Resistance-promoting effects of ependymoma treatment revealed through genomic analysis of multiple recurrences in a single patient
- Christopher A. Miller1,2,
- Sonika Dahiya3,
- Tiandao Li2,
- Robert S. Fulton2,
- Matthew D. Smyth4,
- Gavin P. Dunn4,
- Joshua B. Rubin5 and
- Elaine R. Mardis6
- 1Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
- 2McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
- 3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
- 4Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
- 5Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
- 6Institute for Genomic Medicine, Nationwide Children's Hospital, and The Ohio State University College of Medicine, Columbus, Ohio 43205, USA
- Corresponding authors: Elaine.Mardis{at}nationwidechildrens.org; Rubin_J{at}wustl.edu
Abstract
As in other brain tumors, multiple recurrences after complete resection and irradiation of supratentorial ependymoma are common and frequently result in patient death. This standard-of-care treatment was established in the pregenomic era without the ability to evaluate the effect that mutagenic therapies may exert on tumor evolution and in promoting resistance, recurrence, and death. We seized a rare opportunity to characterize treatment effects and the evolution of a single patient's ependymoma across four recurrences after different therapies. A combination of high-depth whole-genome and exome-based DNA sequencing of germline and tumor specimens, RNA sequencing of tumor specimens, and advanced computational analyses were used. Treatment with radiation and chemotherapies resulted in a substantial increase in mutational burden and diversification of the tumor subclonal architecture without eradication of the founding clone. Notable somatic alterations included a MEN1 driver, several epigenetic modifiers, and therapy-induced mutations that impacted multiple other cancer-relevant pathways and altered the neoantigen landscape. These genomic data provided new mechanistic insights into the genesis of ependymoma and pathways of resistance. They also revealed that radiation and chemotherapy were significant forces in shaping the increased subclonal complexity of each tumor recurrence while also failing to eradicate the founding clone. This raises the question of whether standard-of-care treatments have similar consequences in other patients with ependymoma and other types of brain tumors. If so, the perspective obtained by real-time genomic characterization of a tumor may be essential for making effective patient-specific and adaptive clinical decisions.
Footnotes
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[Supplemental material is available for this article.]
- Received November 15, 2017.
- Accepted December 26, 2017.
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