Cancer medicine is evolving from an empirical approach to one in which disease classification and therapeutic strategies become based on the presence on critical mechanistic alterations of the cancer. Integrating the emerging landscape of molecular alterations into the traditional classification systems, which are primarily based on clinical and histopathological features, is an important task likely to improve the relevancy of current disease taxonomies. In melanoma, distinct patterns of clinical and genetic features have suggested the existence of biologically distinct subtypes. Primary oncogenic events that arise early during progression are closely correlated with clinical and/or histologic aspects of primary tumor such as its anatomic site, ethnic distribution, relationship to UV radiation, age of onset and histopathological features. These associations suggest the existence of distinct biological subtypes. One distinct category of melanocytic neoplasms includes intradermal melanocytic proliferations such as blue nevi, melanomas arising within blue nevi as well as uveal melanoma and is categorized by frequent mutations in GNAQ and GNA11, two closely related Ga protein subunits, which occur in a mutually exclusive pattern. Oncogenic GNAQ and GNA11 activate several downstream signaling pathways including specific isoforms of PKC that convey signals to the MAP-kinase pathway. Melanomas with these mutations express selective sensitivity to PKC inhibitors and their sensitivity can be significantly enhanced by combining the treatment with MEK inhibitors. These findings offer an opportunity for novel therapeutic strategies for uveal melanoma that is currently investigated clinically. Spitz tumors are morphologically and clinically distinct group and are notorious among pathologists and clinicians, as histopathological features do not reliably predict their biological behavior. These tumors have a high frequency of specific oncogenic alterations, which will be presented.
Conclusively, these findings provide strong genetic support for the notion that melanoma is a heterogeneous group of diseases, which show characteristic genetic and morphological findings that depend on the cell of origin, constitutional genetic and environmental factors. These associations provide an opportunity to update and improve current melanoma classifications and offer new opportunities for treatment and prevention.