Acral melanoma—a rare, aggressive form of skin cancer—has long puzzled researchers due to its unique biological characteristics and its uneven incidence among different populations. Unlike the more common UV-driven melanoma, which primarily results from sun exposure, acral melanoma originates in areas typically shielded from ultraviolet radiation, such as the palms, soles, and nail beds. This distinction has profound implications on both its development and clinical behavior, demanding deeper investigation to unravel its genetic and biological complexities.
A multidisciplinary team from the Wellcome Sanger Institute and the National Autonomous University of Mexico (UNAM), alongside international collaborators, has delved into the somatic and genetic underpinnings of acral melanoma within a predominantly Mexican cohort. The scientists performed an extensive genomic analysis on 123 tumorous samples drawn from 92 Mexican individuals diagnosed with acral melanoma. Employing cutting-edge DNA sequencing technologies paired with sophisticated transcriptomic profiling, they sought to map not only the mutations present in the cancer genome but also the dynamic patterns of gene expression that drive tumor biology.
A particularly innovative aspect of this study was the incorporation of genetic ancestry analysis. By correlating patients’ inherited genetic backgrounds with the molecular features of their tumors, the researchers were able to reveal how genetic ancestry shapes tumor mutations and gene activity, thereby influencing disease trajectory. This approach addresses a significant gap in oncological genomics, where individuals of Latin American descent have historically been underrepresented, leading to less tailored clinical insights for this demographic.
The team’s findings underscore the heterogeneity within acral melanoma, disproving the erstwhile notion of a monolithic disease entity. Instead, acral melanoma manifests as at least three distinct molecular subtypes, each characterized by unique gene expression profiles and clinical outcomes. Tumors rich in immune-related gene activity were linked to improved prognosis, suggesting an intrinsic immunological surveillance that may suppress cancer progression. Conversely, cancers exhibiting heightened proliferative and pigmentation pathways were correlated with higher recurrence rates and poorer survival, pointing to aggressive tumor phenotypes driven by rapid cell division and altered pigment cell biology. A third cluster demonstrated metabolic rewiring, with variable patient outcomes, indicating metabolic plasticity as a potential driver of tumor behavior.
A critical insight implicated the BRAF gene, a well-known oncogenic player in melanoma biology. Mutations in BRAF are prevalent in roughly half of all UV-induced melanomas, driving aberrant cell signaling that fosters unchecked proliferation. However, the frequency of BRAF mutations in this Mexican acral melanoma cohort was notably diminished. Intriguingly, the presence of mutated BRAF was more common among patients with higher European genetic ancestry than those with predominantly Indigenous American heritage, revealing ancestry-specific molecular distinctions that could impact therapeutic responsiveness.
These discoveries are not only scientifically significant but diagnostically and therapeutically transformative. Currently, acral melanoma is treated much like other melanoma subtypes, predominantly based on data derived from European populations afflicted by UV-induced variants. The nuanced understanding that acral melanoma comprises diverse molecular subclasses, shaped intricately by genetic ancestry, argues for tailored diagnostic criteria and personalized treatment strategies. An improved stratification of patients according to tumor gene expression could usher in more precise prognostic models and the emergence of targeted therapies that address specific biological pathways within tumor subtypes.
Moreover, the study highlights an urgent need to rectify global disparities in cancer research. Latin American populations have been dramatically underrepresented in cancer genomics databases, comprising roughly one percent of samples in major datasets such as The Cancer Genome Atlas (TCGA) and the Pan-Cancer Analysis of Whole Genomes. This lack of diversity has stymied efforts to fully comprehend cancer biology across humanity’s genetic mosaic and has perpetuated inequities in treatment efficacy for underrepresented groups.
The researchers emphasize the importance of establishing robust cancer registries and genomic research infrastructures in Latin America to support large-scale, population-specific studies. Such efforts will augment the richness of the global oncogenomic landscape and accelerate the discovery of clinically actionable insights relevant to diverse ancestral backgrounds. This endeavor is critical for diseases like acral melanoma, where the intersection of ancestry and tumor biology is pronounced.
In addition to shedding light on acral melanoma’s molecular landscape, the study exemplifies the power of integrative genomics—melding somatic mutation data, gene expression profiles, and patient ancestry—to unravel the complex interplay between genetics and cancer evolution. By charting this integrative roadmap, the study paves the way for precision oncology approaches that are truly inclusive and broadly applicable.
Looking ahead, the research team envisions developing therapeutic modalities that exploit the vulnerabilities inherent to each acral melanoma subtype. For instance, immunotherapy regimens might be optimized for tumors enriched in immune gene signatures, while therapies targeting cell cycle regulators or pigmentation pathways could be explored for more proliferative subtypes. Additionally, metabolic interventions may hold promise for the metabolically distinct group. This stratified approach could significantly enhance the efficacy of treatments and improve patient quality of life.
This groundbreaking work not only advances the biological understanding of acral melanoma but also galvanizes a broader movement toward equity in cancer research. It underscores that the diversity of human populations is a critical variable in disease manifestation and treatment, urging the scientific community to pursue inclusivity as a cornerstone of future oncological investigations.
As the findings circulate among clinicians and researchers worldwide, they herald a paradigm shift in how rare melanoma subtypes are recognized, studied, and managed. The study’s integrative model may serve as a blueprint for investigating other under-studied cancers prevalent in diverse populations but neglected in current research frameworks, thereby fostering a more equitable future in cancer care.
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Subject of Research: Genetic and molecular characterization of acral melanoma in a Latin American population; influence of genetic ancestry on tumor biology and clinical outcomes.
Article Title: Ancestry and somatic profile indicate acral melanoma origin and prognosis
News Publication Date: 18 February 2026
Web References:
• Wellcome Sanger Institute – www.sanger.ac.uk
• Melanoma Research Alliance – https://www.curemelanoma.org/about-melanoma/types/acral-melanoma
References:
1. Mingyue Wang et al. (2025). Recent global patterns in skin cancer incidence, mortality, and prevalence. Chinese Medical Journal. DOI: 10.1097/CM9.0000000000003416
2. Melanoma Research Alliance. Acral Melanoma [Online resource].
3. Molina-Aguilar, C. & Robles-Espinoza, C. D. (2023). Tackling the lack of diversity in cancer research. Disease Models & Mechanisms. DOI: 10.1242/dmm.050275
Keywords: Acral melanoma, genetic ancestry, somatic mutations, BRAF mutation, Latin American population, genomic diversity, skin cancer, tumor heterogeneity, gene expression profiling, cancer prognosis, personalized oncology, integrative genomics
