Heterogeneity

Heterogeneity is an important term for all genetic diseases and EHE, like all cancers, can be considered a genetic disease. Only in EHE, unlike most cancers, there is a single responsible genetic alteration (mutation) that starts the disease in each person - I say it this awkward way because each cell can obviously later develop additional mutations. Heterogeneity refers to the fact a range of different mutations can lead to a single type of disease. For instance, hundreds of different mutations can lead to dwarfism (disproportionate short stature), or hemoglobinopathy. Within any given category of disease you can slice the distinctions with an ever sharper blade and still come up with variations in the particular mutations that cause that disease. So, even within a type of hemoglobinopathy, like sickle cell, you might find that most patients have a specific mutation that leads to the most common amino acid substitution in the beta-globin molecule, but there are other, rarer beta globin mutations that also lead to red cell sickling. Thus heterogeneity means it can be important to know what specific mutation a patient has because it will affect their clinical course and possibly their treatment. This is especially true for targeted therapy or precision medicine since the treatment will depend on the specific mutation.

This all leads up to pointing out that EHE is heterogeneous. The most common mutation (~90%) result from a balanced, reciprocal translocation (see future 'words of the day') that fuses the gene coding for TAZ (a transcritional co-activator) to that coding for CAMTA1. The other 10% are caused by a similar fusion between YAP (a close relation to TAZ) to TFE3. We don't know yet if the different mutations result in different clinical outcomes. Or whether they might be similar in terms of response to different treatments. These questions are an important part of future research. Furthermore, if we can find a way to use 'precision medicine' to stop the expression or effects of a particular fusion protein, then we will clearly need to define the underlying mutation for each EHE patient.