Clinical Importance of Myc Family Oncogene Aberrations in Epithelial Ovarian Cancer

Abstract

Abstract Background The Myc oncogene family has been implicated in many human malignancies and is often associated with particularly aggressive disease, suggesting Myc as an attractive prognostic marker and therapeutic target. However, for epithelial ovarian cancer (EOC), there is little consensus on the incidence and clinical relevance of Myc aberrations. Here we comprehensively investigated alterations in gene copy number, expression, and activity for Myc and evaluated their clinical significance in EOC. Methods To address inconsistencies in the literature regarding the definition of copy number variations, we developed a novel approach using quantitative polymerase chain reaction (qPCR) coupled with a statistical algorithm to estimate objective thresholds for detecting Myc gain/amplification in large cohorts of serous (n = 150) and endometrioid (n = 80) EOC. MYC, MYCN, and MYCL1 mRNA expression and Myc activity score for each case were examined by qPCR. Kaplan–Meier and Cox-regression analyses were conducted to assess clinical significance of Myc aberrations. Results Using a large panel of cancer cell lines (n = 34), we validated the statistical algorithm for determining clear thresholds for Myc gain/amplification. MYC was the most predominantly amplified of the Myc oncogene family members, and high MYC mRNA expression levels were associated with amplification in EOC. However, there was no association between prognosis and increased copy number or gene expression of MYC/MYCN/MYCL1 or with a pan-Myc transcriptional activity score, in EOC, although MYC amplification was associated with late stage and high grade in endometrioid EOC. Conclusion A systematic and comprehensive analysis of Myc genes, transcripts, and activity levels using qPCR revealed that although such aberrations commonly occur in EOC, overall they have limited impact on outcome, suggesting that the biological relevance of Myc oncogene family members is limited to certain subsets of this disease.