Abstract 1928: High-grade serous ovarian cancer subtypes are similar across diverse populations
Authors: Way Gregory P. , Rudd James , Greene Casey S. , Doherty Jennifer A. 
Published: August 2015

The most common and lethal type of invasive epithelial ovarian cancer is high grade serous (HGSC). Three to four gene expression-based HGSC subtypes have been identified in prior studies. In contrast to most previous studies, which have assessed the performance of survival classifiers in validation sets, we sought to determine the degree of similarity of gene expression patterns in subtypes between populations using systematic unsupervised clustering within populations.

We analyzed publically-available mRNA expression data from studies with &gt;200 HGSC tumors: The Cancer Genome Atlas (TCGA, US, n = 519, Affymetrix HT U133a), Tothill et al. (GSE9891, Australia, n = 242, Affymetrix U133 Plus 2.0) and Yoshihara et al. (GSE32062, Japan, n = 258, Agilent G4112a). We restricted analyses to the 12,249 genes shared across all datasets and selected from these the union of the 1,500 most variant genes per population (2,824). Using these datasets, we performed k-means clustering within each population for k = 3 and k = 4. We compared each cluster to all other clusters using Significance Analysis of Microarrays, which outputs an F score for all 12,249 genes, measuring cluster-specific differential expression. We then calculated the correlation of the resulting F score vectors across populations and within populations across both numbers of centroids (k = 3 or k = 4). We identified analogous clusters by high F score correlations and determined each cluster's similarity to the TCGA subtypes based on cluster-specific differentially expressed genes.

We observed high concordance of gene expression patterns for clusters across populations and across k-means runs, suggesting that analogous clusters exist in most analyses. For k = 3, F score correlations across populations for clusters 1, 2 and 3, respectively, ranged between 0.77-0.85, 0.80-0.90, and 0.66-0.72. For k = 4, F score correlations for clusters 1-4 were, respectively: 0.76-0.85, 0.82-0.85, 0.65-0.78, and 0.52-0.78. Across k = 3 and k = 4, correlations for cluster 1 within TCGA, Tothill, and Yoshihara were 0.99, 1.00 and 1.00, and correlations for cluster 2 were 0.96, 0.98, and 0.95, respectively. Correlations for cluster 3 were less strong: 0.56, 0.88, and 0.60, respectively. For k = 4, cluster 4 was composed mainly of samples that belonged to cluster 3 for k = 3; 88% for TCGA, 54% for Tothill, and 95% for Yoshihara. When compared to TCGA subtypes, cluster 1 corresponded most strongly to mesenchymal, cluster 2 to proliferative, cluster 3 to differentiated, and cluster 4 to immunoreactive.

Our observation of highly correlated gene expression patterns between clusters across populations, across platforms, and across the number of centroids provides strong evidence that at least three biological HGSC subtypes exist. The mesenchymal-like and proliferative-like subtypes are particularly consistent across populations, and could be uniquely targeted for treatment.

Citation Format: Gregory P. Way, James Rudd, Casey S. Greene, Jennifer A. Doherty. High-grade serous ovarian cancer subtypes are similar across diverse populations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1928. doi:10.1158/1538-7445.AM2015-1928