Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas.

OBJECTIVE: Reliable biomarkers associated with aggressiveness of non-functioning gonadotroph adenomas (GAs) are lacking. As the growth of tumor remnants is highly variable, molecular markers for growth potential prediction are necessary. We hypothesized that fast- and slow-growing GAs present different gene expression profiles and reliable biomarkers for tumor growth potential could be identified, focusing on the specific role of epithelial-mesenchymal transition (EMT).

DESIGN AND METHODS: Eight GAs selected for RNA sequencing were equally divided into fast- and slow-growing group by the tumor volume doubling time (TVDT) median (27.75 months). Data were analyzed by tophat2, cufflinks and cummeRbund pipeline. 40 genes were selected for RT-qPCR validation in 20 GAs based on significance, fold-change and pathway analyses. The effect of silencing MTDH (metadherin) and EMCN (endomucin) on in vitro migration of human adenoma cells was evaluated.

RESULTS: 350 genes were significantly differentially expressed (282 genes upregulated and 68 downregulated in the fast group, P -adjusted <0.05). Among 40 selected genes, 11 showed associations with TVDT (-0.669< R <-0.46, P  < 0.05). These were PCDH18, UNC5D, EMCN, MYO1B, GPM6A and six EMT-related genes ( SPAG9, SKIL, MTDH, HOOK1, CNOT6L and PRKACB ). MTDH , but not EMCN , demonstrated involvement in cell migration and association with EMT markers.

CONCLUSIONS: Fast- and slow-growing GAs present different gene expression profiles, and genes related to EMT have higher expression in fast-growing tumors. In addition to MTDH , identified as an important contributor to aggressiveness, the other genes might represent markers for tumor growth potential and possible targets for drug therapy.