Acral melanoma study finds ancestry-linked genetic drivers in Latin American patients

Acral melanoma study reveals ancestry-linked differences

Researchers have completed the largest genomic study of acral melanoma in a Latin American population, analyzing tumors from 92 Mexican patients. The work, published in Nature, reveals significant differences in genetic drivers compared to studies in predominantly European populations. It directly addresses a critical gap, as Latin American samples are severely under-represented in global cancer genomics databases.

Acral melanoma is the most common type of melanoma reported in several non-European-descent populations, including people of Mexican descent. Unlike most skin melanomas, it is not primarily linked to ultraviolet radiation exposure and often appears on the palms, soles, or under nails.

Key genetic findings in Mexican cohort

The team sequenced the genome and transcriptome of 123 tumors. They found far fewer mutations in classic melanoma driver genes like BRAF, NRAS, or NF1 than typically seen in studies of European-ancestry patients.

Most patients in the cohort had predominantly Amerindian genetic ancestry. Intriguingly, patients with higher European ancestry showed an increased frequency of BRAF mutations.

• Fewer mutations in classical drivers (BRAF, NRAS, NF1).
• Higher European ancestry linked to more BRAF mutations.
• Tumors with BRAF mutations resembled cutaneous melanocytes.

Ancestry points to different cell of origin

The study suggests that the cell giving rise to the cancer may differ based on ancestry. Tumors with activating BRAF mutations had a transcriptional profile more similar to cutaneous, non-volar melanocytes.

This indicates that acral melanomas in patients with higher European ancestry may originate from a distinct cell type compared to tumors arising in the same physical locations in patients with different genetic backgrounds.

Three clusters predict patient survival

Through transcriptional profiling, the researchers defined three distinct molecular expression clusters within the acral melanoma tumors. The characteristics of these clusters were strongly associated with patient outcomes.

Membership in a specific cluster was linked to significant differences in both recurrence-free survival and overall survival. This classification could provide a new framework for prognosis and future treatment strategies.

Study underscores need for diverse genomics

The findings highlight how cancer risk and biology can be influenced by genetic ancestry and environmental factors. The researchers conclude that their work "enhances knowledge of this understudied disease."

More broadly, the study serves as a powerful reminder of the urgent need to include samples from diverse ancestral backgrounds in cancer research. Without this diversity, precision medicine approaches will remain incomplete and inequitable.