Largest Acral Melanoma Study Uncovers Three Distinct Subtypes – Wellcome Sanger Institute Breakthrough

Understanding Acral Melanoma: A Rare and Aggressive Skin Cancer

Acral melanoma, also known as acral lentiginous melanoma (ALM), is a subtype of skin cancer that develops on the palms of the hands, soles of the feet, or under the nails—areas not typically exposed to sunlight. Unlike the more common cutaneous melanoma, which is strongly linked to ultraviolet (UV) radiation from sun exposure, acral melanoma arises independently of UV light, making traditional prevention strategies less effective. This rarity and unique biology contribute to its aggressive nature and poorer prognosis compared to other melanomas.

In the United Kingdom, melanoma skin cancer diagnoses total around 16,700 annually, with acral melanoma accounting for approximately 1-3% of cases, or roughly 170-500 instances per year. While overall melanoma survival rates exceed 90% at 10 years for early detection, acral melanoma's five-year survival drops to about 80%, largely due to late diagnosis when tumors are thicker and more invasive. Risk factors include chronic trauma or friction in acral sites, genetic predisposition in non-European ancestries, and possibly environmental exposures, though no definitive causes like Agent Orange—linked in U.S. veterans—are prevalent in the UK.

Current standard treatment involves wide local excision surgery, often with sentinel lymph node biopsy for staging. For advanced stages, immunotherapy (e.g., checkpoint inhibitors like pembrolizumab) or targeted therapies (e.g., BRAF inhibitors if mutated) are used, but response rates are lower in acral melanoma due to distinct genomic drivers like NRAS or KIT mutations rather than BRAF. Sentinel node positivity occurs in up to 20% of cases, underscoring the need for better prognostic tools.

The Landmark Study from Wellcome Sanger Institute and Mexican Collaborators

Published on February 18, 2026, in Nature, this collaborative effort between the UK-based Wellcome Sanger Institute, Mexico's National Autonomous University (UNAM), and the National Cancer Institute of Mexico represents the largest genomic analysis of acral melanoma in a Latin American cohort. Led by first author Dr. Patricia Basurto-Lozada and senior authors Dr. Carla Daniela Robles-Espinoza (UNAM) and Dr. David Adams (Sanger Institute), the study sequenced 123 tumors from 92 Mexican patients, generating whole-exome and RNA data at Sanger.

Mexican patients, with high genetic admixture (median 81% Indigenous American ancestry), provide a unique lens, as acral melanoma predominates in non-European populations globally. The Sanger Institute's expertise in large-scale genomics was pivotal, highlighting UK leadership in international cancer research. Dr. Patrícia Abrão Possik, a Sanger International Fellow, emphasized the scarcity of Latin American cancer registries, making this dataset invaluable.

The study's scale—far surpassing prior efforts in diverse ancestries—challenges the view of acral melanoma as a uniform disease, paving the way for subtype-specific strategies applicable worldwide, including in the UK's multicultural population.

Methods: Unprecedented Genomic Profiling

Researchers employed whole-exome sequencing on tumor DNA to detect mutations, copy number alterations (via ASCAT and Sequenza), and mutational signatures. RNA sequencing on 77 primary tumors enabled gene expression clustering using the Cola R package. Patient ancestry was inferred via ADMIXTURE on genotyping arrays, revealing predominant Amerindian (90%), European (median ~10%), and minor African components.

Tumors were primarily from foot soles (median Breslow thickness 4.0 mm, 68% ulcerated, stage III common), reflecting real-world acral melanoma presentation. Clinical follow-up tracked recurrence-free and overall survival, integrating genomic data with outcomes.

• Mutation calling: cgpCaVEMan, MuTect2, VarScan2 consensus.
• Clustering: Non-negative matrix factorization identified three robust transcriptional subtypes.
• Validation: Compared to TCGA cutaneous melanoma and prior acral cohorts.

This rigorous multi-omics approach, powered by Sanger's high-throughput platforms, sets a benchmark for understudied cancers.

Key Discovery: Three Distinct Molecular Subtypes

The hallmark finding is the identification of three gene expression clusters, each with unique biology and prognostic implications:

• Cluster 1 (Immune/Epidermal): High expression of immune genes, epidermal markers; enriched cancer-associated fibroblasts (CAFs), CD4+ T cells. Associated with best outcomes—lowest recurrence.
• Cluster 2 (Proliferative/Pigmentation): Upregulated mitotic, pigmentation pathways; higher B cells. Linked to poorer prognosis, higher recurrence (OR 6.68), rapid progression.
• Cluster 3 (Metabolic/Oxidative): Altered respiration, oxidative stress genes; intermediate survival, variable outcomes.

