NEW YORK (GenomeWeb) – A new study has delved more deeply than ever into the coding and non-coding alterations that occur in various forms of melanoma — including those do not seem to be attributable to mutations caused by sun exposure.
Researchers from Australia, Spain, and the US did whole-genome sequencing on tumor samples from nearly 200 individuals with melanoma subtypes affecting mucosal tissues, the hands or feet (called acral melanoma), or cutaneous skin sites. The findings, published online today in Nature, expanded the set of mutational signatures identified in ultraviolet light-associated melanomas, while highlighting structural variants and other alterations in melanoma tumors from mucosal and hand or foot sites.
"The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation," corresponding author Graham Mann, a researcher with the University of Sydney's Melanoma Institute Australia, and his co-authors wrote. "However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown etiology, not previously identified in melanoma."
While the genomics of cutaneous melanoma in particular have been addressed by efforts such as The Cancer Genome Atlas, forms of melanoma that are not associated with ultraviolet light exposure and/or those that form in the eye, mucosal tissues, and hands or feet are less well characterized.
"Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body sources (mucosal sites) and on the hands and feet (acral sites) in people throughout the world," the authors wrote, noting that "[m]elanomas driven by non-ultraviolet radiation are uncommon in cutaneous sites, but dominate those occurring in eyes, mucosal surfaces, and acral sites."
For their analysis, the researchers focused on 183 melanoma samples, including nearly three dozen acral melanomas, and eight melanoma tumors formed on mucosal tissue. The set encompassed 75 primary tumors, 93 metastases, and 15 cell lines, the researchers noted.
After using Illumina Hiseq 2000 instruments to generate genome sequences for the tumors and matched normal samples, they sifted through these sequences to uncover almost 20.1 million substitutions, tens of thousands of small insertions or deletions, and a dozen mutational signatures across the melanoma samples.
As reported in the past, the team found that cutaneous melanomas contained recurrent mutations affecting genes such as BRAF, TP53, NRAS, and CDKN2A. Some of the same genes — particularly BRAF and NRAS — were recurrently mutated in the acral melanomas as well, along with the NF1 gene, while SF3B1 gene mutations were recurrent in mucosal tissue melanomas.
The acral and mucosal melanomas appeared more prone to structural variants, breakpoint clusters, and copy number changes than the cutaneous tumor types, the researchers reported. Similarly, their analyses pointed to varied mutational signatures by melanoma subtype — for example, they uncovered six signatures linked to other cancer types that were especially common in some of the melanoma samples from sites with low sun exposure.
With the new genome sequences, the team was also able to get a glimpse at the prevalence and placement of gene fusions and non-coding mutations in tumor genomes from each melanoma subtype. That analysis led to mutations affecting the promoter of the telomere-related gene TERT that were particularly common in cutaneous melanoma, for example, and several 5'-UTR mutations that fell near other genes in the melanoma set.
"The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis," the researchers added.