RT Journal Article
SR Electronic
T1 Cross-population analysis of high-grade serous ovarian cancer reveals only two robust subtypes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 030239
DO 10.1101/030239
A1 Gregory P. Way
A1 James Rudd
A1 Chen Wang
A1 Habib Hamidi
A1 Brooke L. Fridley
A1 Gottfried Konecny
A1 Ellen L. Goode
A1 Casey S. Greene
A1 Jennifer A. Doherty
YR 2015
UL http://biorxiv.org/content/early/2015/11/18/030239.abstract
AB Background Three 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.Methods We 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 Pearson’s 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.Results Across 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.Conclusions The 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.