Genetic variations in angiogenesis pathway genes associated with clinical outcome in localized gastric adenocarcinoma.

ABSTRACT

BACKGROUND: Angiogenesis has been attributed to be a well-recognized aspect of human cancer biology. As such, proteinase-activated receptor (PAR)-1, endostatin (ES) and interleukin-8 (IL-8) mediate the regulation of early-onset angiogenesis and in turn impact the process of tumor-growth and disease progression. PATIENTS AND METHODS: Formalin-fixed paraffin-embedded tissues were obtained from 137 patients with localized gastric cancer at University of Southern California and Memorial Sloan-Kettering Cancer Center medical facilities. DNA was extracted and genotyping was carried out using PCR-restriction fragment length polymorphism-based protocols. RESULTS: In false discovery rate-adjusted univariate analysis, PAR-1 -506 ins/del (P < 0.001), ES +4349 G>A (P = 0.004), and IL-8 -251 T>A (P < 0.0001) were associated with time to tumor recurrence (TTR). Further, PAR-1 -506 ins/del and IL-8 -251 were associated with overall survival (OS). After adjusting for covariates, IL-8 remained significantly associated with TTR (adjusted P = 0.003) and OS (adjusted P = 0.049), whereas ES was significantly associated with TTR (adjusted P = 0.026). CONCLUSIONS: Polymorphisms in PAR-1, ES, and IL-8 may serve as independent molecular prognostic markers in patients with localized gastric adenocarcinoma. The assessment of the patients' individual risk on the basis of interindividual genotypes may therefore help to identify patient subgroups at high risk for poor clinical outcome.