Abstract A9: Expression of insulin-like growth factor II and of the type 1 receptor gene in esophageal adenocarcinoma

Abstract

Abstract A9 Aim To explore potential biological mechanisms underlying the association between obesity and esophageal malignancy, we studied the expression of insulin-like growth factor-II (IGF-II) and of the type 1 receptor (IGF-IR) gene in a well characterized series of patients with primary esophageal adenocarcinoma (EADC) and matched histologically normal esophageal epithelia (NE). Patients and Methods Banked esophageal tissues (EADC and matched NE, obtained with informed consent) were available from a consecutive series of 52 patients who underwent esophageal resection without preoperative chemoradiation therapy. Following extraction of RNA, expression of IGF-II and IGF-IR mRNA was determined using reverse transcription and real time polymerase chain reaction (RT-PCR). The 2-ΔΔCT (Livak) method was used to quantitate tissue expression of IGF-II and IGF-IR mRNA, which was correlated with measured body mass index (BMI), clinicopathological findings, and outcome. Results As expected, significant correlations between tumor stage, differentiation and survival were found for the 49 male and 3 female patients in this series, who ranged in age from 36 to 85 years (median: 60.5 years). A significant association was seen between BMI and IGF-II mRNA expression in NE tissues (rs=0.26, p=0.075). Significantly higher IGF-II mRNA expression was seen in EADC tumors (median 6.45, 95%CI 7.00-13.46) compared to matched NE tissues (median 1.32, 95%CI 1.37-4.31, p<0.01), particularly in poorly differentiated tumors. On multivariate analysis, IGF-II expression was an independent predictor of disease-free survival (p=0.02) and overall survival (p=0.03). Expression levels of IGF-II mRNA correlated significantly with IGF-IR in both EADC (rs=0.47, p<0.01) and NE (rs=0.46, p<0.01). Furthermore, IGF-IR mRNA expression was found to be significantly higher in EADC (median 1.57; 95%CI 1.47-3.86) compared with matched NE (median 0.57; 95%CI 0.50-0.85) (p<0.01), but only in patients with the A variant of the common IGF-IR G3174A polymorphism, which has recently been shown to modulate the obesity risk for EADC. Conclusions These studies further implicate perturbations of the IGF axis in the molecular pathogenesis of human EADC, and suggest a plausible mechanistic basis to explain the association between obesity and risk for malignancy. The significant association between IGF-II expression and survival suggests that IGF-II may be a clinically relevant biomarker for prognosis, or molecular target for novel anti-cancer therapies. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A9.