Editors' ChoiceCancer

Tracing glioblastoma’s roots

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Science Translational Medicine  29 Aug 2018:
Vol. 10, Issue 456, eaau8877
DOI: 10.1126/scitranslmed.aau8877

Abstract

Subventricular zone neural stem cells with low-level driver mutations are likely the origin cells for glioblastoma.

Glioblastoma (GBM) diagnosis implies on average a 15-month survival. After diagnosis, patients and their families inevitably ask what caused the tumor. Physician answers are usually uncertain, consisting of multiple plausible but unproven etiologies. One such hypothesis suggests that the subventricular zone (SVZ) harbors neural stem cells that are capable of self-renewal and have the potential to accumulate mutations, resulting in GBMs. Data supporting this theory, however, had yet to be directly demonstrated in GBM patients because obtaining normal SVZ tissue, sometimes far beyond tumor borders, is not common during standard neurosurgical tumor resection.

Lee and colleagues did exactly that in 28 patients, obtaining matched tumor, normal SVZ distinct from tumor, and cortical tissue, with SVZ samples collected up to 2.6 cm from the tumors. Tumor, SVZ, and normal cortical tissue had an average of 80.7, 23.0, and 4.3 mutations, respectively. Mutations were shared between tumor and matched nontumor SVZ only in isocitrate dehydrogenase (IDH)–wild-type GBMs. However, in 56.3% of IDH–wild-type patients, SVZ contained low-level driver (TERT) mutations, which were more extensive in the matched tumors. EGFR, PTEN, and TP53 driver mutations were similarly shared between the tumors and SVZ.

Single-cell sequencing subsequently revealed clonal evolution of SVZ cells with driver mutations to GBM, and laser dissection of anatomically intact SVZ revealed the astrocytic ribbon as the relevant layer of the SVZ. Last, introduction of driver mutations into SVZ neural stem cells (NSCs) in a mouse model caused migration of mutant SVZ cells, resulting in the formation of tumor in the dorsolateral-caudal cortex.

Further studies may include more patients, characterize IDH-mutant populations, and refine SVZ-specific driver mutations, but this study suggests the SVZ as a likely source for GBM. Because the near certainty of GBM recurrence after resection contributes to its poor outcome, adjuvant therapeutic strategies may potentially target the SVZ, although this would need further testing in subsequent studies.

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