Opening the melanoma black box
Authors: H. Tsao
Journal: British Journal of Dermatology (2014)

Knowledge and practice gaps in medicine appear when the pace of discovery at the benchside outstrips the flow of information at the bedside. For a disease like melanoma, the dedicated pursuit of a biological understanding has propelled the field forward at a frenetic rate. In 2002, a group at the Wellcome Trust Sanger Institute published a short but decisive article describing a recurrent mutation in a specific protein kinase called BRAF.1 Originally dubbed the Val599Glu mutation, this modest missense alteration (which was later properly aligned to Val600Glu, i.e. V600E) turned out to be the pivotal key to a new generation of targeted treatments in melanoma. Nine years later, the first selective anti-BRAF(V600E) drug, vemurafenib, was approved by the United States Food and Drug Administration. This relatively brief journey underscores the power of purpose, determination and innovation. Although there were many critics of the Human Genome Project when it was first proposed 20 years ago, the return on its investment is now unassailable. Like the lunar mission, major technological breakthroughs matured side-by-side with the ‘blueprint of life’, i.e. the complete DNA sequence of the human genome. The bold undertaking of multiple sequencing centres led to the systematic decoding of cancer including seminal findings like BRAF mutagenesis. Other less common forms of melanoma have also been subjected to the genetic prism. In contrast to the more common superficial spreading and nodular melanoma subtypes, molecular analyses of acral/mucosal melanomas and ocular melanomas have revealed activating KIT and GNAQ/GNA11 alterations; however, these more recent discoveries have yet to be leveraged for therapeutic gain.2 Finally, with the mapping of the human genome also came the ability to examine expression levels of all genes simultaneously using small wafer-like microarrays commonly referred to as ‘chips’. These extraordinary gains in genomics, transcriptomics, proteomics and all things ‘omic’ have shed tremendous light on both the structure and function of the melanoma engine. Not all advances in melanoma have been on molecular fronts. More than ever, melanoma is now a global disease. International consortia exist for almost all facets of melanoma disease. Collaborations among countries have led to new risk insights and to greater awareness of international practice guidelines. In light of all the progress that has occurred in melanoma, this special issue of the BJD will highlight a few areas that have both ignited the imagination of the scientific community and yet remained pertinent to working dermatologists. Drs Nikolaou and Stratigos summarize recent epidemiological trends and findings related to melanoma risk.3 Compared with male patients, there is clearly a female ‘survival advantage’ that has been observed worldwide and yet remains a biological mystery. The role of tanning beds as a causative agent in melanoma and the careful dissection of genetic risk factors through genome-wide association studies have been nicely summarized by these two authors. Drs Fong and Tanabe survey recent guidelines of melanoma practice from around the world.4 In a rare comparative evaluation, it is instructive to see how practice methods have evolved in different healthcare systems internationally. Overall, there is reasonable consensus on the practice of melanoma medicine, although certain areas, such as sentinel lymph node biopsies in early-stage patients, are still embroiled in controversy. Dr Kashani-Sabet reviews recent progress in the use of molecular markers to identify subsets of melanoma and to refine prognosis.5 The genetic classification of melanoma has played a fundamental role in understanding the core drivers of this disease and in determining therapy. As outlined by Dr Kashani-Sabet, the use of expression profiles has also opened up new possibilities for more refined, and biologically meaningful, prognostication. Lastly, the recent waves of successful clinical trials in melanoma have ushered in a new generation of highly effective drugs in melanoma. Drs Sullivan and Flaherty discuss the fertile pipeline of small molecule inhibitors and immunological effectors that are revolutionizing treatment for advanced disease.6 On behalf of the authors and the British Journal of Dermatology, I invite you to taste, chew or voraciously digest the information presented in the ensuing pages. Our panel of experts has created an up-to-date perspective on an extraordinary period in melanoma research geared specifically for the practising clinician. Dr Hensin Tsao is the Director of the Massachusetts General Hospital (MGH) Melanoma and Pigmented Lesion Center, Director of the MGH Melanoma Genetics Program, Head of the Skin Cancer Genetics Laboratory in the Wellman Center for Photomedicine and Associate Professor of Dermatology at Harvard Medical School. His interests are in the genetic underpinnings of melanoma predisposition, progression and pharmacological response.