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 language | English (US) |
|---|---|
| Journal | British Journal of Cancer |
| DOIs | |
| State | Accepted/In press - Jan 14 2016 |
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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 journal › Article
}
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 -