miRNA landscape in Stage I Epithelial Ovarian Cancer defines the histotype specificities

Abstract

PURPOSE:

epithelial Ovarian cancer (EOC) is one of the most lethal gynecological 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 performed without any patient stratification. The aim of the present study is to generate miRNA profiles characteristic of each stage I EOC histotype, in order to identify subtype-specific biomarkers to improve our understanding underlying the tumor mechanisms.

EXPERIMENTAL DESIGN:

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=183) and validation sets (n=74). Microarray and 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:

robust miRNA markers for clear cell and mucinous histotypes were found. Specifically, the clear cell histotype is characterized by a five-fold (log scale) higher expression of miR-30a and miR-30a*, while mucinous histotype has five-fold (log scale) higher levels of miR-192/194. Furthermore a mucinous-specific regulatory loop involving miR-192/194 cluster and a differential regulation of E2F3 in clear cell histotype were identified.

CONCLUSIONS:

our findings demonstrated that stage I EOC histotypes have their own characteristic miRNA expression and specific regulatory circuits.