Carcinogenesis Advance Access published online on October 20, 2009
Carcinogenesis, doi:10.1093/carcin/bgp254
Loss of imprinting of the insulin-like growth factor II (IGF2) gene in esophageal normal and adenocarcinoma tissues
1 Department of Surgery
2 The Cancer Stem Cell Research Group
3 Department of Pathology
4 Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
5 Center for Epigenetics, Division of Molecular Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed Email: alan.casson{at}usask.ca
To evaluate loss of imprinting and expression of the IGF2 gene in matched esophageal normal and adenocarcinoma tissues, we studied a prospective cohort of 77 patients who underwent esophageal resection between 1998 and 2003. IGF2 imprinting status was determined by RT-PCR following Apa I digestion, and quantitative polymerase chain reaction was used to evaluate IGF2 expression, which was correlated with clinico-pathologic findings, disease-free and overall survival. 32% (14/44) of informative tissues showed loss of IGF2 imprinting, with a strong correlation between the tumor and normal esophageal epithelia (Kappa = 0.89, p<0.01). Normal epithelia with loss of imprinting had increased expression of IGF2 (median: 2.91, 95%CI: 0.93-5.06) compared with imprinted normal epithelia (median: 1.13, 95%CI: 0.85-1.39) (p = 0.03). In contrast, tumors with loss of imprinting had significantly reduced IGF2 expression (median: 1.87, 95%CI: 0.53-5.21) compared with normally imprinted tumors (median: 6.79, 95%CI: 3.39-15.89) (p = 0.016). Patients below the age of 65 years with normally imprinted tumors had significantly reduced 5-year disease free survival (24%) compared with patients whose tumors had loss of imprinting for IGF2 (55%) (p = 0.03). Cox regression analysis showed IGF2 overexpression was associated with significantly reduced disease free survival (p = 0.04). We conclude that in a subgroup of younger patients, loss of IGF2 imprinting was associated with improved outcome following esophageal resection. Expression of IGF2 in esophageal adenocarcinoma and normal esophageal epithelia depended on imprinting status and tissue type, suggesting novel molecular regulatory mechanisms in esophageal tumorigenesis.
Key Words: Adenocarcinoma • Esophagus • Loss of imprinting • Insulin-like growth factor II
Received June 22, 2009; revised September 22, 2009; accepted October 12, 2009.