Our research is focussing on identifying new familial melanoma genes. These are genes or mutations that are high penetrants that occur in melanoma families with large numbers of cases. We’ve been sequencing using exome or genome sequencing multiple members of families with four, five or even more cases of melanoma and looking for some common extremely rare variant that is segregating with melanoma in those families.
Have you found any?
We actually have found quite a few variants that do segregate but the hard part is actually working out which ones of these are actually the smoking guns. We started by looking at the ones that are clear loss of function mutations so these are mutations that cause a premature truncation of the gene products. We found a number of those in the DNA repair pathway that intuitively make good candidates for melanoma predisposition genes.
Have you looked into organoids?
We have not looked at organoids yet. One of the issues with melanoma is that it’s actually not an epithelial cancer and organoids work really well for epithelial cancers. Melanocytes in the normal skin actually are dispersed so they don’t actually sit adjacent to each other, there are a lot of cells in between. So they don’t actually meet the criteria for easily forming an organoid but an organoid could be made, of course, if they were co-cultured with keratinocytes for example. So this is something that could be done in the future but it’s not an area of research that we’re actually investigating at this point.
Could this be applied to a targeted therapy?
Yes, the issue with some of these familial melanoma genes is their applicability to therapy. They have a clinical utility up front in that once they’ve been proven and they are robust findings then they can be going straight into genetic counselling, clinical genetics applications where people can be screened and given counselling depending on what their mutation status is. Those people can also then have more rigorous surveillance, they can actually have the whole body scans for nevus or melanoma development on a regular basis. But depending on the actual gene product it’s an open question of whether or not targeted therapies can be useful.
If we look at the genes that are already known familial melanoma genes then those in the CDKN2A–CDK4 axis clearly do have a therapeutic angle in that they signal to cell cycle and there are now a number of CDK4 inhibitors actively in clinical trials. So at least in those patients that carry germline mutations of CDKN2A-CDK4 you would expect that those kinds of inhibitors would actually prove to be quite useful. But for a number of the other genes there’s no obvious target at this early point in time.
Do you have a take home message?
One important thing for people to think about is that whilst about half of all the high density familial melanoma families are yet to be explained in terms of their genetic risk at this point in time, it’s possible that while some very rare or even private mutations do account for predisposition in a number of those families, it is also possible that a number of the other families have multiple melanoma cases by other means – either shared environmental factors or shared genetics at the polygenic level, so many genes acting together. So what I’m thinking of then is a number of people in families could all have the sun sensitive skin type, so they could be pale, they could have red hair and freckles, they could not tan very easily. Mixing that with shared environmental risks such as the families all go to the beach together and decide not to use sunscreens could be a reason why you get this clustering of cases in some families. So it’s not purely an autosomal dominant single gene mutation that accounts for that.
