Evolutionary dynamics of residual disease in human glioblastoma

I. Spiteri, G. Caravagna, G. D. Cresswell, A. Vatsiou, D. Nichol, A. Acar, L. Ermini, K. Chkhaidze, B. Werner, R. Mair, E. Brognaro, R. G.W. Verhaak, G. Sanguinetti, Sara Grazia Maria Piccirillo, C. Watts, A. Sottoriva

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background Glioblastoma is the most common and aggressive adult brain malignancy against which conventional surgery and chemoradiation provide limited benefit. Even when a good treatment response is obtained, recurrence inevitably occurs either locally (∼480%) or distally (∼420%), driven by cancer clones that are often genomically distinct from those in the primary tumour. Glioblastoma cells display a characteristic infiltrative phenotype, invading the surrounding tissue and often spreading across the whole brain. Cancer cells responsible for relapse can reside in two compartments of residual disease that are left behind after treatment: the infiltrated normal brain parenchyma and the sub-ventricular zone. However, these two sources of residual disease in glioblastoma are understudied because of the difficulty in sampling these regions during surgery. Patient and methods Here, we present the results of whole-exome sequencing of 69 multi-region samples collected using fluorescence-guided resection from 11 patients, including the infiltrating tumour margin and the sub-ventricular zone for each patient, as well as matched blood. We used a phylogenomic approach to dissect the spatio-temporal evolution of each tumour and unveil the relation between residual disease and the main tumour mass. We also analysed two patients with paired primary-recurrence samples with matched residual disease. Results Our results suggest that infiltrative subclones can arise early during tumour growth in a subset of patients. After treatment, the infiltrative subclones may seed the growth of a recurrent tumour, thus representing the 'missing link' between the primary tumour and recurrent disease. Conclusions These results are consistent with recognised clinical phenotypic behaviour and suggest that more specific therapeutic targeting of cells in the infiltrated brain parenchyma may improve patient's outcome.

Original languageEnglish (US)
Pages (from-to)456-463
Number of pages8
JournalAnnals of Oncology
Volume30
Issue number3
DOIs
StatePublished - Mar 1 2019

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Glioblastoma
Neoplasms
Brain
Recurrence
Exome
Therapeutics
Growth
Seeds
Clone Cells
Fluorescence
Phenotype

Keywords

  • cancer evolution
  • glioblastoma
  • phylogenetics
  • sub-ventricular zone
  • tumour margin

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Spiteri, I., Caravagna, G., Cresswell, G. D., Vatsiou, A., Nichol, D., Acar, A., ... Sottoriva, A. (2019). Evolutionary dynamics of residual disease in human glioblastoma. Annals of Oncology, 30(3), 456-463. https://doi.org/10.1093/annonc/mdy506

Evolutionary dynamics of residual disease in human glioblastoma. / Spiteri, I.; Caravagna, G.; Cresswell, G. D.; Vatsiou, A.; Nichol, D.; Acar, A.; Ermini, L.; Chkhaidze, K.; Werner, B.; Mair, R.; Brognaro, E.; Verhaak, R. G.W.; Sanguinetti, G.; Piccirillo, Sara Grazia Maria; Watts, C.; Sottoriva, A.

In: Annals of Oncology, Vol. 30, No. 3, 01.03.2019, p. 456-463.

