Introduction

BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)


Identification of these genetic events has been integral in guiding the development of targeted therapies, which have improved progression free or overall survival of patients in some cases, as compared to prior standard of care therapies. Cutaneous melanoma is the most aggressive form of skin cancer and its incidence continues to increase, in contrast to some other cancers such as breast, colon, and lung [6]. Genetic and molecular studies have detected a number of somatic mutations in melanoma cell lines and tumor samples integral to the pathogenesis of melanoma (reviewed in [7–10]). The discovery of mutant BRAF as a driver mutation in melanoma led to the development of targeted inhibitors, which have demonstrated an increased overall survival in patients with advanced melanomas containing mutant BRAF [1, 3, 4, 11, 12]. In addition, mixed responses have been observed in KIT mutant melanomas, treated with the tyrosine kinase inhibitors imatinib or dasatinib [13–19]. Moreover, new driver mutations are continually being identified in melanoma tumor samples [20, 21] which may serve as future targets for therapeutic intervention.

Recently, genetic and genomic profiling of tumors has moved from research to clinical laboratories as targeted therapies have become the new standard of care for the treatment of a sub-set of malignancies, including melanoma, and as techniques have been optimized for high-throughput analysis of somatic mutations. Moreover, tumor mutational analysis is advancing beyond single gene mutation testing; new sequencing methods allow for the simultaneous analysis of multiple genetic mutations within an individual tumor sample. These advances in sequencing techniques continue to have a large impact on the clinical testing of patient tumor samples, with the results having implications for therapeutic interventions such as inclusion or exclusion from clinical trials and initial therapy choices. This chapter will focus on techniques used in molecular diagnostics and mutational analysis of melanoma tumor samples, review sequencing methods, and discuss current and future technologies integral to the field of genetic sequencing. In addition, we will highlight relevant somatic mutations in melanoma tumors, which may be important in the development of future targeted therapies.

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