Ancestry and somatic profile indicate acral melanoma origin and prognosis

Nature News · Feb 18, 2026 · Collected from RSS

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MainMelanoma is classified into several clinicopathological subtypes on the basis of tumour site of presentation and histopathological features. Acral melanoma is an understudied melanoma subtype due to its low incidence globally, and because it represents a small proportion of melanoma cases in European-descent populations2,10; however, acral melanoma represents the vast majority of melanoma cases in some Latin American, African and Asian countries due to the lower incidences of ultraviolet-induced melanoma subtypes11. Furthermore, the causes of this type of disease are unknown, with patients managed in a similar way to ultraviolet-associated cutaneous melanoma. However, its site of presentation and genomic characteristics are vastly different12.Acral melanoma arises on the glabrous (non-haired) skin of soles, palms and in the nail unit (subungual location), and its genome differs substantially from other cutaneous melanoma subtypes13. In contrast to ultraviolet-linked subtypes, acral melanoma has a lower burden of single nucleotide variants (SNVs), a higher burden of structural variants and a low prevalence of mutational signatures SBS7a/b/c/d, which are associated with ultraviolet irradiation14,15,16,17,18. Genes that are mutated frequently in cutaneous melanoma such as BRAF, the RAS genes and NF1, are reported to be altered at a significantly lower frequency in acral melanoma. This, coupled with the comparatively lower number of studies of acral melanoma when compared with other cutaneous melanoma subtypes, has translated into limited available therapies for acral melanoma management.It is known that cancer risk and incidence, as well as tumour genomic profiles, vary with ancestry and geographical location6,19,20. As most genomic studies on acral melanoma have been performed on patients of European or Asian ancestry, we considered it necessary to examine the genomics of this subtype of melanoma in Latin American people. Specifically, Latin American populations have been substantially under-represented in cancer genomic studies, with only about 1% of all samples in cohorts such as the Pan-Cancer Analysis of Whole Genomes, The Cancer Genome Atlas (TCGA) and other repositories, and those contributing to cancer genome-wide association studies, being of Latin American origin5,21,22. Identification of differences in the genomic profile among populations can potentially aid the discovery of germline/inherited or environmental factors related to acral melanoma aetiology, as well as identify optimal therapeutic strategies for all patients.In this study, we analysed 123 acral melanoma samples from 92 Mexican patients through genotyping, exome sequencing, SNV and insertion/deletion (indel) variant calling, copy number estimation and gene expression profiling, and examined the correlation of these molecular characteristics with clinical variables. We reveal a significant correlation between genetic ancestry and BRAF somatic mutations, as well as a distinct transcriptomic profile in tumours with BRAF-activating mutations compared with samples without activating mutations in BRAF. We also identify significant differences in recurrence-free and overall survival among patients with tumours with distinct gene expression profiles.Ancestry and clinical characteristicsA total of 123 uniformly ascertained samples from 92 patients from a large Mexican tertiary referral hospital were analysed in this study (Supplementary Table 1; Methods). Of these tumours, 89 were primaries, 27 were metastases, five were recurrences, one was a lesion in transit and one was unknown (Supplementary Table 1). Latin American genomes are generally a mixture of European, African and Amerindian ancestry. Of note, 90% of genotyped samples (n = 80) in this study had predominantly Amerindian ancestry (median 81%) (Supplementary Fig. 1 and Supplementary Table 2) with European and African ancestries contributing a median of 13.6% and 2.5%, respectively. The median age of the patients in this cohort was 60, with 59% of the patients being female. Most patients were stage III (American Joint Committee on Cancer, 8th edn)23 at diagnosis, and the most common primary site was the foot—most frequently the sole. The median Breslow thickness was 4.0 mm and most primary tumours were ulcerated (68%) (Table 1). It should be noted that only four patients received immune checkpoint inhibitors or targeted therapy, due to lack of access.Table 1 Clinical information for patients included in this studyFull size tableSex and ancestry link to somatic profileConsidering all 123 samples, acral melanoma tumours showed a SNV+indel (hereafter referred to as tumour mutational burden (TMB)) mean of 0.95 mutations per megabase and a median of 0.87 mutations per megabase (range, 0–3.49 mutations per megabase). When including only one sample per patient, with primaries being selected preferentially, the