Photo Credit: Svetlana

The following is a summary of “Uncovering molecular mechanisms for amelanotic/hypopigmented primary cutaneous melanoma,” published in the August 2024 issue of Dermatology by Sturm et al.

Amelanotic/hypopigmented melanoma (AHM), representing 2-20% of cutaneous melanoma (CM), poses a diagnostic challenge due to its lack of or reduced pigmentation.

Researchers conducted a retrospective study examining the role of somatic mutations and copy number aberrations in pigmentation genes in determining the loss of tumor pigmentation in samples of AHM.

They analyzed 34 fresh frozen primary CM samples, graded by pigmentation amount, using clinical, histopathological, and whole exome sequencing data. In addition to germline and somatic variant analysis, 30 samples were assessed for copy number alteration (CNA) changes. The study focused on 16 genes associated with albinism/hypopigmentation or variation in human pigmentation, examining chromosomal regions for DNA copy loss or gain.

The results validated the association between red hair-related MC1R and TYR R402Q loss-of-function gene variants with AHM. Germline AHM-related gene variants were present in 70% (7 of 10) of patients with AHM compared to 8.3% (2 of 24) of patients with PM. This high frequency of rare germline variants in patients with AHM, the “first hit,” indicates that patients with AHM were more likely to carry albinism alleles than patients with PM. In the CNA analysis, 50% (4 of 8) of AHM samples with pigmentation gene variants showed loss of heterozygosity (LOH) in the respective gene regions. In comparison, 25% (2 of 8) exhibited LOH in chromosomal regions of 2 AHM-related genes.

Investigators concluded that amelanogenesis in AHM was likely caused by the inheritance of an albinism/hypopigmentation allele and subsequent loss of heterozygosity in the corresponding gene.

Source: https://academic.oup.com/bjd/advance-article/doi/10.1093/bjd/ljae336/7738007