Ependymomas overexpress chemoresistance and DNA repair-related proteins
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Sherise D. Ferguson1, Shouhao Zhou2, Joanne Xiu3, Yuuri Hashimoto1, Nader Sanai4, Lyndon Kim5, Santosh Kesari6, John de Groot7, David Spetzler2 and Amy B. Heimberger1
1Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3Caris Life Sciences, Phoenix, AZ, USA
4Division of Neurosurgical Oncology, Barrow Neurological Institute, Phoenix, AZ, USA
5Department of Neurological Surgery and Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, PA, USA
6Department of Translational Neurosciences and Neurotherapeutics, Pacific Neuroscience Institute and John Wayne Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA, USA
7Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Sherise D. Ferguson, email: [email protected]
Keywords: ependymoma, chemoresistance, molecular profiling, DNA repair
Received: July 20, 2017 Accepted: October 05, 2017 Published: December 15, 2017
Background: After surgery and radiation, treatment options for ependymoma are few making recurrence a challenging issue. Specifically, the efficacy of chemotherapy at recurrence is limited. We performed molecular profiling on a cohort of ependymoma cases in order to uncover therapeutic targets and to elucidate the molecular mechanisms contributing to treatment resistance.
Results: This ependymoma cohort showed minimal alterations in gene amplifications and mutations but had high expression rates of DNA synthesis and repair enzymes such as RRM1 (47%), ERCC1 (48%), TOPO1 (62%) and class III β-tublin (TUBB3) (57%), which are also all associated with chemoresistance. This cohort also had high expression rates of transporter proteins that mediate multi-drug resistance including BCRP (71%) and MRP1 (43%). Subgroup analyses showed that cranial ependymomas expressed the DNA synthesis enzyme TS significantly more frequently than spinal lesions did (57% versus 15%; p = 0.0328) and that increased TS expression was correlated with increased tumor grade (p = 0.0009). High-grade lesions were also significantly associated with elevated expression of TOP2A (p = 0.0092) and TUBB3 (p = 0.0157).
Materials and Methods: We reviewed the characteristics of 41 ependymomas (21 cranial, 20 spinal; 8 grade I, 11 grade II, 22 grade III) that underwent multiplatform profiling with immunohistochemistry, next-generation sequencing, and in situ hybridization.
Conclusions: Ependymomas are enriched with proteins involved in chemoresistance and in DNA synthesis and repair, which is consistent with the meager clinical effectiveness of conventional systemic therapy in ependymoma. Adjuvant therapies that combine conventional chemotherapy with the inhibition of chemoresistance-related proteins may represent a novel treatment paradigm for this difficult disease.
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