Document Type

Article

Publication Date

1-30-2018

Keywords

DNA repair; chemoresistance; ependymoma; molecular profiling

Abstract

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%;

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

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.

Clinical Institute

Cancer

Clinical Institute

Neurosciences (Brain & Spine)

Department

Neurosciences

Department

Oncology

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