Abstract 815: Patterns of metagene activation in ovarian cancer subtypes
Authors: Rudd James , Shea Emily K. , Way Gregory P. , Greene Casey S. , Doherty Jennifer A. 
Published: July 2016

Abstract
High grade serous ovarian cancer (HGSC) is a complex and aggressive disease. Recently, three or four gene expression-based subtypes, which may be differentially associated with survival, have been reported in several populations. To identify the biological functions that define the subtypes, we determined the extent to which metagenes—linear combinations of gene expression vectors—were differentially activated across subtypes, could be reliably identified across populations, and showed consistent associations with survival.
We previously clustered HGSC samples using gene expression data from TCGA, Tothill (GSE9891), Yoshihara (GSE32062), and Mayo (GSE74357) to identify subtypes across populations. We found subtype-specific genes within each population through differential expression analysis (p &lt; 4.6×10-6). Using the intersection of differentially expressed genes for parallel subtypes across these four populations, we applied non-negative matrix factorization to identify metagenes. To determine whether the metagenes were consistently observed across populations, we performed leave-one-dataset-out cross validation. For each metagene, we performed gene set enrichment analysis against the National Cancer Institute pathway interaction database to annotate metagene pathways. We examined whether increasing tertiles of metagene activity, which we termed low, medium, and high activity, were associated with survival using a random effects meta-analysis of Cox regression estimates adjusting for age at diagnosis, tumor stage, tumor grade, and debulking status.
Five metagenes were consistently identified and significantly associated with HGSC subtypes (p &lt; 0.0001). Of these, a metagene weakly enriched for the CMYB pathway was associated with subtype 1; three metagenes (one significantly enriched with the IL12 pathway and the others weakly enriched with the FCER1 and CXCR4 pathways) were associated with subtype 2; and a metagene weakly enriched with the AVB3 Integrin pathway distinguished between all 3 subtypes. Neither the CYMB metagene nor the IL12 metagene was significantly associated with survival. High activity of the CXCR4 and AVB3 metagenes was associated with poorer survival (hazard ratios (HR) and 95% confidence intervals (CI) are, respectively: 1.21, 0.99-1.48 and 1.34, 1.09-1.64). In contrast, high activity of the FCER1 metagene was associated with improved survival (HR 0.76, 95% CI 0.62-0.93).
Metagenes that are consistently and statistically significantly associated with subtype may be indicative of functional differences between HGSC subtypes. The contrast in hazard estimates for metagenes associated with subtype 2 may indicate that the metagenes capture survival signal distinct from the subtype association. Future work associating metagene activity with subtype uncertainty may better enable the refinement of subtype definitions and the development of subtype specific treatment strategies.
Citation Format: James Rudd, Emily K. Shea, Gregory P. Way, Casey S. Greene, Jennifer A. Doherty. Patterns of metagene activation in ovarian cancer subtypes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 815.