Prognostic effect of EIF4EBP1 on ovarian cancer: A single gene biomarker for overall survival and platinum response.

Abstract

5565 Background: Using a novel computational approach, Gene Set Outcome Analysis (GSOA), we were able to identify an area of amplification on chromosome 8p12 that leads to worse prognosis in high grade/high stage ovarian cancer. Located within this amplicon is EIF4EBP1, an effector of DNA translation that is activated by mTOR. Methods: We utilized the MSKCC CBIO cancer genetics portal and the ovarian TCGA clinical dataset, to detect variation in mRNA expression (EXP), (z-scores thresholds ± 2) and copy number variation (CNV), determined using GISTIC 2.0, that are associated with significant differences in PFS and overall survival in grade 3 and stage III/IV ovarian cancer. Results: 6.7% of tumors exhibited upregulation of EIF4EBP1 (CNV amplified and mRNA z > 2) and poorer prognosis with OS of 30.2 vs. 43.8 months (p = 0.0007, n = 445) in tumors not upregulated. Patients with upregulated vs. normal expression showed inferior PFS with first line, platinum based therapy, 10.0 vs. 15.2 months (p = 0.0406, n = 400), respectively. An additional 4.9% of cases had downregulation of EIF4EBP1, with homozygous deletion or mRNA expression z-scores < -2. Downregulation vs. normal expression also showed worse OS of 27.0 vs. 42.1 months (p = 0.0178) and PFS of 11.0 vs. 15.0 months (p = 0.028), respectively. As these groups are mutually exclusive and show a similar trend towards poor prognosis, when combined to compare aberrant vs. normal mRNA expression and copy number, we found an OS of 28.2 vs. 44.6 months (p = <0.0001) and PFS for first line platinum therapy of 10.2 vs. 15.3 months (p = 0.0024), respectively. Conclusions: In this dataset of 445 high-risk ovarian cancer patients, 11.8% exhibited aberrant expression of EIF4EBP1. While amplification of this region showed highly significant changes in OS and PFS, inclusion of both increased and decreased EIF4EBP1 mRNA expression achieved high statistical significance, demonstrating a “Goldilocks effect”, wherein normal expression leads to better outcomes. The potential relationship of gene expression levels of EIF4EBP1 to responsiveness to mTOR inhibitors should be explored in ovarian carcinomas.