title: A large microRNA cluster on chromosome 19 is a transcriptional hallmark of WHO type A and AB thymomas.
abstract: BACKGROUND
  Thymomas are one of the most rarely diagnosed malignancies. To better understand its biology and to identify therapeutic targets, we performed next-generation RNA sequencing.
  
  
  METHODS
  The RNA was sequenced from 13 thymic malignancies and 3 normal thymus glands. Validation of microRNA expression was performed on a separate set of 35 thymic malignancies. For cell-based studies, a thymoma cell line was used.
  
  
  RESULTS
  Hierarchical clustering revealed 100% concordance between gene expression clusters and WHO subtype. A substantial differentiator was a large microRNA cluster on chr19q13.42 that was significantly overexpressed in all A and AB tumours and whose expression was virtually absent in the other thymomas and normal tissues. Overexpression of this microRNA cluster activates the PI3K/AKT/mTOR pathway. Treatment of a thymoma AB cell line with a panel of PI3K/AKT/mTOR inhibitors resulted in marked reduction of cell viability.
  
  
  CONCLUSIONS
  A large microRNA cluster on chr19q13.42 is a transcriptional hallmark of type A and AB thymomas. Furthermore, this cluster activates the PI3K pathway, suggesting the possible exploration of PI3K inhibitors in patients with these subtypes of tumour. This work has led to the initiation of a phase II clinical trial of PI3K inhibition in relapsed or refractory thymomas (http://clinicaltrials.gov/ct2/show/NCT02220855).
authors.affiliation: Department of Surgery, Indiana University School of Medicine, 980 W Walnut Street, Room C312, Indianapolis, IN 46202, USA.
authors.forename: Milan
authors.initials: M
authors.lastname: Radovich
authors.affiliation: Department of Surgery, Indiana University School of Medicine, 980 W Walnut Street, Room C312, Indianapolis, IN 46202, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Solzak
authors.affiliation: Department of Surgery, Indiana University School of Medicine, 980 W Walnut Street, Room C312, Indianapolis, IN 46202, USA.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Hancock
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, 980 W Walnut Street, Room C312, Indianapolis, IN 46202, USA.
authors.forename: Madison L
authors.initials: ML
authors.lastname: Conces
authors.affiliation: Department of Surgery, Indiana University School of Medicine, 980 W Walnut Street, Room C312, Indianapolis, IN 46202, USA.
authors.forename: Rutuja
authors.initials: R
authors.lastname: Atale
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, 980 W Walnut Street, Room C312, Indianapolis, IN 46202, USA.
authors.forename: Ryan F
authors.initials: RF
authors.lastname: Porter
authors.affiliation: Cofactor Genomics, LLC, 4044 Clayton Avenue, St Louis, MO 63110, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Cofactor Genomics, LLC, 4044 Clayton Avenue, St Louis, MO 63110, USA.
authors.forename: Jarret
authors.initials: J
authors.lastname: Glasscock
authors.affiliation: Department of Surgery, Indiana University School of Medicine, 980 W Walnut Street, Room C312, Indianapolis, IN 46202, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Kesler
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, 980 W Walnut Street, Room C312, Indianapolis, IN 46202, USA.
authors.forename: Sunil S
authors.initials: SS
authors.lastname: Badve
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, 980 W Walnut Street, Room C312, Indianapolis, IN 46202, USA.
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Schneider
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, 980 W Walnut Street, Room C312, Indianapolis, IN 46202, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Loehrer
mesh_terms: D002888:Chromosomes, Human, Pair 19; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D013945:Thymoma / Q000145:classification / Q000235:genetics*; D013953:Thymus Neoplasms / Q000235:genetics*
chemical_list: D035683:MicroRNAs