What is ETMR/ETANTR and who does it affect?
Embryonal tumours with multilayered rosettes (ETMR) are rare, deadly brain tumours that affect mainly children below the age of 4 years. There are 300 cases reported but probably there are many more as this tumour is often misdiagnosed.
This newly suggested entity has been recognized based on a hallmark genetic alteration in the form of an excess copy number of a chromosomal locus Chromosome 19q34. Pathologists who help establish the diagnosis say it resembles to an undifferentiated neural tube, the most primitive form of our brain at the stage of the embryo.
Why is the tumour only seen in children under four?
We do not know why this tumour is only seen in this age group. However, there is enough data and rationale to suggest that it may be associated with a problem in the development of the brain.
Our recent findings suggest that it may either occur very early in the first trimester of gestation of the embryo or that it "re-awakens" in a young child a very early developmental pathway mandated for brain development at this stage.
ETMR/ETANTR is almost always fatal even with aggressive treatment. Why is this the case?
This is the case for a group of cancer in children and adults (glioblastoma, pancreatic cancer for example) that seem "locked" in a state that makes them inaccessible to current therapies.
This is why we need further studies to improve our understanding to what a tumour is potentially "addicted" and how it forms as this might help us "unlock" this state and/or make it responsive to current therapies or even better determine targeted therapies directed against what makes it grow/come back and resist treatment.
This is the aim of the study we undertook which is helping us come closer to more effective therapies.
What is currently known about the way the ETMR/ETANTR brain tumour develops?
ETMR are still under-diagnosed with less than 300 reported cases in the literature and so the development process of this tumour is still unclear. What we do know is that these are tumors that develop very early on in life and possibly originate from neural stem cells.
The research group of Dr. Annie Huang from SickKids in Toronto, our collaborator and co-PI in this study, identified this entity in 2009 and showed it to be specific to young infants and to be characterized by a genetic hallmark, the amplification (excess number of copies) of a genetic region within chromosome 19 which contains a microRNA cluster C19MC.
This microRNA cluster is very intriguing as it is only present in primates (humans and apes), and expressed in a very tight and narrow window in normal conditions: exclusively during the first trimester of gestation in the placenta and not elsewhere in kids or adult tissues.
MicroRNAs regulate the expression of our genes, and this cluster is large and little is known about its effects except that it is mandated for proper placental development.
Other than this, more research is definitely needed to clarify the exact mechanism of what these do and their role in this brain tumour.
Please can you outline your research into ETMR/ETANTR?
We stumbled across these tumours. We receive samples from pediatric brain tumours from collaborators across the world as we have an ongoing initiative to characterize the genetic make-up of deadly brain tumours in order to improve our understanding and identify alternative therapies.
A set of samples we received had a very specific genetic profile and showed the presence of the amplification Dr. Huang had described. Several had been misdiagnosed as is often the case and had been labelled under the name of another brain tumour. We were able to correct the diagnosis and studied further their genetic make-up with the help of Dr. Jacek Majweski and his group from the McGill University and Génome Québec Innovation Centre in Montreal.
Our aim was to see what drove the expression of this microRNA C19MC cluster and what it was doing in this tumour to help identify targets amenable to therapy.
What are the key findings of this study?
We found that a fusion between the C19MC cluster and a member of the "Tweety" family of genes, TTYH1 which is ironic in a way for a tumour that affects exclusively children. This "Tweety" gene is highly expressed mainly in the brain and actually help drive the very high expression of the C19MC cluster which would not have been able to be expressed otherwise.
In simpler terms, this fusion is a doorway that allows this cluster to be expressed at high levels in the brain.
We further showed that this led in ETMR, to the deregulation of a brain developmental pathway whereby an enzyme called DNMT3B is expressed at a very high level when it shouldn't be. This may be a new therapeutic target for future therapeutic avenues in patients with this tumor.
Notably, in an era where cognitive defects and other issues related with brain development are becoming increasingly important to study, our work provides insight into a previously unsuspected pathway in early brain development.
How close do you think we are to developing better treatments for this deadly childhood brain cancer?
We are one step closer to finding an effective therapy. This enzyme is involved in other high grade cancers and targeted therapies are underway there. We need to confirm in experimental models of ETMR that shutting it off will be of benefit and we can rapidly translate this to the clinic.
In addition, we are providing added tools to improve the diagnosis of this entity in children so that appropriate management based on how deadly ETMR are can be undertaken. This will allow these children to hopefully access the targeted therapy when they become available in the near future.
In a way, if they are not correctly diagnosed, these children will not be able to benefit from any targeted therapy when these become available and our study also helps correct this.
What are the main hurdles that need to be overcome?
We need to establish reliable experimental models to confirm our model of how ETMR form, and we will definitely need to see if we can control the levels of this DNMT3B enzyme to affect tumor cells in the lab before moving this to the clinic.
What are your future research plans?
The next step is to continue our research on the effects of controlling levels of DNMT3B in tumor cells and determine if we can change their growth patterns.
Dr. Huang will be fast-tracking the investigation of drugs targeting this enzyme in experimental models and we will be studying further the effects of tis enzyme on ETMR formation but also in brain development.
