Genetic ancestry may play a key role in how acral melanoma, a rare and aggressive type of skin cancer, develops and behaves, with important implications for diagnosis and treatment, new research shows. Researchers at the Wellcome Sanger Institute, National Autonomous University of Mexico (UNAM) and their collaborators analysed the genetic makeup of over 100 acral melanoma tumours from Mexican patients to understand how this cancer develops, including studying how ancestry influences tumour biology. They uncovered that acral melanoma varies, with three groups showing distinct gene expressions that are associated with different outcomes. Published today (18 February) in Nature, the study provides one of the most comprehensive genetic studies of acral melanoma in a Latin American population to date. The findings highlight the importance of including diverse populations in cancer research and clinical trials to fully understand how cancers develop and respond to treatment. Most melanomas, a type of skin cancer, are caused by exposure to ultraviolet (UV) radiation from the sun and are commonly studied in populations from European ancestries. However, acral melanoma is a different subtype of skin cancer as it arises in parts of the body that are not exposed to sunlight, in particular the palms of hands, soles of feet and under the nails. Over 330,000 people were diagnosed with melanoma globally in 20221 but acral melanoma is considered a rare type, accounting for only about one to three per cent of all melanoma cases diagnosed.2 However, in many cases it represents the majority of the diagnosed cases in people with Indigenous American, Asian and African ancestry. Despite the differences seen in acral melanoma, melanoma is often treated as a single disease based on knowledge from studies of UV-driven melanoma, despite growing evidence showing that acral melanoma behaves differently to UV-driven melanoma. As a result, acral melanoma has been historically under-studied, underrepresented in cancer genomic studies3 and lacks an approved specific targeted treatment. These gaps are particularly evident in Latin America where national cancer registries are limited or absent. In a new study, researchers at the Sanger Institute, UNAM, and their collaborators sought to understand what genetic changes underlie acral melanoma in Latin America, focusing on tumours from Mexican patients. The team analysed 123 tumours from 92 Mexican patients diagnosed with acral melanoma by generating genomic data at the Sanger Institute. Using a combination of DNA sequencing and gene expression analysis, the researchers examined tumour mutations, large-scale genetic changes and patterns of gene activity. They also looked at the genetic ancestry of patients, allowing them to directly study how ancestry relates to tumour DNA. This allowed the researchers to link the molecular structure of acral melanoma tumours with clinical outcomes, providing deep insight into how genetic background shapes the behaviour of this type of cancer. The researchers found that classic melanoma mutations were far less common overall in the acral melanoma tumours from Mexican patients. For example, the BRAF gene normally includes instructions to make the BRAF protein, which is involved in cell development pathways. A mutated version of BRAF is present in around half of UV-driven melanomas. However, in this cohort, patients with more European ancestry were more likely to carry BRAF mutations than those from Indigenous American ancestry. By analysing the gene activity across tumours, the researchers also identified three distinct clusters of acral melanoma that were associated with different outcomes. Firstly, tumours showing higher expression of immune-related genes were associated with better outcomes. Secondly, tumours that showed rapid cell growth and pigmentation pathways – the cellular processes that regulate pigment production in cells – were linked with recurrence and poorer outcomes. Thirdly, a group of tumours that showed a change in their metabolic pathway were associated with more variable outcomes. Together, these results bolster the understanding of acral melanoma. It is not a single disease but shows groups of high variability, which are distinctly associated with how the cancer behaves. Therefore, incorporating genetic information of tumours could improve prognosis and support a more personalised treatment plan. More broadly, the study highlights a key issue in cancer research: the lack of genomic data from non-European populations. By focusing on a Latin American population, the study demonstrates how research that includes diverse populations can lead to a more accurate and equitable understanding of disease. Dr Patricia Basurto-Lozada, first author at the National Autonomous University of Mexico, said: "We found that acral melanoma is not a single disease. Tumours fall into distinct biological groups that are linked to different patient outcomes. This information may be crucial for developing targeted treatments for acral melanoma in the future and ultimately improving the lives of patients." Dr Patrícia Abrão Possik, co-author, International Fellow at the Wellcome Sanger Institute and Group Leader at the Brazilian National Cancer Institute (INCA), said: "We have an issue in Latin America where we have limited cancer registries, which are essential for tracking cancer trends over time. That's why it's key for us to gather and analyse data that helps scientists, clinicians and ultimately patients, to deliver the best care possible for those diagnosed with acral melanoma." Dr Carla Daniela Robles-Espinoza, senior author and former International Fellow at the Wellcome Sanger Institute, based at the National Autonomous University of Mexico, said: "When patients enter clinical trials, it is not a one size fits all approach. To understand how well treatments work, we need studies that include people from diverse ancestral backgrounds. This research provides crucial context about the genetic makeup of acral melanoma, which may influence response to treatments." Dr David Adams, co-senior author at the Wellcome Sanger Institute, said: "Our research highlights the underrepresented nature of cancer genomics studies. By emphasising the need for more diversity in research and clinical trials, we hope the findings contribute to improved outcomes for patients with rare and aggressive cancers like acral melanoma." |
