NEW YORK – A team from Canada and the US has identified frequently-mutated genes and other informative tumor features in nearly 1,500 new and previously profiled cutaneous melanoma cases.
Beyond the potential insights that significantly mutated genes might offer into treatment targets for the disease, the combined data might provide insights into variable treatment outcomes, they reasoned, as well as the overrepresentation of cutaneous melanoma in males, who also tend to have poorer survival after their diagnoses.
"[O]ur multi-omic analysis provides insights into melanoma etiology and supports contribution of specific mutations to the sex bias observed in this cancer," senior and corresponding author Ian Watson, a cancer and biochemistry researcher at McGill University, and his colleagues wrote in a paper published in Nature Cancer on Monday.
For that study, the researchers brought together new protein-coding sequences for more than 1,000 melanoma cases with multi-omic data for another 470 melanoma cases. Along with oft-mutated genes such as PBRM1, PLXNC1, and the protein kinase A holoenzyme-coding gene PRKAR1A, they tracked down a protein kinase A pathway-related transcriptional signature in cutaneous melanoma, which involved oxidative phosphorylation genes.
The team also highlighted loss-of-function alterations that affected DDX3X in male melanoma cases, while using the broader sample set to get a look at ties between tumor mutational burden (TMB) and immune cell infiltration of tumors — features that each appeared to provide clues to melanoma patient survival.
Indeed, ultraviolet radiation-related mutation signatures in the tumor and TMB burden "provide prognostic information complementary to immune infiltration," the authors reported, noting that TMB "provides information on survival of patients with melanoma not included in the [UV radiation] signature."
Past efforts to find frequently mutated genes in cutaneous melanoma have been thwarted to some extent by the high mutational burden of these tumors, the team explained, since they tend to form at so-called nonacral skin sites that are exposed to the sun and undergo related DNA damage from the ultraviolet radiation.
With that in mind, the researchers combined data for a large set of cutaneous melanoma tumors, including 1,014 primary or metastatic cases enrolled through five studies that were profiled by exome sequencing and another 470 melanomas assessed with copy number, gene expression, methylation, and other analyses for the Cancer Genome Atlas project.
"We controlled for background mutational processes by analyzing samples with different mutational signatures separately and limited the risk of false positives by accounting for [mutation signature-related alterations in ETS transcription factor] binding sites and other confounding factors," they noted.
Using this approach, the team found more than three dozen significantly mutated genes — from alterations affecting oncogenes or tumor suppressor pathways to changes in immune, signaling, regulatory, splicing, or cell cycle genes. Along with mutational analyses focused on specific cutaneous melanoma subtypes, the analysis pointed to a role for DDX3X as a male-specific tumor suppressor in melanoma.
By adding in copy number, transcriptome, and other clues, meanwhile, the researchers teased out tumor and immune features that appear to coincide with cutaneous melanoma survival, including TMB, immune-related gene expression signatures, and ultraviolet radiation-related mutation patterns.
"We observed that TMB provides complementary information to immune infiltration on patient survival, even when restricting our analysis to nonacral cutaneous melanomas with a high [ultraviolet radiation] signature, although this effect was weaker in the latter case," the authors noted. "These results support the notion that TMB is not simply distinguishing melanoma subtypes (nonacral versus acral, mucosal, and uveal), but is having an impact on patient survival."