ETMR: a tumor entity in its infancy

Abstract

Embryonal tumor with Multilayered Rosettes (ETMR) is a relatively rare but typically deadly type of brain tumor that occurs mostly in infants. Since the discovery of the characteristic chromosome 19 miRNA cluster (C19MC) amplification a decade ago, the methods for diagnosing this entity have improved and many new insights in the molecular landscape of ETMRs have been acquired. All ETMRs, despite their highly heterogeneous histology, are characterized by specific high expression of the RNA-binding protein LIN28A, which is, therefore, often used as a diagnostic marker for these tumors. ETMRs have few recurrent genetic aberrations, mainly affecting the miRNA pathway and including amplification of C19MC (embryonal tumor with multilayered rosettes, C19MC-altered) and mutually exclusive biallelic DICER1 mutations of which the first hit is typically inherited through the germline (embryonal tumor with multilayered rosettes, DICER1-altered). Identification of downstream pathways affected by the deregulated miRNA machinery has led to several proposed potential therapeutical vulnerabilities including targeting the WNT, SHH, or mTOR pathways, MYCN or chromosomal instability. However, despite those findings, treatment outcomes have only marginally improved, since the initial description of this tumor entity. Many patients do not survive longer than a year after diagnosis and the 5-year overall survival rate is still lower than 30%. Thus, there is an urgent need to translate the new insights in ETMR biology into more effective treatments. Here, we present an overview of clinical and molecular characteristics of ETMRs and the current progress on potential targeted therapies.

Fig. 1

Histology of ETMRs. Each panel shows diverse histological variants of ETMRs with the last panel showing an example of an atypical osteoid differentiation pattern in an ETMR [105]

Fig. 2

Clinical characteristics of ETMRs. The first panel shows the distribution of ETMRs throughout the brain divided by the presence of C19MC amplification, indicating that C19MC − ETMRs are more often located infratentorially. The second and third panel show the age and gender distribution of ETMR patients. The few data that is available for C19MC − ETMR suggests that there is no difference in age or gender distribution with C19MC + ETMRs, which is the reason why they are not visualized separately. The fourth panel shows the overall survival of ETMRs. There is a slight trend that C19MC − ETMR patients may do worse, but the difference with the C19MC + ETMRs is not significant. C19MC + denotes tumors having C19MC amplifications, C19MC − denotes tumors lacking C19MC amplifications

Fig. 3

miRNA processing in ETMRs. a Overview of miRNA processing and maturation using the C19MC miRNA cluster as an example. The effects on C19MC target genes are colored based on the result on mRNA translation, green showing an increase and red a decrease in translation. The processing steps shown in this Figure are applicable to all miRNAs and not exclusive to C19MC. b Overview of different scenarios that mutations in DICER1 have on the abundance of 3p and 5p forms of mature miRNAs

Fig. 4

Aberrations found in ETMRs. Figure showing the four identified potential drivers of ETMRs schematically in the top row, the distribution of these aberrations in the second row and the distribution of gains and losses in the last row. In the distribution of potential drivers colors denote C19MC + (red) and C19MC − (blue). In the distribution of copy number aberrations green denotes a gain and red denotes a loss. No significant differences in copy number changes have been observed between C19MC + and C19MC − [80]

Fig. 5

Regulation of let-7 by LIN28A. Schematic overview of miRNA processing of let-7 and repression of let-7 targets in the absence (left) or presence (right) of LIN28A. ETMRs have low expression of let-7 miRNAs and high expression of LIN28A as is shown in the right overview. This pathway is exclusive to let-7 miRNAs and does not apply to all miRNAs

Fig. 6

Active pathways in ETMR. Figure illustrating genes and pathways active in ETMR downstream of DICER1 (mutations) and C19MC and that have been investigated in ETMRs