most frequently mutated genes were NRAS (14% of samples; Q-value < 4.97 × 10−10), KIT (14% of samples not counting deletions, as they are unlikely to be activating; Q-value = 4.97 × 10−10), BRAF (13%, Q-value = 3.86 × 10−7) and NF1 (9%, Q-value = 0.0001) (Fig. 1a and Supplementary Table 3). Two of these samples had homozygous NF1 deletions, in addition to a further two secondary samples from other patients (Extended Data Fig. 1a). For BRAF, all mutations except one were V600E, with one L597R (Fig. 1b). These genes, which represent known drivers, were identified as being under positive selection (Methods) and exhibit mutual exclusivity (only one patient has tumours with mutations in more than one of these genes), which reflects their functional redundancy in activating the MAPK pathway. Separate capillary sequencing of the TERT promoter in 76 samples belonging to 64 patients identified that six carry the −124 promoter mutation (9.3%) and two out of 59 patients for which the −146 position was amplified successfully carry a mutation in this position (3.4%) (Supplementary Table 4). In total, we estimate that about 10.5% of patients have an activating TERT promoter mutation, which is similar to estimates in other studies15,24. All samples from all patients that had several samples sequenced and that could be assessed had a concordant TERT genotype, in agreement with an early emergence of this mutation during tumour evolution24. Other genes reported previously as mutated in other melanoma subtypes, as well as other cancer types are also mutated in this cohort, such as TP53, HRAS and KRAS (Fig. 1a and Extended Data Fig. 2). In summary, the ‘classic’ melanoma driver genes (N/H/KRAS, BRAF and NF1) are mutated in 40% of Mexican acral melanoma samples, with most of the samples in this cohort therefore being classified as ‘triple wild-type’ melanomas. Apart from the known HRAS, SPRED1, TP53 and KRAS driver genes, we also find mutations in PTPRJ, ATM, NF2 and RDH5 (Extended Data Fig. 2a,b). Specifically, in those tumours without mutations in any of the abovementioned four driver genes (BRAF, NRAS, KIT, NF1, ‘quadruple wild type’ (QWT)), we find two tumours each from different patients with deleterious mutations in ATM and RDH5 (Extended Data Fig. 2b). The mutations in these genes are all protein-changing and deleterious. All these genes have been linked previously to tumour suppressor activities in either acral or mucosal melanomas25,26,27,28,29,30, as well as other cancer types, and may represent low-frequency drivers. We also observe a significantly higher proportion of women versus men carrying mutations in driver genes (two-tailed Fisher’s test P value = 0.003) (Supplementary Table 5). After adjusting for date of diagnosis, age at diagnosis, ancestry and tumour stage, the odds ratio of having a mutation in a driver gene in female patients (compared with men) was estimated to be 3.83 (95% confidence interval, 1.32, 11.03) (multivariate logistic regression, P value = 0.013).Fig. 1: Somatic landscape of acral melanoma in Mexican patients.a, Oncoplot depicting the seven most mutated genes according to dNdScv and their status in the samples with mutations in these (52 samples out of 92, one per patient). Mutational classification, sample type, tumour stage, sex, age at diagnosis, ulceration status, tumour site and mutational spectra are shown by sample. In the mutational spectra plot, asterisks indicate that these mutations occurred in the same sample. LN metastasis, lymph node metastasis. b, Mutations found in KIT, NRAS, BRAF and NF1, which are the most significantly mutated genes. For NF1, the two mutations in blue font occurred in the same sample. c, A logistic regression model controlling for age, sex and total TMB was fitted to predict the presence or absence of a mutation on the acral melanoma samples using the inferred ADMIXTURE cluster related to the European ancestry component. The log odds estimate and confidence intervals are depicted for the four driver genes. The estimate and its two-sided P value were obtained from the summary of the model. d, Barplot depicting the number and mutational classification of samples in different acral and cutaneous melanoma studies14,15,18,31,32,33,34.Full size imageWhen examining the relationship between ancestry and somatic profile, we identified significantly higher odds (P value = 0.02) of carrying a BRAF somatic mutation with increasing European ancestry in a linear model controlling for age at diagnosis, sex and total TMB (Fig. 1c). Patients with mutations in KIT showed a tendency for higher Amerindian ancestry (Supplementary Fig. 2). We also found that patients with NRAS mutations were younger at diagnosis (median and mean age of diagnosis for patients with NRAS mutations was 49 years and 50.84 years versus 63 years and 62.9 years without, respectively), but this effect is probably mediated by ulceration status, as patients with NRAS mutations have a significantly lower rate of ulceration (two-tailed Fisher’s exact test P value = 0.016).Out of 22 pat