Introduction
Melanoma is the most dangerous subtype of skin cancer, with a very high mortality rate. It is aggressive and spreads rapidly. However, if detected early, it can be managed and cured. Melanoma arises from pigmented skin cells called melanocytes. These cells give skin the color it possesses. They are usually brown or black, but they are also seen in pink, red, purple, or other skin colors.
What Is Acral Lentiginous Melanoma?
Acral melanoma is a rare type of melanoma. It is usually seen in glabrous skin (smooth skin that does not have any hairs or filaments), such as the palm and soles of the feet. It is also found in the subungual regions (part of the nail between the nail plate and the nail bed).
The risk factors of acral lentiginous melanoma differ from those of cutaneous melanoma, including sun exposure, fair skin type, family history of melanoma, and pre-existing melanocytic nevi. It is not linked to exposure to ultraviolet radiation. As a result, it has a lower tumor mutational burden (an average mutation that occurs in a cancerous cell).
What Are the Genetic and Signaling Characteristics of Acral Melanoma?
Early melanoma and acral melanoma studies showed genetic variations across the various anatomic locations. Large-scale genomic alterations linked to increased copy number gains and losses were among the characteristics of acral melanoma. Furthermore, acral lentiginous melanoma had a lower frequency of activating mutations in BRAF (a gene associated with cell growth) and increased CDK4 amplifications (an increase in CDK4 shows an increased probability of developing melanoma).
A study compared the genomes of acral melanoma, cutaneous melanoma, and malignant melanoma using whole genome sequencing (WGS) and targeted exome sequencing. Compared to the other types, acral melanoma had the highest number of structural variations in chromosomes, the largest percentage of whole genome doubling, and the fewest single nucleotide variants. Advanced computational approaches to mapping genomes have identified unique structural genomic features in acral lentiginous melanoma.
Analysis of recurrent mutational signatures also showed that acral melanoma differed from other types of melanoma spots. (Mutational signatures are characteristic features of mutations in cancer genomes). The SBS38 mutational signature was more frequently found in this type of melanoma, and the etiology of the mutational signature still remains unknown. However, it is still found to have an association with melanoma. Other mutation signatures, like SBS40, SBS2/13, and SBS1/5, were also found to be associated with acral melanoma.
Genomic signatures of Chromothripsis were also found in the acral lentiginous melanoma genomes. Chromothripsis is a mutational phenomenon where massive clusters of chromosomal rearrangements occur in a single event. It is usually found to be associated with different types of cancers and congenital anomalies. Certain genomic regions containing MAP2K1, CCND1, CDK4, GAB2, PAK1, EP300, and MDM2 were found to have specific amplifications in acral melanoma. Deletions in CDK2NA and NF1 were also detected in this condition. TERT alterations (mutations in the telomerase reverse transcriptase enzyme) were found in 46 percent of this malignant condition. However, the frequency of TERT promoter mutations was lower than that of other melanomas.
What Are Hailstorms in the Genetic Evolution of Acral Melanoma?
Studies show that most of the genomes in acral melanoma had areas of high density of point mutations. These regions of clusters of transitions were called ‘hailstorms’. It was found that about 92.2 percent of the hailstorms were found in the earliest stages of acral melanoma, (even during the in situ stages). It was identical even during the later stages. Studies show that only seven percent were acquired in the last stages as the condition progressed.
Tert Activation: The most frequent genetic change in acral melanoma is TERT activation. This usually appears early in the course of the disease. Hailstorms appear intermittently. This suggests that there could be possible breaks in the double-stranded DNA that can cause these hailstorms. Studies show that TERT amplifications are commonly seen as part of a hailstorm on chromosome 5p. However, chromosome promoter mutations and copy number transitions that occur upstream of TERT were found, which suggests the possibility of TERT activation. Most of the TERT alterations were found in the earlier stages of progression. As a result, they were placed on the trunks of phylogenic trees in all found tumors.
V Signature Mutations: Some cases of acral melanoma have been linked to UV radiation signatures, which are most commonly the cause of cutaneous melanoma. Studies show that these signatures were commonly seen in the in situ stages in most cases. However, it was absent in most of the advanced stages of the condition. Hence, acral melanoma, which is caused by exposure to UV rays (or the sun), mainly starts after the neoplastic growth starts. As a result, it might not be an initiating mutational mechanism but can potentially increase intratumoral heterogeneity.
Early Genetic Divergence in Metastatic Clones: In some melanomas, the timing of metastatic dissemination was revealed by the distinct patterns of genetic alterations found in the primary tumors and their metastases. Some studies show that during the early evolution of the primary tumor, there could be a divergence in the metastatic population. The metastasis of the tumor cells during the early stages of development of the primary tumor was found in more cases in studies done later.
Conclusion
Acral melanoma is an aggressive type of melanoma. The condition's etiology is still unclear, though various associations have been assumed. The condition is more common among dark-skinned people. The treatment of the condition is challenging, as the exact cause is still unclear. Frequent series of genetic alterations, called ‘hailstorms,’ were considered to cause great changes in the progression of the condition. Studies conclude that acral melanoma could originate from the melanomas caused by sun exposure and diverge to show the characteristics of the condition. The sporadic formation of hailstorms and early TERT activation suggest a distinct mutational mechanism for the genesis of acral melanoma.
