposing prognostic impact of the heme oxygenase-1 promoter polymorphism in complete resected esophageal cancer

Purpose: Germ line polymorphism represent stable genetic markers that are unbiased by the genomic instability occurring in tumor tissue DNA. The basal transcription of heme oxygenase-1 regulation is dependent upon a GTn repeat polymorphism in the promoter of the heme oxygenase-1 gene. Here, we evaluated the prognostic impact of the GTn polymorphism in complete resected esophageal cancer patients who neither received neoadjuvant or adjuvant therapy.

Patients and methods: Genomic DNA was extracted from peripheral blood leucocytes 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 in bone marrow (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 opposing role of GTn was evident in squamous cell carcinoma (SCC) and adenocarcinoma (AC). In SCC the SS genotype patients presented with less aggressive tumors in terms of tumor size (P=0.01), presence of lymph-node metastases (P<0.001), DTC (P<0.001) and lower relapse rate (P=0.002) compared to SL and LL genotype patients. In contrast, in AC patients the SS genotype patients displayed more aggressive tumor biology with bigger tumors (P<0.001), higher rate of lymph-node metastases (P=0.001) and DTC (P=0.02) as well as tumor recurrence rate (P=0.03) compared to SL and LL 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 (P<0.001 each, log-rank test). In parallel, in AC the SS genotype patients displayed the worst DFS and OS (P<0.001 each). In gender, age, disease stage and differentiation adjusted multivariate Cox regression analysis the GTn was identified as an independent prognostic factor with complete opposing impact on tumor recurrence and survival in SCC and AC.

Conclusion: GTn represents a easily detectable and stable prognostic factor in esophageal cancer with antidromic prognostic value for tumor recurrence and survival in AC and SCC.