Detection of gene mutations and gene–gene fusions in circulating cell-free DNA of glioblastoma patients: an avenue for clinically relevant diagnostic analysis

Vikrant Palande, Tali Siegal, Rajesh Detroja, Alessandro Gorohovski, Rainer Glass, Charlotte Flueh, Andrew A. Kanner, Yoseph Laviv, Sagi Har-Nof, Adva Levy-Barda, Marcela Viviana Karpuj, Marina Kurtz, Shira Perez, Dorith Raviv Shay, Milana Frenkel-Morgenstern

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Glioblastoma (GBM) is the most common type of glioma and is uniformly fatal. Currently, tumour heterogeneity and mutation acquisition are major impedances for tailoring personalized therapy. We collected blood and tumour tissue samples from 25 GBM patients and 25 blood samples from healthy controls. Cell-free DNA (cfDNA) was extracted from the plasma of GBM patients and from healthy controls. Tumour DNA was extracted from fresh tumour samples. Extracted DNA was sequenced using a whole-genome sequencing procedure. We also collected 180 tumour DNA datasets from GBM patients publicly available at the TCGA/PANCANCER project. These data were analysed for mutations and gene–gene fusions that could be potential druggable targets. We found that plasma cfDNA concentrations in GBM patients were significantly elevated (22.6 ± 5 ng·mL−1), as compared to healthy controls (1.4 ± 0.4 ng·mL−1) of the same average age. We identified unique mutations in the cfDNA and tumour DNA of each GBM patient, including some of the most frequently mutated genes in GBM according to the COSMIC database (TP53, 18.75%; EGFR, 37.5%; NF1, 12.5%; LRP1B, 25%; IRS4, 25%). Using our gene–gene fusion database, ChiTaRS 5.0, we identified gene–gene fusions in cfDNA and tumour DNA, such as KDR–PDGFRA and NCDN–PDGFRA, which correspond to previously reported alterations of PDGFRA in GBM (44% of all samples). Interestingly, the PDGFRA protein fusions can be targeted by tyrosine kinase inhibitors such as imatinib, sunitinib, and sorafenib. Moreover, we identified BCR–ABL1 (in 8% of patients), COL1A1–PDGFB (8%), NIN–PDGFRB (8%), and FGFR1–BCR (4%) in cfDNA of patients, which can be targeted by analogues of imatinib. ROS1 fusions (CEP85L–ROS1 and GOPC–ROS1), identified in 8% of patient cfDNA, might be targeted by crizotinib, entrectinib, or larotrectinib. Thus, our study suggests that integrated analysis of cfDNA plasma concentration, gene mutations, and gene–gene fusions can serve as a diagnostic modality for distinguishing GBM patients who may benefit from targeted therapy. These results open new avenues for precision medicine in GBM, using noninvasive liquid biopsy diagnostics to assess personalized patient profiles. Moreover, repeated detection of druggable targets over the course of the disease may provide real-time information on the evolving molecular landscape of the tumour.

Original languageEnglish
Pages (from-to)2098-2114
Number of pages17
JournalMolecular Oncology
Volume16
Issue number10
DOIs
StatePublished - May 2022

Bibliographical note

Publisher Copyright:
© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Funding

The authors thank the members of the Laboratory of Cancer Genomics and Biocomputing of Complex Diseases lead by Dr. Frenkel‐Morgenstern for their keen observational inputs and their participation in multiple discussions at different stages of this project. The authors also thank Prof. Alfonso Valencia, Barcelona Supercomputing Center and Dana Cohen from Zotal LTD, for their valuable comments on the article. Support came from the Israel Cancer Association (ICA grant to MF‐M 2017‐2019), and from a Kamin grant from the Israel Innovation Authority (to MF‐M). The authors thank the members of the Laboratory of Cancer Genomics and Biocomputing of Complex Diseases lead by Dr. Frenkel-Morgenstern for their keen observational inputs and their participation in multiple discussions at different stages of this project. The authors also thank Prof. Alfonso Valencia, Barcelona Supercomputing Center and Dana Cohen from Zotal LTD, for their valuable comments on the article. Support came from the Israel Cancer Association (ICA grant to MF-M 2017-2019), and from a Kamin grant from the Israel Innovation Authority (to MF-M).

FundersFunder number
Israel Innovation Authority
Zotal LTD
International Communication Association2017‐2019
Israel Cancer Association

    Keywords

    • circulating cell-free DNA
    • druggable
    • gene mutation
    • gene-gene fusion
    • glioblastoma
    • liquid biopsy

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