A large microRNA cluster on chromosome 19 is a transcriptional hallmark of WHO type A and AB thymomas

Milan Radovich, Jeffrey P. Solzak, Bradley A. Hancock, Madison L. Conces, Rutuja Atale, Ryan F. Porter, Jin Zhu, Jarret Glasscock, Kenneth Kesler, Sunil Badve, Bryan Schneider, Patrick Loehrer

Research output: Contribution to journalArticle

11 Citations (Scopus)

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).British Journal of Cancer advance online publication, 14 January 2016; doi:10.1038/bjc.2015.425 www.bjcancer.com.

Original languageEnglish (US)
JournalBritish Journal of Cancer
DOIs
StateAccepted/In press - Jan 14 2016

Fingerprint

Chromosomes, Human, Pair 19
Thymoma
MicroRNAs
Phosphatidylinositol 3-Kinases
Neoplasms
RNA Sequence Analysis
Cell Line
Phase II Clinical Trials
Multigene Family
Thymus Gland
Cluster Analysis
Publications
Cell Survival
RNA
Gene Expression
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A large microRNA cluster on chromosome 19 is a transcriptional hallmark of WHO type A and AB thymomas. / Radovich, Milan; Solzak, Jeffrey P.; Hancock, Bradley A.; Conces, Madison L.; Atale, Rutuja; Porter, Ryan F.; Zhu, Jin; Glasscock, Jarret; Kesler, Kenneth; Badve, Sunil; Schneider, Bryan; Loehrer, Patrick.

In: British Journal of Cancer, 14.01.2016.

Research output: Contribution to journalArticle

Radovich, Milan ; Solzak, Jeffrey P. ; Hancock, Bradley A. ; Conces, Madison L. ; Atale, Rutuja ; Porter, Ryan F. ; Zhu, Jin ; Glasscock, Jarret ; Kesler, Kenneth ; Badve, Sunil ; Schneider, Bryan ; Loehrer, Patrick. / A large microRNA cluster on chromosome 19 is a transcriptional hallmark of WHO type A and AB thymomas. In: British Journal of Cancer. 2016.
@article{e0e49b1a129c4e6f8e3f6101b4a16531,
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).British Journal of Cancer advance online publication, 14 January 2016; doi:10.1038/bjc.2015.425 www.bjcancer.com.",
author = "Milan Radovich and Solzak, {Jeffrey P.} and Hancock, {Bradley A.} and Conces, {Madison L.} and Rutuja Atale and Porter, {Ryan F.} and Jin Zhu and Jarret Glasscock and Kenneth Kesler and Sunil Badve and Bryan Schneider and Patrick Loehrer",
year = "2016",
month = "1",
day = "14",
doi = "10.1038/bjc.2015.425",
language = "English (US)",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - A large microRNA cluster on chromosome 19 is a transcriptional hallmark of WHO type A and AB thymomas

AU - Radovich, Milan

AU - Solzak, Jeffrey P.

AU - Hancock, Bradley A.

AU - Conces, Madison L.

AU - Atale, Rutuja

AU - Porter, Ryan F.

AU - Zhu, Jin

AU - Glasscock, Jarret

AU - Kesler, Kenneth

AU - Badve, Sunil

AU - Schneider, Bryan

AU - Loehrer, Patrick

PY - 2016/1/14

Y1 - 2016/1/14

N2 - 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).British Journal of Cancer advance online publication, 14 January 2016; doi:10.1038/bjc.2015.425 www.bjcancer.com.

AB - 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).British Journal of Cancer advance online publication, 14 January 2016; doi:10.1038/bjc.2015.425 www.bjcancer.com.

UR - http://www.scopus.com/inward/record.url?scp=84954348450&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84954348450&partnerID=8YFLogxK

U2 - 10.1038/bjc.2015.425

DO - 10.1038/bjc.2015.425

M3 - Article

C2 - 26766736

AN - SCOPUS:84954348450

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

ER -