Whole genome sequencing of matched primary and metastatic acral melanomas

Abstract

Next generation sequencing has enabled systematic discovery of mutational spectra in cancer samples. Here, we used whole genome sequencing to characterize somatic mutations and structural variation in a primary acral melanoma and its lymph node metastasis. Our data show that the somatic mutational rates in this acral melanoma sample pair were more comparable to the rates reported in cancer genomes not associated with mutagenic exposure than in the genome of a melanoma cell line or the transcriptome of melanoma short-term cultures. Despite the perception that acral skin is sunprotected, the dominant mutational signature in these samples is compatible with damage due to ultraviolet light exposure. A nonsense mutation in ERCC5 discovered in both the primary and metastatic tumors could also have contributed to the mutational signature through accumulation of unrepaired dipyrimidine lesions. However, evidence of transcription-coupled repair was suggested by the lower mutational rate in the transcribed regions and expressed genes. The primary and the metastasis are highly similar at the level of global gene copy number alterations, loss of heterozygosity and single nucleotide variation (SNV). Furthermore, the majority of the SNVs in the primary tumor were propagated in the metastasis and one nonsynonymous coding SNV and one splice site mutation appeared to arise de novo in the metastatic lesion.

Unexpected UVR and non-UVR mutation burden in some acral and cutaneous melanomas

“…Examining of human cadaveric nails has previously showed that all of UVB and the vast majority of UVA light is blocked by the nail plate. 14 The fact that two of the cases we reported in the thumb and a previous case report in the toe 28 of subungual melanoma with a dominant UVR signature appears to refute these findings. It would therefore appear that in some patients sufficient UVR can penetrate the nail plate to cause mutation effects in the melanocytes in the underlying subungual tissue.…”

“…In previous exome and whole-genome sequencing studies, mutations per Mb in acral melanomas have been reported to range from 1.02 to 3.68 (5 cases), 15 1.95, 28 and 2.79 to 14 (two cases). 27 In contrast, the mean mutation rate of The Cancer Genome Atlas Network study, 20 which consisted entirely of cutaneous melanomas, was 16.8 mutations/Mb.…”

“…27 There have been recent conflicting reports on UVR signatures in sequenced acral melanomas. Some studies report no dominant UVR signature within acral melanomas 10,15,26 while other studies report a dominant UVR signature in cases of acral melanoma: one case report of whole-genome sequencing; 28 two of six cases of melanoma cell lines examined; 29 and one of two cases of whole-genome sequencing. 27 In our view, these findings probably relate to the case selection; some cases designated as arising from acral sites may have involved the non-acral surfaces of the hands or feet.…”

Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination

“…Melanoma, like other cancers, arises and evolves through the accumulation of genetic alterations within tumor cells (7)(8)(9). Comparing somatic mutations in primary tumor and regional and distant metastases from the same patient can provide insight into the phylogenetic relationships between these distinct tumor cell populations and the order of metastatic dissemination (8,10).…”

“…Comparing somatic mutations in primary tumor and regional and distant metastases from the same patient can provide insight into the phylogenetic relationships between these distinct tumor cell populations and the order of metastatic dissemination (8,10). These analyses may also establish whether cells in the primary tumor that metastasize acquired this ability to disseminate and seed other anatomic sites by a newly acquired genetic alteration, or whether metastatic colonization is simply a stochastic process of which all cells in the primary are capable but few succeed.…”