Objectives: The IGF-II gene has four promoters (P1-P4); each initiates promoter-specific transcription. Studies have shown that IGF-II promoters normally active during fetal growth, but silent in postnatal life, are reactivated in cancer. In a previous study, we found IGF-II transcription evaluated at a common translated region was associated with ovarian cancer progression. This study was conducted to further determine which IGF-II promoters were responsible for the association.
Methods: Promoter-specific transcription at each IGF-II promoter was analyzed in 201 ovarian tumor samples using quantitative RT-PCR. Cox regression analysis was performed to determine the association of IGF-II promoter-specific expression with patient survival.
Results: P3 and P4 transcripts were detected more frequently and at significantly higher levels than the transcripts of P1 and P2. P3 and P4 transcripts were strongly correlated with the common IGF-II translated region and were significantly higher in patients with late stage disease, large residual tumor, suboptimal debulking or serous histology compared to those with early stage, small residual tumor, optimal debulking or non-serous histology. Survival analysis showed that patients with high P3 or P4 expression had a 2-fold increase in risk for death compared to those with low P3 or P4. These associations remained significant after adjustment for patient age at surgery, disease stage, tumor grade and histology. P1 and P2 transcripts, however, were not associated with disease characteristics or survival.
Conclusions: These findings suggest that IGF-II transcription from P3 and P4 promoters is important in ovarian cancer and evaluation of IGF-II promoter-specific transcription may have clinical implications in ovarian cancer prognosis and treatment.