Research output: Contribution to journalArticle

Spiteri, I, Caravagna, G, Cresswell, GD, Vatsiou, A, Nichol, D, Acar, A, Ermini, L, Chkhaidze, K, Werner, B, Mair, R, Brognaro, E, Verhaak, RGW, Sanguinetti, G, Piccirillo, SGM, Watts, C & Sottoriva, A 2019, 'Evolutionary dynamics of residual disease in human glioblastoma', Annals of Oncology, vol. 30, no. 3, pp. 456-463. https://doi.org/10.1093/annonc/mdy506
Spiteri I, Caravagna G, Cresswell GD, Vatsiou A, Nichol D, Acar A et al. Evolutionary dynamics of residual disease in human glioblastoma. Annals of Oncology. 2019 Mar 1;30(3):456-463. https://doi.org/10.1093/annonc/mdy506
Spiteri, I. ; Caravagna, G. ; Cresswell, G. D. ; Vatsiou, A. ; Nichol, D. ; Acar, A. ; Ermini, L. ; Chkhaidze, K. ; Werner, B. ; Mair, R. ; Brognaro, E. ; Verhaak, R. G.W. ; Sanguinetti, G. ; Piccirillo, Sara Grazia Maria ; Watts, C. ; Sottoriva, A. / Evolutionary dynamics of residual disease in human glioblastoma. In: Annals of Oncology. 2019 ; Vol. 30, No. 3. pp. 456-463.
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abstract = "Background Glioblastoma is the most common and aggressive adult brain malignancy against which conventional surgery and chemoradiation provide limited benefit. Even when a good treatment response is obtained, recurrence inevitably occurs either locally (∼480{\%}) or distally (∼420{\%}), driven by cancer clones that are often genomically distinct from those in the primary tumour. Glioblastoma cells display a characteristic infiltrative phenotype, invading the surrounding tissue and often spreading across the whole brain. Cancer cells responsible for relapse can reside in two compartments of residual disease that are left behind after treatment: the infiltrated normal brain parenchyma and the sub-ventricular zone. However, these two sources of residual disease in glioblastoma are understudied because of the difficulty in sampling these regions during surgery. Patient and methods Here, we present the results of whole-exome sequencing of 69 multi-region samples collected using fluorescence-guided resection from 11 patients, including the infiltrating tumour margin and the sub-ventricular zone for each patient, as well as matched blood. We used a phylogenomic approach to dissect the spatio-temporal evolution of each tumour and unveil the relation between residual disease and the main tumour mass. We also analysed two patients with paired primary-recurrence samples with matched residual disease. Results Our results suggest that infiltrative subclones can arise early during tumour growth in a subset of patients. After treatment, the infiltrative subclones may seed the growth of a recurrent tumour, thus representing the 'missing link' between the primary tumour and recurrent disease. Conclusions These results are consistent with recognised clinical phenotypic behaviour and suggest that more specific therapeutic targeting of cells in the infiltrated brain parenchyma may improve patient's outcome.",
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N2 - Background Glioblastoma is the most common and aggressive adult brain malignancy against which conventional surgery and chemoradiation provide limited benefit. Even when a good treatment response is obtained, recurrence inevitably occurs either locally (∼480%) or distally (∼420%), driven by cancer clones that are often genomically distinct from those in the primary tumour. Glioblastoma cells display a characteristic infiltrative phenotype, invading the surrounding tissue and often spreading across the whole brain. Cancer cells responsible for relapse can reside in two compartments of residual disease that are left behind after treatment: the infiltrated normal brain parenchyma and the sub-ventricular zone. However, these two sources of residual disease in glioblastoma are understudied because of the difficulty in sampling these regions during surgery. Patient and methods Here, we present the results of whole-exome sequencing of 69 multi-region samples collected using fluorescence-guided resection from 11 patients, including the infiltrating tumour margin and the sub-ventricular zone for each patient, as well as matched blood. We used a phylogenomic approach to dissect the spatio-temporal evolution of each tumour and unveil the relation between residual disease and the main tumour mass. We also analysed two patients with paired primary-recurrence samples with matched residual disease. Results Our results suggest that infiltrative subclones can arise early during tumour growth in a subset of patients. After treatment, the infiltrative subclones may seed the growth of a recurrent tumour, thus representing the 'missing link' between the primary tumour and recurrent disease. Conclusions These results are consistent with recognised clinical phenotypic behaviour and suggest that more specific therapeutic targeting of cells in the infiltrated brain parenchyma may improve patient's outcome.

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