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A developmental program drives aggressive embryonal brain tumors

Nature Genetics volume 46, pages 2–3 (2014)Cite this article

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Embryonal tumors with multilayered rosettes (ETMRs) are primitive neuroectodermal tumors arising in infants. A new study shows that these tumors are universally driven by fusion of the promoter of a gene with brain-specific expression, TTYH1, to C19MC, the largest human microRNA cluster, activating a fetal neural development program.

Supratentorial primitive neuroectodermal tumors (sPNETs) are a heterogeneous group of childhood brain tumors that have been notoriously difficult to classify1,2. All are poorly differentiated small blue cell tumors with a high nucleus-to-cytoplasm ratio. Before the advent of genomics, histological classification schemes did not accurately predict patient risk and outcome. ETMRs are a newly defined sPNET subclass with consistently poor prognosis and a unique molecular signature3,4. ETMRs primarily occur in children less than 2 years of age, and they have poor outcome, despite treatment with aggressive therapies. ETMRs are defined histologically by rosettes, which resemble primitive neural tubes, and have high levels of LIN28 and IGF2 expression and low levels of OLIG2 expression3. On page 39 of this issue5, Nada Jabado, Jacek Majewski, Annie Huang and colleagues report that ETMRs are characterized by a recurrent fusion that joins the promoter of a gene with brain-specific expression (TTYH1) to a microRNA (miRNA) cluster at chromosome 19q13.41 (C19MC). This fusion event, which is unique to ETMRs, drives high levels of expression of the miRNA cluster in these tumors, reawakening a transcriptional program that is normally only active during the early stages of embryonic development.

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Figure 1: A recurrent TTYH1-C19MC fusion drives tumor formation by co-opting a developmental circuit.

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  1. Tenley C. Archer and Scott L. Pomeroy are in the Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,

    Tenley C Archer & Scott L Pomeroy

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  1. Tenley C Archer
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  2. Scott L Pomeroy
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Correspondence to Scott L Pomeroy.

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Archer, T., Pomeroy, S. A developmental program drives aggressive embryonal brain tumors. Nat Genet 46, 2–3 (2014). https://doi.org/10.1038/ng.2857

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