A rare skin disorder linked to cancer has been traced to four more genes, opening the door to diagnosis at birth and targeted therapies.
Veronica Kinsler at the Crick, where she studies mosaic disorders caused by genetic mutations that arise during development, alongside her clinical work at Great Ormond Street Hospital for Children. Credit: Steve Potvin.
Some blue birthmarks mean nothing at all. However, more and more are being found to be caused by a gene change before birth, that could pave the way to cancer. New research now helps identify which are which.
Every year, around 200 babies are born in the UK with Extensive Dermal Melanocytosis (EDM), a ‘mosaic’ skin disorder caused by genetic mutations occurring during pregnancy.
“One or two mutations happen in every cell of the developing embryo, every time it divides. Often these mutations don’t appear to do anything, however sometimes the mutation is serious. That cell continues to divide and produce new cells containing that same mutation, so these abnormal cells can end up in many different organs in the body,” explains Veronica Kinsler, Principal Group Leader for the Mosaicism and Precision Medicine Laboratory at the Crick, who also works as a clinician at Great Ormond Street Hospital for Children.
“When some of these cells end up in the skin we recognise them as birthmarks. With this particular type of birthmark, we know it is a clue that there may be cells in other parts of the body, and also that there is a risk of cancer in the skin, eye or brain,” says Veronica. “So a child with this type of birthmark may need to have other investigations to see if there are problems in other areas of the body,” she says.
At Great Ormond Street, Veronica runs NHS England’s Rare Disease Collaborative Network for Mosaic Disorders, the national specialist service for mosaic disorders, and connecting her clinical expertise to her Crick research lab unlocks enormous potential.
“I was always interested in the science intrinsic to medicine, and I was lucky that my training in medicine included a basic science degree. Once I was in clinical practice, I found I had many questions about my patients and their diseases that I couldn’t answer, and that apparently nobody could answer,” says Veronica. “So, someone recommended I do a PhD to answer these questions. Getting into a lab was transformational as I found I could move our understanding forward.”
“I now spend about 20% of my time on clinical practice, and the rest on discovery science – because that’s the best way to move things forward for my patients, and they remain my primary motivation,” she says. “Over the years, our findings have identified the genetic causes of birthmarks, and when we need to worry about brain scans or other investigations.”
Until recently only a single gene, GNAQ, was known to be linked to EDM, found by Veronica’s group. They have now identified four more genes, never previously linked to the condition. Changes to these genes – HRAS, ACTB, PIK3CA and GNA11 – can affect other organs beside the skin and some can increase the risk of melanoma in eyes, skin and brain.
The skin findings in each case look the same, but the different genetic causes have potentially very different risks for the child. Understanding these different causes identifies which children need which investigations and opens the door to genetargeted therapies.
Over the last 10 years, Veronica and her team have been developing precision medicine therapies, which are designed to target the genetic mutations that are the root causes of mosaic disorders, using a gene silencing technology called short interfering RNAs (siRNAs).
“Having identified five different causes of EDM, we are not only able to offer more patients a genetic diagnosis, but we hope soon to be able to offer patients gene-targeted therapies for the first time” she says. “Theoretically, causing reversal of the birthmarks with the therapies should reduce the risk of melanoma.”
