Making Noise About Silent Mutations in Treating Skin Cancer

Mutations that affect splicing in oncogenes may facilitate tumor progression.

Melanoma and other types of skin cancer are among the many types of cancer poised to benefit greatly from genomic research that identifies susceptibilities and potential targets for genetic-based therapy.

A recent paper in Pigment Cell & Melanoma Research suggests, however, that an entire category of genetic mutations — one that could be incredibly fruitful in terms of diagnosis and treatment – is largely being ignored. The overlooked category, synonymous mutations or substitutions, consist of single nucleotide changes in gene coding sequences that do not affect the amino acid encoded by the affected codon. For this reason, they are often referred to as “silent mutations.”

“Many cancer studies completely ignore synonymous mutations…” the study authors explained, “…whereas others use them to build neutral background models of mutation clustering for the detection of activating mutations.”

There is reasonable scientific logic for ignoring synonymous mutations, but the authors noted that a number of recent studies show that evidence for functional molecular consequences of synonymous mutations has been accumulating and should constitute a greater part of cancer research. The paper looks closely at the recent evidence that synonymous mutations represent fertile ground for more research, including several that show that such mutations work in parallel with mutations that alter the amino acid sequence in both certain types of cancer and in heritable conditions.

The researchers also analyzed 501 of their own melanoma samples for mutations. Their analysis suggested that instead of being the main driver mutations, mutations that affect splicing in oncogenes may facilitate tumor progression in concert with additional mutation events, in agreement with a model in which mutations that provide growth advantage to the cell are acquired gradually.

“These mutations also raise the intriguing question of whether the impact on splicing may in fact extend beyond a handful of oncogenes, and whether any relationship exists between mutation frequency and impact on splicing,” the researchers wrote.

One of the challenges of genetic research is that the sheer number of genes and gene mutations make identifying drivers of genetic mutations incredibly difficult. Thus, the need to extend the pool of usual suspects isn’t necessarily ideal. But the study authors make a strong case that synonymous mutations hold one of the keys to uncovering novel driver mutations and potential novel oncogenes.

“The challenges of identifying causal synonymous mutations loom large, but in silico approaches can be used to prioritize candidates prior to any experimental undertaking,” the authors conclude. “Refining the functional relevance of synonymous mutations should take into account the known properties of driver mutations, such as their recurrence in multiple patients, their localization at known oncogene mutational hotspots or functional sites evolving under selective pressure.”