www.impactjournals.com/oncotarget/

Oncotarget, 2017, Vol. 8, (No. 13), pp: 21770-21777 Research Paper

Next generation chondrosarcoma

sequencing

of

extraskeletal

myxoid

Elizabeth J. Davis1, Yi-Mi Wu2, Dan Robinson2, Scott M. Schuetze1, Laurence H. Baker1, Jyoti Athanikar2, Xuhong Cao2, Lakshmi P. Kunju2, Arul M. Chinnaiyan2, Rashmi Chugh1 1

Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

2

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA

Correspondence to: Rashmi Chugh, email: [email protected] Keywords: extraskeletal myxoid chondrosarcoma, next generation sequencing, EWSR1-NR4A3 Received: July 29, 2016     Accepted: January 09, 2017     Published: February 21, 2017

ABSTRACT Extraskeletal myxoid chondrosarcoma (EMC) is an indolent translocationassociated soft tissue sarcoma with a high propensity for metastases. Using a clinical sequencing approach, we genomically profiled patients with metastatic EMC to elucidate the molecular biology and identify potentially actionable mutations. We also evaluated potential predictive factors of benefit to sunitinib, a multi-targeted tyrosine kinase inhibitor with reported activity in a subset of EMC patients. Between January 31, 2012 and April 15, 2016, six patients with EMC participated in the clinical sequencing research study. High quality DNA and RNA was isolated and matched normal samples underwent comprehensive next generation sequencing (whole or OncoSeq capture exome of tumor and normal, tumor PolyA+ and capture transcriptome). The expression levels of sunitinib targeted-kinases were measured by transcriptome sequencing for KDR, PDGFRA/B, KIT, RET, FLT1, and FLT4. The previously reported EWSR1-NR4A3 translocation was identified in all patient tumors; however, other recurring genomic abnormalities were not detected. RET expression was significantly greater in patients with EMC relative to other types of sarcomas except for liposarcoma (p 3-6+ months) harbored the EWSR1-NR4A3 translocation [7]. Two patients who progressed had a TAF-15-NR4A3 translocation, t(9;17). This variant translocation as well as a NR4A3-TCF12/HTF4, t(9;15) translocation were previously reported [8, 9]. Immunohistochemical and biochemical analyses did not reveal any significant predictive markers; however, analysis of receptor tyrosine kinase (RTK) activity demonstrated elevated expression and activation of RET, a known target of sunitinib [7]. There is a need to better understand EMC biology and identify therapeutic approaches. Here, we utilized a clinical sequencing approach to genomically profile patients with metastatic EMC to elucidate the biology of EMC and identify potentially actionable mutations or predictive factors of sunitinib response.

The expression levels of sunitinib targetedkinases were measured by transcriptome sequencing for PDGFRA/B, KIT, RET, FLT1(VEGFR1), KDR (VEGFR2), and FLT4(VEGFR3) (Figure 3) for patient cohort with EMC and other sarcoma histologies. Only RET expression was significantly greater in patients with EMC relative to other types of sarcomas excluding liposarcoma (p

Next generation sequencing of extraskeletal myxoid chondrosarcoma.

Extraskeletal myxoid chondrosarcoma (EMC) is an indolent translocation-associated soft tissue sarcoma with a high propensity for metastases. Using a c...
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