The evolutionary pattern of mutations in glioblastoma reveals therapy-mediated selection

Andrea M. Muscat, Nicholas C. Wong, Katharine J. Drummond, Elizabeth M. Algar, Mustafa Khasraw, Roel Verhaak, Kathryn Field, Mark A. Rosenthal, David M. Ashley

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Glioblastoma presents as a heterogeneous disease with poor prognosis despite the use of multimodal therapy. Analysis of genomic DNA changes between initial diagnosis and recurrence in response to standard treatment protocols would enhance understanding of disease progression and better inform new treatment strategies. A cohort of 21 patients with primary glioblastoma were examined between diagnosis and first recurrence. This study presented a rare opportunity to characterize molecular alterations in tumors observed in three patients who received no therapeutic intervention, other than surgery, offering a unique control. We focused this study by comparing the dynamic mutation profiles between the primary tumors and their matched recurrent counterparts. Molecular profiling of tumors was performed using multiplexed targeted deep sequencing of 409 well characterized cancer-associated genes, achieving a mean read depth of 1272 x. Three levels of evidence suggested an evolutionary pattern consistent with a response to therapy-mediated selection pressures exists in treated patients: 1) variant burden was reduced in recurrent tumors, 2) neutral evolutionary dynamics apparent in untreated tumors shifted toward a non-neutral mode of evolution in treated patients at recurrence, and 3) the recurrent tumor of one patient displayed an increased mutation rate attributable to a temozolomide-associated hypermutator phenotype. Our observations suggest that current treatment modalities are likely to fail in achieving long term remission with the majority of relapse samples containing distinct mutations when compared to primary diagnostic samples.

Original languageEnglish
Pages (from-to)7844-7858
Number of pages15
JournalOncotarget
Volume9
Issue number8
DOIs
Publication statusPublished - 1 Jan 2018

Keywords

  • Glioblastoma
  • Mutation profiling
  • Neutral evolution
  • Selection pressure
  • Tumor heterogeneity

Cite this

Muscat, Andrea M. ; Wong, Nicholas C. ; Drummond, Katharine J. ; Algar, Elizabeth M. ; Khasraw, Mustafa ; Verhaak, Roel ; Field, Kathryn ; Rosenthal, Mark A. ; Ashley, David M. / The evolutionary pattern of mutations in glioblastoma reveals therapy-mediated selection. In: Oncotarget. 2018 ; Vol. 9, No. 8. pp. 7844-7858.
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Muscat, AM, Wong, NC, Drummond, KJ, Algar, EM, Khasraw, M, Verhaak, R, Field, K, Rosenthal, MA & Ashley, DM 2018, 'The evolutionary pattern of mutations in glioblastoma reveals therapy-mediated selection' Oncotarget, vol. 9, no. 8, pp. 7844-7858. https://doi.org/10.18632/oncotarget.23541

The evolutionary pattern of mutations in glioblastoma reveals therapy-mediated selection. / Muscat, Andrea M.; Wong, Nicholas C.; Drummond, Katharine J.; Algar, Elizabeth M.; Khasraw, Mustafa; Verhaak, Roel; Field, Kathryn; Rosenthal, Mark A.; Ashley, David M.

In: Oncotarget, Vol. 9, No. 8, 01.01.2018, p. 7844-7858.

Research output: Contribution to journalArticleResearchpeer-review

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