Acral Melanoma Is Three Diseases, Not One, Largest Latin American Study Shows

Acral melanoma is a form of skin cancer that behaves unlike the melanoma most people know. It does not arise on sun-exposed skin, and ultraviolet radiation - the dominant driver of common melanoma - plays little or no role in its development. Instead, it grows on the palms of hands, the soles of feet, and beneath fingernails and toenails. Globally, it accounts for roughly one to three percent of all melanoma diagnoses, but in populations of Indigenous American, Asian, and African ancestry, it is often the most common form of the disease.

Despite this profile, acral melanoma has been studied primarily through the lens of UV-driven melanoma. Most genomic datasets, most clinical trials, and most approved targeted therapies were developed based on research conducted predominantly in populations of European ancestry with sun-driven tumors. The result is a disease that is simultaneously rare, aggressive, disproportionately affecting non-European populations, and lacking any specific approved targeted treatment.

A study published in Nature, conducted by researchers at the Wellcome Sanger Institute and the National Autonomous University of Mexico (UNAM) with collaborators across Latin America, represents the most comprehensive genomic characterization of acral melanoma in a Latin American population to date. The findings confirm that acral melanoma is not a single disease - and reveal that who the patient is, genetically, shapes what mutations their tumor carries.

Three Subtypes With Different Outcomes

The research team analyzed 123 tumors from 92 Mexican patients diagnosed with acral melanoma. Using both DNA sequencing and gene expression analysis, they examined tumor mutations, large-scale chromosomal changes, and patterns of gene activity simultaneously - producing a multi-dimensional portrait of the tumor landscape.

When the gene expression data were analyzed across all tumors, three distinct clusters emerged. The first cluster was characterized by high expression of immune-related genes and was associated with better patient outcomes. The immune activity in these tumors may indicate that the patient's own immune system is actively engaging the cancer, a state that also predicts better responses to immunotherapy in other cancer types.

The second cluster showed elevated activity in pathways driving rapid cell proliferation and pigmentation - the cellular machinery regulating melanin production. Tumors in this cluster were associated with recurrence and poorer outcomes, suggesting a more aggressive growth phenotype.

The third cluster displayed altered metabolic pathways and showed more variable outcomes - neither uniformly good nor uniformly poor, suggesting biological heterogeneity within this group that may require further subdivision in future studies.

"We found that acral melanoma is not a single disease," said first author Dr. Patricia Basurto-Lozada of UNAM. "Tumors 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."

Ancestry Shapes Which Mutations Appear

One of the study's most distinctive features was its direct analysis of patients' genetic ancestry alongside their tumor genomics - an approach that allowed researchers to ask whether ancestral background predicts which mutations arise in these tumors.

It does. The BRAF gene mutation, present in roughly half of UV-driven melanomas and the target of several approved therapies, was far less common overall in this cohort of acral melanoma tumors. But within the cohort, the frequency varied by ancestry: patients with greater European ancestry were more likely to carry BRAF mutations than those with predominantly Indigenous American ancestry. This finding has direct clinical implications. BRAF-targeted therapies only work in patients whose tumors carry BRAF mutations. If BRAF mutation rates vary with ancestral background, then a treatment evaluation conducted predominantly in European-ancestry populations will systematically overestimate how many Latin American patients will respond to BRAF inhibitors.

A Gap in Cancer Genomics

Latin American populations represent approximately one percent of all samples in major cancer genomic databases such as The Cancer Genome Atlas and the Pan-Cancer Analysis of Whole Genomes. The consequences of that underrepresentation extend beyond statistics: treatments are developed, approved, and standardized based on data that do not reflect the biology of a substantial fraction of the global cancer burden.

The situation is compounded in Latin America by the absence or incompleteness of national cancer registries in many countries, which limits even basic epidemiological understanding of how common different cancer subtypes are in these populations. Dr. Patricia Abraao Possik, co-author and group leader at the Brazilian National Cancer Institute, noted that filling this data gap requires active efforts to generate and share genomic data from diverse patient populations across the region.

Limitations and Future Directions

The 92 patients in this study were all from Mexico, which, while representing a significant contribution to acral melanoma genomics in Latin America, does not capture the full diversity of ancestry and environmental exposures across the continent. Whether the three biological subtypes identified here replicate in Brazilian, Peruvian, or Colombian populations - each with different admixture patterns and different healthcare systems - remains to be established.

The study identifies subtypes and their associations with outcomes but does not constitute a clinical validation study for any specific treatment approach. Moving from subtype identification to approved targeted therapies requires prospective clinical trials that enroll patients on the basis of subtype classification - trials that do not yet exist for acral melanoma.

The research was supported by Wellcome, the Melanoma Research Alliance, and the Mexican National Council of Humanities, among others.