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Precision Medicine and Imaging

TERT Promoter Mutation Analysis for Blood-Based Diagnosis and Monitoring of Gliomas

Koushik Muralidharan, Anudeep Yekula, Julia L. Small, Zachary S. Rosh, Keiko M. Kang, Lan Wang, Spencer Lau, Hui Zhang, Hakho Lee, Chetan Bettegowda, Michael R. Chicoine, Steven N. Kalkanis, Ganesh M. Shankar, Brian V. Nahed, William T. Curry, Pamela S. Jones, Daniel P. Cahill, Leonora Balaj and Bob S. Carter
Koushik Muralidharan
1Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Anudeep Yekula
1Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Julia L. Small
1Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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  • ORCID record for Julia L. Small
Zachary S. Rosh
1Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Keiko M. Kang
1Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
2School of Medicine, University of California, San Diego, La Jolla, California.
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Lan Wang
1Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Spencer Lau
1Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Hui Zhang
3Biostatistics, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Hakho Lee
4Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Chetan Bettegowda
5Department of Neurosurgery, Johns Hopkins Medical Institutions, Baltimore, Maryland.
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Michael R. Chicoine
6Department of Neurosurgery, Washington University Medicine in St. Louis, St. Louis, Missouri.
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Steven N. Kalkanis
7Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan.
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Ganesh M. Shankar
1Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Brian V. Nahed
1Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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William T. Curry
1Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Pamela S. Jones
1Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Daniel P. Cahill
1Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Leonora Balaj
1Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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  • For correspondence: Balaj.Leonora@mgh.harvard.edu Bcarter@mgh.harvard.edu
Bob S. Carter
1Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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  • For correspondence: Balaj.Leonora@mgh.harvard.edu Bcarter@mgh.harvard.edu
DOI: 10.1158/1078-0432.CCR-20-3083 Published January 2021
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Abstract

Purpose: Liquid biopsy offers a minimally invasive tool to diagnose and monitor the heterogeneous molecular landscape of tumors over time and therapy. Detection of TERT promoter mutations (C228T, C250T) in cfDNA has been successful for some systemic cancers but has yet to be demonstrated in gliomas, despite the high prevalence of these mutations in glioma tissue (>60% of all tumors).

Experimental Design: Here, we developed a novel digital droplet PCR (ddPCR) assay that incorporates features to improve sensitivity and allows for the simultaneous detection and longitudinal monitoring of two TERT promoter mutations (C228T and C250T) in cfDNA from the plasma of patients with glioma.

Results: In baseline performance in tumor tissue, the assay had perfect concordance with an independently performed clinical pathology laboratory assessment of TERT promoter mutations in the same tumor samples [95% confidence interval (CI), 94%–100%]. Extending to matched plasma samples, we detected TERT mutations in both discovery and blinded multi-institution validation cohorts with an overall sensitivity of 62.5% (95% CI, 52%–73%) and a specificity of 90% (95% CI, 80%–96%) compared with the gold-standard tumor tissue–based detection of TERT mutations. Upon longitudinal monitoring in 5 patients, we report that peripheral TERT-mutant allele frequency reflects the clinical course of the disease, with levels decreasing after surgical intervention and therapy and increasing with tumor progression.

Conclusions: Our results demonstrate the feasibility of detecting circulating cfDNA TERT promoter mutations in patients with glioma with clinically relevant sensitivity and specificity.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2021;27:169–78

  • Received August 5, 2020.
  • Revision received September 15, 2020.
  • Accepted October 8, 2020.
  • Published first October 13, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 27 (1)
January 2021
Volume 27, Issue 1
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TERT Promoter Mutation Analysis for Blood-Based Diagnosis and Monitoring of Gliomas
Koushik Muralidharan, Anudeep Yekula, Julia L. Small, Zachary S. Rosh, Keiko M. Kang, Lan Wang, Spencer Lau, Hui Zhang, Hakho Lee, Chetan Bettegowda, Michael R. Chicoine, Steven N. Kalkanis, Ganesh M. Shankar, Brian V. Nahed, William T. Curry, Pamela S. Jones, Daniel P. Cahill, Leonora Balaj and Bob S. Carter
Clin Cancer Res January 1 2021 (27) (1) 169-178; DOI: 10.1158/1078-0432.CCR-20-3083

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TERT Promoter Mutation Analysis for Blood-Based Diagnosis and Monitoring of Gliomas
Koushik Muralidharan, Anudeep Yekula, Julia L. Small, Zachary S. Rosh, Keiko M. Kang, Lan Wang, Spencer Lau, Hui Zhang, Hakho Lee, Chetan Bettegowda, Michael R. Chicoine, Steven N. Kalkanis, Ganesh M. Shankar, Brian V. Nahed, William T. Curry, Pamela S. Jones, Daniel P. Cahill, Leonora Balaj and Bob S. Carter
Clin Cancer Res January 1 2021 (27) (1) 169-178; DOI: 10.1158/1078-0432.CCR-20-3083
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