Montreal Cancer Consortium team sheds light on why men may be genetically more prone to melanoma

This year, an estimated 8,000 Canadians will be diagnosed with melanoma. While both men and women are affected by this form of skin cancer, men are more likely to be diagnosed with it and have a worse prognosis than women.

It remains unclear exactly why this happens, but a recently published study by researchers from the Montreal Cancer Consortium (MCC) is shedding new light on the role genes found on the sex chromosomes may play in melanoma.

Led by Dr. Ian Watson at the Goodman Cancer Research Centre and published in Nature Cancer, the study analyzed genetic mutations in over a thousand melanoma cases, identifying three genes on the X chromosome with significant mutations linked to UV exposure. Females have two X-chromosomes whereas males have an X and a Y chromosome.

“Importantly, of the three significantly mutated genes we found on the X-chromosome, one gene had a specific type of mutation found only in males”, noted Dr. Watson.

The role of genes found on the sex chromosomes in melanoma

Females can develop other types of mutations in the gene in question, but since they have two X chromosomes, they have two copies allowing the second to serve as a backup if the first gets mutated. Males of course only have one copy of the X chromosome.

“These mutations may help explain why male melanoma patients have higher incidence and worse survival rates,” says Rached Alkallas, a McGill University PhD student and co-first author of the published work.

“We’re continuing to do more research in this area, including determining how these mutations affect melanoma biology, and response to immunotherapy,” explained Dr. Mathieu Lajoie, a research associate in the Watson lab and co-lead of the study.

More effective personalized treatment on the horizon

The MCC is a groundbreaking program that brings together researchers from cancer centres across Montreal to work together on projects that accelerate the implementation of precision medicine for cancer. One of these projects, led by Dr. Watson, is trying to understand why some patients with melanoma respond positively to immunotherapies while others do not.

“Immunotherapy has been life-changing for many melanoma patients,” Dr. Watson says of the form of treatment that reactivates a cancer patient’s immune system to get rid of cancer cells. “Unfortunately, a large subset of patients still don’t respond to this treatment and we’re working in collaboration to understand where the problems lie in order to connect all the dots.”

In addition to men and women having different incidence and survival rates, data is beginning to emerge that suggest they may also have different response rates to the latest forms of therapy. Dr. Watson is now investigating whether the sex difference in mutations he uncovered might help explain the reason. Deepening our knowledge of the genetics of various melanoma subtypes could also go a long way in providing personalized treatment whereby patients are matched with the therapies that are most likely to treat their specific cancer.

The importance of working together

Dr. Watson underlines the important role that the wider health community has played in his research, including oncologists, surgeons, dermatopathologists, immunologists and basic science researchers.

“Without the V Foundation and the Terry Fox Research Institute, my research would not have been possible,” he says. “In cancer research, you need experts from a variety of fields who can delve into our fundamental understanding of cancer, all this requires collaborations in both Canada and abroad.”

While there are still many unknowns, this study has significantly progressed our understanding of how UV exposure causes genetic changes that can lead to melanoma. The research also strengthens the rationale for following recommendations when it comes to safe sun exposure.

This article was developed from a press release produced by the Goodman Cancer Research Centre.

Study

Multi-omic analysis reveals significantly mutated genes and DDX3X as a sex-specific tumor suppressor in cutaneous melanoma

Authors

Rached Alkallas, Mathieu Lajoie, Dan Moldoveanu, Karen Vo Hoang, Philippe Lefrançois, Marine Lingrand, Mozhdeh Ahanfeshar-Adams, Kevin Watters, Alan Spatz, Jonathan H. Zippin, Hamed S. Najafabadi & Ian R. Watson