The Genetics of Melanoma Goes Deep

Due to rapid advancements in DNA sequencing, our understanding of the genetic drivers of cancer has increased substantially in the past decade. In the case of melanoma, researchers have now characterized in great detail the genetic changes that occur within tumor cells in melanoma of the skin (cutaneous melanoma), leading to the FDA approval of drugs targeting mutations in BRAF and MEK (info on BRAF and MEK targeted treatments can be found here. Despite this, researchers still do not have a good understanding of the genetic changes that occur in more rare and deadlier forms of melanoma, such as acral melanoma (which affects the palms, soles and nail beds) and mucosal melanoma (which arises in mucous membranes in the lining of gastrointestinal, respiratory and urogenital tracts). 

While researchers have extensively cataloged the mutations within genes in cutaneous melanoma, genes only make up approximately 1% of the genome. Mutations in the other 99%, known as the noncoding, “dark matter”, are not well characterized for any type of melanoma, including cutaneous melanoma. Two recent studies, however, start to address these shortcomings and reveal important new insights for both common and rare types of melanoma.

The first study, published in May in Nature and supported in part by MRA, describes results from the Australian Melanoma Genome Project. Researchers analyzed samples from 183 patients to discern genetic differences between different types of melanoma, with the hopes of identifying new drug targets. Unlike many previous studies on melanoma genetics, the researchers in this study sequenced the entire genome of tumors, not just the small fraction that encodes genes. Samples included 35 acral melanomas, eight mucosal melanomas and 140 cutaneous melanomas.

The researchers found that cutaneous melanomas had an extremely large number and range of mutations compared to acral or mucosal melanomas, which consistently had relatively few mutations. Cutaneous melanomas were also more likely to have a pattern of mutations indicative of UV damage, whereas acral and mucosal melanomas had a different genetic signature, whose causes are unknown. Surprisingly, the team found that three acral melanoma samples had a UV damage mutational signature, suggesting that nails may not be as strong a barrier to UV radiation as previously thought.

An analysis of mutations found within genes uncovered genetic mutations commonly reported in other studies, including BRAF, NRAS, PTEN, CDKN2A, NF1 and RB1. Researchers did not identify any new common sites of mutations that may drive cancer development and/or progression in the acral melanoma samples, but four mucosal tumors had mutations typically seen in ocular melanoma, suggesting genetic similarities between these two types of melanoma. In addition, the analysis uncovered recurrent noncoding mutations, including functionally significant mutations in control regions called the promoters. The most common noncoding mutations (that is, found outside of genes) were found in a region of DNA that controls the expression of the TERT gene. TERT encodes an enzyme that regulates chromosome length and is frequently mutated in several types of cancer. For more info on implications of TERT in acral melanoma, check out this article. 

Although acral and mucosal melanomas contain fewer mutations compared to cutaneous melanomas, the researchers discovered that these cancers have a higher rate of another kind of genomic abnormality called chromosomal rearrangements. Cells package their genomes into structures called chromosomes and breaks or rearrangements of these structures can drive cancer. Knowing that acral and mucosal melanomas often contain this type of genomic damage may help inform researchers about potential treatment strategies to pursue for these cancers.

A second study published in the journal Genome Research in April and carried out by the Stand Up to Cancer-MRA Dream Team focused on the genetic changes present in tumor samples from 34 acral melanoma patients. Similar to the Australian project, these researchers also found that acral melanoma tumors had fewer mutations than cutaneous melanoma tumors and that the majority of tumors (74%) contained chromosomal alterations. These researchers also failed to identify new mutational drivers in acral melanoma, but did identify NRAS and BRAF driver mutations in nearly a third of patients. Moreover, and again similar to the Australian effort, a small fraction of tumors harbored a UV damage signature.

Finally, these researchers also identified mutations in and around the TERT gene in 41% of tumors. To better understand the functional significance of these findings, they inhibited TERT activity in TERT-mutant melanoma cell lines and found that this reduced the cells’ viability by 75%, suggesting TERT may be a potential therapeutic target for acral melanoma.

Collectively, these studies give researchers a more complete picture of the underlying genetic changes that occur in melanoma, particularly in acral melanoma. Importantly, the majority of patient tumor samples analyzed in the Australian study had actionable targets, that is, the tumor contained at least one genetic alteration that could sensitize it to either an FDA-approved drug or a drug undergoing clinical testing. Therefore, critical next steps include starting to target some of these alterations therapeutically in preclinical models to determine the most promising leads to move forward towards the clinic.  

Wayward NK, et al. Whole-genome landscapes of major melanoma subtypes. Nature545, 175 (2017).

Liang, WS, et al. Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma. Genome Research27, 524 (2017).