Neuroscience

Somatic cell

Gene expression

Subventricular zone

Human brain

Biology

Mutation

Gene

Stem cell

Glioma

Neural stem cell

Genetics

Medicine

Cancer research

Biochemistry

IDH1

Enzyme

Laser capture microdissection

Isocitrate dehydrogenase

Pathology

Nature

Glioblastoma (GBM) is a devastating and incurable brain tumour, with a median overall survival of fifteen&nbsp;months1,2. Identifying the cell of origin that harbours mutations that drive GBM could provide a fundamental basis for understanding disease progression and developing new treatments. Given that the accumulation of somatic mutations has been implicated in gliomagenesis, studies have suggested that neural stem cells (NSCs), with their self-renewal and proliferative capacities, in the subventricular zone (SVZ) of the adult human brain may be the cells from which GBM originates3–5. However, there is a lack of direct genetic evidence from human patients with GBM4,6–10. Here we describe direct molecular genetic evidence from patient brain tissue and genome-edited mouse models that show astrocyte-like NSCs in the SVZ to be the cell of origin that contains the driver mutations of human GBM. First, we performed deep sequencing of triple-matched tissues, consisting of (i) normal SVZ tissue away from the tumou...

Human glioblastoma arises from subventricular zone cells with low-level driver mutations