A deep dive into the genome of mucosal melanomas has delivered some leads on potential new therapies for the disease and challenged some previously held understanding about its aetiology.
The international research, led by the Professor Richard Scolyer from the Melanoma Institute of Australia and the University of Sydney, comprised whole genome sequencing on 67 tumour samples.
The study found a large proportion of the tumours (70%) had mutations which would potentially be responsive to CDK4/6 inhibitors currently used to treat HR positive, HER2 negative breast cancer.
Professor Scolyer told the limbic the finding might be particularly relevant for Asian countries, which had higher rates of mucosal melanoma than Australia.
“In China, their incidence of melanoma is about 1/80 of Australia but their population is 80 times that of Australia. So they actually have the same amount of cases all up and their melanomas are predominately acral and mucosal melanomas,” he said.
Mucosal melanoma did not respond as well to immunotherapy as cutaneous melanoma, he noted.
“With combination immunotherapy, about 60% of patients with cutaneous melanoma will respond to it. For acral melanoma it’s probably about 40% and for mucosal melanoma it’s more like 20%.”
“The other problem that we’ve got with mucosal melanoma is because they arise in sites that are more hidden from view, they often present at a more advanced stage than cutaneous melanoma.”
Professor Scolyer said the study also demonstrated some heterogeneity in the mutational signatures of mucosal melanomas depending on their site.
“In contrast to cutaneous melanoma, we don’t think ultraviolet light is a primary aetiological factor but when we look carefully for ultraviolet light DNA mutation signatures within the tumours, we saw that there was low level signatures within the upper body mucosal tumours, so those arising from the nose and inside the mouth.”
“That raises the possibility that perhaps UV light is playing a part for those upper body tumours.”
“Melanoma is not one disease. Mucosal melanoma is a different disease from cutaneous melanoma and potentially has different causes but we’re still working hard to identify the causes.”
The study, published in Nature Communications, was also able to provide some clues as to why immunotherapy was not as effective in mucosal melanoma as in cutaneous melanoma.
“We know for acral and mucosal melanomas, they don’t respond as well to immunotherapy as cutaneous melanomas. Part of that story is likely to be related to the mutation burden of the tumours. So if you have got more mutations in the tumour you express more neoantigens on the surface of the tumour cells, which stimulate the body’s immune system to recognise them.”
“There are not so many of those in acral and mucosal melanomas. We saw mutations in HLA-A and in a small proportion of cases, mutations in the beta-catenin pathway and we know that pathway, if abnormal, can result in T-cell exclusion so potentially that is another reason why mucosal melanoma patients don’t respond to immunotherapy.”
He said with HLA-A mutations, there would not be presentation of the antigens of the surface of the cell.
“The body would have trouble recognising the tumours as being non-self basically. That is another mechanism potentially for why these tumours don’t respond so well to immunotherapy.”