Uncovering the molecular mechanisms of amelanotic/hypopigmented primary cutaneous melanoma

Approximately 2-20% of cutaneous melanomas (CMs) are diagnosed as amelanotic/hypopigmented melanoma (AHM) and represent a challenge for early diagnosis.

To investigate loss-of-function mutations in key pigmentation genes in matched germline and AHM, as well as pigmented melanoma (PM), tumour DNA samples.

Analysis of clinical and histopathological characteristics - together with whole-exome sequencing data of 34 fresh frozen primary CMs, graded according to the amount of pigmentation present - was performed. Together with germline and somatic variant analysis, 30 samples had previously been analysed for copy number aberration (CNA) changes. This study focused on germline and somatic variants in the coding region of 16 genes known to be associated with albinism/hypopigmentation or variation in human pigmentation in all samples. Chromosomal regions encompassing these 16 genes were examined for DNA copy loss or gain.

The finding that red hair-related MC1R and TYR R402Q loss-of-activity gene variant alleles and genotypes are associated with AHM was confirmed. Germline AHM-related gene variants were enriched in 70% (n = 7/10) of patients with AHM vs. 8% (n = 2/24) of those with PM. This surprisingly high frequency of rare germline variants in people with AHM constitutes the 'first hit' and confirms that those with AHM are more likely to be albinism allele carriers than individuals with PM. Next, in CNA analysis of each tumour sample, 50% (n = 4/8) of AHM samples with a pigmentation gene variant had loss of heterozygosity (LOH) in the region containing the corresponding gene and 25% (n = 2/8) had LOH in chromosomal regions of two AHM-related genes.

This study proposes that the likely molecular mechanism for the development of amelanogenesis in AHM is carriage of an albinism/hypopigmentation allele followed by LOH of the corresponding gene in the tumour.