Human Cancer Biology miRNA Landscape in Stage I Epithelial Ovarian Cancer Defines the Histotype Specificities

Purpose:Epithelial ovarian cancer (EOC) is oneof themost lethal gynecologic diseases, with survival rate virtually unchanged for the past 30 years. EOC comprises different histotypes with molecular and clinical heterogeneity, but up till now the present gold standard platinum-based treatment has been conducted without any patient stratification. The aim of the present study is to generate microRNA (miRNA) profiles characteristic of each stage I EOC histotype, to identify subtype-specific biomarkers to improve our understanding underlying the tumor mechanisms. ExperimentalDesign:A collection of 257 snap-frozen stage I EOC tumor biopsies was gathered together from three tumor tissue collections and stratified into independent training (n 1⁄4 183) and validation sets (n 1⁄4 74). Microarray and quantitative real-time PCR (qRT-PCR) were used to generate and validate the histotype-specific markers. A novel dedicated resampling inferential strategy was developed and applied to identify the highest reproducible results. mRNA and miRNA profiles were integrated to identify novel regulatory circuits. Results: RobustmiRNAmarkers for clear cell andmucinous histotypes were found. Specifically, the clear cell histotype is characterized by a five-fold (log scale) higher expression ofmiR-30a andmiR-30a , whereas mucinous histotype has five-fold (log scale) higher levels ofmiR-192/194. Furthermore, amucinous-specific regulatory loop involving miR-192/194 cluster and a differential regulation of E2F3 in clear cell histotype