Measurement of plasma cell-free mitochondrial tumor DNA improves detection of glioblastoma in patient-derived orthotopic xenograft models Journal Article


Authors: Mair, R.; Mouliere, F.; Smith, C. G.; Chandrananda, D.; Gale, D.; Marass, F.; Tsui, D. W. Y.; Massie, C. E.; Wright, A. J.; Watts, C.; Rosenfeld, N.; Brindle, K. M.
Article Title: Measurement of plasma cell-free mitochondrial tumor DNA improves detection of glioblastoma in patient-derived orthotopic xenograft models
Abstract: The factors responsible for the low detection rate of cell-free tumor DNA (ctDNA) in the plasma of patients with glioblastoma (GBM) are currently unknown. In this study, we measured circulating nucleic acids in patient-derived orthotopically implanted xenograft (PDOX) models of GBM (n 1⁄4 64) and show that tumor size and cell proliferation, but not the integrity of the blood–brain barrier or cell death, affect the release of ctDNA in treatment-na€ve GBM PDOX. Analysis of fragment length profiles by shallow genome-wide sequencing (<0.2 coverage) of host (rat) and tumor (human) circulating DNA identified a peak at 145 bp in the human DNA fragments, indicating a difference in the origin or processing of the ctDNA. The concentration of ctDNA correlated with cell death only after treatment with temozolomide and radiotherapy. Digital PCR detection of plasma tumor mitochondrial DNA (tmtDNA), an alternative to detection of nuclear ctDNA, improved plasma DNA detection rate (82% vs. 24%) and allowed detection in cerebrospinal fluid and urine. Mitochondrial mutations are prevalent across all cancers and can be detected with high sensitivity, at low cost, and without prior knowledge of tumor mutations via capture-panel sequencing. Coupled with the observation that mitochondrial copy number increases in glioma, these data suggest analyzing tmtDNA as a more sensitive method to detect and monitor tumor burden in cancer, specifically in GBM, where current methods have largely failed. Significance: These findings show that detection of tumor mitochondrial DNA is more sensitive than circulating tumor DNA analysis to detect and monitor tumor burden in patient-derived orthotopic xenografts of glioblastoma. © 2018 American Association for Cancer Research.
Journal Title: Cancer Research
Volume: 79
Issue: 1
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2019-01-01
Start Page: 220
End Page: 230
Language: English
DOI: 10.1158/0008-5472.Can-18-0074
PUBMED: 30389699
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 1 February 2019 -- Source: Scopus
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  1. Wai Yi   Tsui
    16 Tsui