Comprehensive cross-population analysis of high-grade serous ovarian cancer supports no more than three subtypes

Abstract

BackgroundThree to four gene expression-based subtypes of high-grade serous ovarian cancer (HGSC) have been previously reported. We sought to systematically determine the similarity of HGSC subtypes between populations.\n\nMethodsWe independently clustered (k = 3 and k = 4) five publicly-available HGSC mRNA expression datasets with >130 tumors using k-means and non-negative matrix factorization. Within each population, we summarized differential expression patterns for each cluster as moderated t statistic vectors using Significance Analysis of Microarrays. We calculated Pearsons correlations of these vectors to determine similarities and differences in expression patterns between clusters. We defined syn-clusters (SC) as sets of clusters that were strongly correlated across populations, and associated their expression patterns with biological pathways using geneset overrepresentation analyses.\n\nResultsAcross populations, for k = 3, moderated t score correlations for clusters 1, 2 and 3, respectively, ranged between 0.77-0.85, 0.80-0.90, and 0.65-0.77. For k = 4, correlations for clusters 1-4, respectively, ranged between 0.77-0.85, 0.83-0.89, 0.51-0.76, and 0.61-0.75. Within populations, comparing analogous clusters (k = 3 versus k = 4), correlations were high for clusters 1 and 2 (0.91-1.00), but were lower for cluster 3 (0.22-0.80). Results are similar using non-negative matrix factorization. SC1 corresponds to previously-reported mesenchymal-like, SC2 to proliferative-like, SC3 to immunoreactive-like, and SC4 to differentiated-like subtypes.\n\nConclusionsThe mesenchymal-like and proliferative-like subtypes are remarkably consistent across populations and could be uniquely targeted for treatment. The other two previously described subtypes are considerably less robust, and since cross-population comparison reveals that k = 3 and k = 4 are both consistent with our results, they may not represent clear subtypes.