Cancer comparison between horses, humans and dogs pinpoints genetic drug targets

Mucosal melanoma tumours from horses, dogs and humans were genetically tested. Photo: Supplied
Mucosal melanoma tumours from horses, dogs and humans were genetically tested. Photo: Supplied

A study of mucosal melanomas in horses, humans and dogs has discovered key genes that will help prioritise targets for new cancer therapies.

The scientists who analysed the genomic data from 46 humans, 65 dog and 28 horse melanomas identified a handful of genes that were mutated in all species.

It is the first time that cancer genes in mucosal melanoma – a rare and poorly understood subtype of melanoma – have been compared across the three species.

The results, reported in the journal Nature Communications, provide insights into how cancer evolves across the tree of life and could guide the development of new therapies.

Mucosal melanoma is a rare form of melanoma, a tumour type usually associated with skin cancer.

Of the 15,400 people diagnosed with melanoma in Britain each year, around 1 percent will be diagnosed with mucosal melanoma.

The cancer arises from the cells that produce pigment, known as melanocytes, which are found not only in the skin but also mucosal surfaces of the body, such as the sinuses, nasal passages, mouth, vagina and anus.

The risk factors for mucosal melanoma are unknown, and there is no known link to exposure to ultraviolet light or family history.

Patients with the cancer often present late in the progression of the disease. The main treatment for mucosal melanoma is surgical removal of the tumour.

The cancer can also affect dogs and horses, with varying outcomes for the different species.

The research was undertaken by scientists at the Wellcome Sanger Institute and their collaborators.

“Genomics gives us a unique view into the hidden similarities and differences of cancer between species,” says Dr David Adams, one of the institute’s researchers involved in the study.

“The genetic changes, or mutations, we found in mucosal melanoma tumours across humans, dogs and horses suggests they are important enough to be conserved between species. These key mutations are likely to drive the cancer and could be targets for the development of new drugs.”

Immunotherapy, the stimulation of the body’s own immune system to attack cancer cells, has been used to treat some people with melanoma, but has not been effective for people with mucosal melanoma. The reason remains unknown.

Researchers now suggest that, unlike skin melanoma, mucosal melanoma tumours carry few mutations so they remain “hidden” to the immune system and do not spark the immune response needed to target the cancer.

“Understanding the genetic changes underpinning mucosal melanoma suggests why people with this particular type of cancer may not benefit from immunotherapies,” explains Kim Wong, another researcher from the institute involved in the study.

“Genomics can help identify who is at greater risk of developing mucosal melanoma and provide information to genetic counsellors and doctors advising patients on disease management.”

The study is the first to sequence horse tumours, and the first genomic experiment of this scale on dog tumours.

Grey horses are genetically predisposed to getting melanoma. However, the cancer is very different in horses as it does not usually spread, unlike the disease in humans and dogs.

“Spontaneous tumours in dogs are gaining recognition as ‘models’ of human cancers for the development of therapies that can benefit both species,” says Professor Geoffrey Wood, from the University of Guelph in Canada, who was involved in the research.

“This study shows the importance of understanding the genetic similarities and differences of cancers across species so that the most biologically relevant drug targets are prioritized.”

Kim Wong, Louise van der Weyden, Courtney R. Schott, Alastair Foote, Fernando Constantino-Casas, Sionagh Smith, Jane M. Dobson, Elizabeth P. Murchison, Hong Wu, Iwei Yeh, Douglas R. Fullen, Nancy Joseph, Boris C. Bastian, Rajiv M. Patel, Inigo Martincorena, Carla Daniela Robles-Espinoza, Vivek Iyer, Marieke L. Kuijjer, Mark J. Arends, Thomas Brenn, Paul W. Harms, Geoffrey A. Wood, David J. Adams. Cross-species genomic landscape comparison of human mucosal melanoma with canine oral and equine melanoma. Nature Communications, 2019; 10 (1) DOI: 10.1038/s41467-018-08081-1

The study, published under a Creative Commons License, can be read here

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