Dr. Basurto-Lozada noted, “Tumours fall into distinct biological groups that are linked to different patient outcomes.” These subtypes explain heterogeneity, with Cluster 2 tumors showing aggressive features akin to high-proliferative melanomas.

Genomically, low tumor mutation burden (TMB 0.95/Mb), frequent structural variants; drivers: NRAS (14%), KIT (14%), BRAF (13%), NF1 (9%). TERT promoter mutations in ~10.5%.

Photo by Europeana on Unsplash

Ancestry's Role: European Link to BRAF Mutations

Mexican admixture revealed ancestry-tumor correlations: higher European ancestry associated with BRAF mutations (P=0.02), suggesting cell-of-origin differences—BRAF tumors transcriptionally resemble cutaneous volar melanocytes. Amerindian ancestry trended with KIT mutations. Women had higher driver mutation rates (OR 3.83).

Dr. Robles-Espinoza stressed, “We need studies that include people from diverse ancestral backgrounds... genetic makeup may influence response to treatments.” This resonates in the UK, where diverse ancestries (e.g., South Asian, Black communities) see higher acral melanoma incidence.

Quadruple wild-type (no BRAF/NRAS/NF1/KIT) tumors dominated (60%), highlighting need for novel targets.

Prognostic Insights: Subtypes Predict Survival

Cluster 2 linked to worse recurrence-free survival (P=0.054); overall survival differences across clusters (P=0.011). Driver mutations increased recurrence risk (OR 5.31, P=0.008). Microenvironment (e.g., immune infiltration in Cluster 1) drives outcomes.

Incorporating transcriptomics could refine staging beyond Breslow thickness/ulceration. For UK patients, where acral melanoma survival lags (67.5% 10-year vs. 90% cutaneous), these biomarkers offer precision prognostication.

Treatment Implications: Towards Personalized Therapies

Current acral treatments mirror cutaneous (surgery, PD-1 inhibitors), but lower response rates (e.g., BRAF inhibitors ineffective in most). Study suggests subtype-targeting: immune Cluster 1 may respond to immunotherapy; proliferative Cluster 2 needs anti-mitotic agents; metabolic Cluster 3 metabolic inhibitors.

BRAF-enriched European-ancestry tumors could benefit from existing drugs. Dr. Adams highlighted underrepresented genomics: “By emphasising... diversity... we hope [for] improved outcomes.” UK trials (e.g., via CRUK) should prioritize diverse cohorts.Cancer Research UK advocates genomic testing expansion.

Future: Clinical trials validating subtypes, ancestry-stratified therapies. Links to research jobs in genomics at UK institutions like Sanger.

Challenges in Acral Melanoma Research and UK Context

Underrepresentation: Latin Americans ~1% in global cohorts; UK data skewed Caucasian. Late diagnosis common—acral sites overlooked. Sanger's role exemplifies UK genomics prowess, partnering globally.

UK incidence rising slowly; higher in ethnic minorities. NHS guidelines emphasize biopsy for pigmented lesions on acral sites. Prognosis gaps persist: 5-year survival ~80% vs. 93% cutaneous.

Photo by Planet Volumes on Unsplash

• Mechanical stress (e.g., foot friction) potential trigger.
• Need diverse biobanks, AI diagnostics for early detection.

Future Directions: Global Collaboration and UK Impact

Study calls for expanded registries, multi-ancestry trials. Sanger's COSMIC database integrates findings for researchers worldwide. UK benefits: Improved minority health outcomes, training in precision oncology via Sanger-Cambridge links.

Explore metabolic vulnerabilities (Cluster 3), immune modulation (Cluster 1). Potential for liquid biopsies monitoring subtypes.

Explore careers in cancer genomics at higher-ed research jobs or academic CV tips.

Conclusion: A Step Forward in Conquering Rare Cancers

The Sanger-led study transforms acral melanoma from monolith to mosaic, offering hope for tailored therapies. UK researchers' global leadership underscores higher education's role in health innovation. Patients: Check acral sites regularly; clinicians: Advocate genomic profiling. Stay informed via Rate My Professor, higher ed jobs, and career advice. Future research promises better survival across ancestries.