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Clinical Genomics for Melanoma Detection


Key Points

  • Recent findings provide proof-of-principle that adhesive tape stripping of pigmented lesions suspicious for melanoma, coupled with epidermal genetic information retrieval (EGIR) and gene expression profiling, can be used to discern melanoma from nevi and solar lentigines.

  • Genes differentially expressed between melanoma and nevi, as identified through these EGIR-harvested specimens, are biologically relevant to disease biology.

  • Class prediction modeling of these EGIR-based genomic data produced a multigene classifier that is highly accurate for detection of melanoma.

  • Further development of a non-invasive assay is underway to validate this approach for routine clinical use.

Introduction

The Human Genome Project (HGP), begun in 1990, ostensibly culminated in 2003 with the sequencing of a complete human genome. The project also provided the research community with substantially more: a physical and genetic map of the human genome, including the locations of more than 3.7 million single nucleotide polymorphisms (SNPs); identification of more than 15,000 human genes; and the basis for a myriad of tools for genomic investigation. This research established a framework for attacking the molecular pathogenesis of human disease, which is now coming to fruition in terms of clinical applications. In addition to enabling development of novel, targeted therapeutics, the genomic technologies spawned by the HGP will impact the ability to: predict the likelihood that a patient will develop a specific disease, detect the presence of a disease, perform molecular disease diagnosis, characterize disease prognosis, and direct treatment management.

Melanoma, the most lethal skin cancer, has become one of the primary focal points of genomic research. Epidemiology studies have established that melanoma has a genetic predisposition, that chronic sun exposure is a significant risk factor for melanoma development, and that patients diagnosed with melanoma are at substantially higher risk for developing an additional primary. This knowledge has increased the vigilance of practitioners and dermatopathologists for the presence of melanoma. However, the application of genomics at a clinical level has the potential to greatly impact how patients are evaluated for melanoma susceptibility ( Chapter 30 ), early detection, diagnosis, and management by means of targeted treatment of advanced disease ( Chapter 55 ). This chapter will focus on the evolving application of genomics for the early detection of melanoma.

Current melanoma detection

Numerous studies have shown that early detection of melanoma is key to disease survival. This observation has placed tremendous pressure on the clinician to discern lesions suspicious for melanoma from those that are benign. The key means for melanoma detection rely upon visual examination of skin lesions and a variety of optical technologies, such as dermoscopy, to further assess the likelihood that a lesion harbors malignant melanocytes. In addition, newer optical methods for melanoma detection, including confocal microscopy and automated image analysis, are now emerging from the research setting.

Because of the highly variable visual and/or optical appearance of melanoma (in particular atypical nevi), many skin lesions are found to confound detection. These factors have substantially lowered the threshold to remove any lesion deemed in the least bit suspicious for melanoma. Yet the vast majority of these lesions considered suspicious for melanoma are found to be negative upon histopathologic analysis. In fact, various studies have shown that the ratio of melanoma to biopsies of suspicious lesions ranges from 1 in 3–5 when the assessment is performed by pigmented lesion experts, to 1 in 12–20 for non-expert practitioners, to 1 in 75–100 for primary care physicians. Therefore, the availability of a non-invasive clinical test that significantly improves the specificity of melanoma detection, without sacrificing sensitivity, could potentially eliminate many unneeded skin biopsies.

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