Transcriptomic analysis of stage 1 versus advanced adult granulosa cell tumors

// Maria Alexiadis 1, * , Simon Chu 1, 2, * , Dilys Leung 1, 2 , Jodee A. Gould 1, 3 , Tom Jobling 4 , Peter J. Fuller 1, 2 1 Hudson Institute of Medical Research (formerly Prince Henry’s Institute of Medical Research), Clayton, Victoria 3168, Australia 2 Monash University Department of Biochemistry and Molecular Biology, Clayton, Victoria 3168, Australia 3 MHTP Medical Genomics Facility, Clayton, Victoria 3168, Australia 4 Department of Gynecology Oncology, Monash Health, Clayton, Victoria 3168, Australia * These authors have contributed equally to this work Correspondence to: Peter J. Fuller, e-mail: peter.fuller@hudson.org.au Keywords: granulosa cells, FOXL2, ovary, transcriptome, stromal tumors Received: September 03, 2015 Accepted: January 29, 2016 Published: February 16, 2016 ABSTRACT Ovarian granulosa cell tumors (GCT) are hormonally-active neoplasms characterized, in the adult-subtype, by a mutation in the FOXL2 gene (C134W). They exhibit an indolent course with an unexplained propensity for late recurrence; ~80% of patients with aggressive, advanced stage tumors die from their disease; aside from surgery, therapeutic options are limited. To identify the molecular basis of advanced stage disease we have used whole transcriptome analysis of FOXL2 C134W mutation positive adult (a)GCT to identify genes that are differentially expressed between early (stage 1) and advanced (stage 3) aGCT. Transcriptome profiles for early ( n = 6) and stage 3 ( n = 6) aGCT, and for the aGCT-derived KGN, cell line identified 24 genes whose expression significantly differs between the early and stage 3 aGCT. Of these, 16 were more abundantly expressed in the stage 3 aGCT and 8 were higher in the stage 1 tumors. These changes were further examined for the genes which showed the greatest fold change: the cytokine CXCL14, microfibrillar-associated protein 5, insulin-like 3 and desmin. Gene Set Enrichment Analysis identified overexpression of genes on chromosome 7p15 which includes the homeobox A gene locus. The analysis therefore identifies a small number of genes with clearly discriminate patterns of expression arguing that the clinicopathological-derived distinction of the tumor stage is robust, whilst confirming the relative homogeneity of expression for many genes across the cohort and hence of aGCT. The expression profiles do however identify several overexpressed genes in both stage 1 and/or stage 3 aGCT which warrant further study as possible therapeutic targets.