Unraveling the melanoma pathogenome


As with any costly endeavor, the decision to generously fund efforts to sequence the cancer genome in an unbiased fashion, particularly in an era of ever diminishing resources, was predictably met with both praise and skepticism. Proponents anticipated that the obvious success of more selective sequencing approaches, which led to the identification of BRAFV600E, was just the tip of the iceberg, while detractors sensed that the minor fishing exercises would evolve into a deep sea expedition. Like most such enterprises, the ultimate value of that decision will become evident over time. However, there is no denying that significant progress is being made, as a steady stream of discoveries is now being reported in both the literature and media. Unbiased next-generation sequencing incorporates a variety of approaches, including exome and whole-genome sequencing as well as RNA-seq, to uncover the molecular etiology underpinning the genesis and progression of melanoma and other cancers. Literally, thousands of genes can be sequenced simultaneously, permitting the detection of any existing point mutations, insertions, deletions, amplifications, and translocations in any given tumor. In my opinion, the greatest successes of next-generation sequencing to date have been in the identification of genes associated with familial cancer, where the potential of sequencing technology can be magnified by the power of genetics. This is strikingly illustrated in melanoma by the recent identification of a germline SUMOylation-defective MITF mutation. However, next-generation sequencing has also begun to shed significant light on the somatic mutation landscape in melanoma. This was illustrated earlier when melanoma cells were shown to uniquely harbor a legion of UV radiation signature mutations. Since then, reports of somatic melanoma mutations have been accumulating, mostly deregulating members of the pRB, p53, MAPK, or PI3K pathways – thought to be fundamental to melanomagenesis. However, there have been many surprises as well, implicating genes that were not likely to be prioritized for study as melanoma candidate genes, such as GRIN2A and GRM3, which encode components of the glutamate signaling pathway. Despite the promise of next-generation sequencing technology, challenges still abound, mostly involving data management and interpretation. The computational expertise required for success in this field is still considerable, while deconvoluting the vast sets of bioinformatic data that are generated by these approaches remains a daunting task. But the biggest challenge is perhaps the difficulty in distinguishing functionally the so-called driver mutation, equivalent to a bona fide oncogene that might be therapeutically targeted, from the passenger mutation, which will have little clinical value. In this issue of Pigment Cell & Melanoma Research, three outstanding Perspectives by Dutton-Regester and Hayward, Walia et al. and Harbour bring the reader up to date on recent advances in defining the melanoma pathogenome (those mutated components of the melanocyte genome responsible for driving melanoma pathogenesis), while discussing the prospects for the future. Of these, the most critical is the potential for transforming recent advances in sequencing technology and bioinformatics into routine clinical tools, allowing patient treatment to be crafted in accord with the molecular makeup of their individual melanoma. Whether you agreed with the original decision to fund the unbiased sequencing of cancer genomes or not, the resulting information being uncovered will undoubtedly move us ever closer to the dream of effective personalized medicine.