Malignant melanoma: modern black plague and genetic black box

Abstract

References to ‘black cancer’ and ‘fatal black tumors with metastasis’ date to the writings of the legendary Greek physician Hippocrates in the fifth century B.C. However, it was not until the time of Napolean’s Prussian Campaign in 1806 that Rene Laennec, inventor of the stethoscope, provided the first description of melanoma as a disease entity in his presentation to the Faculte de Medecine in Paris (Bennett and Hall 1994). His 1812 manuscript reporting a case of disseminated melanoma also marks the first published use of the word ‘melanoma’ (Laennec 1812). Several years later, a truly remarkable conceptual leap was made in the context of melanoma by a general practitioner William Norris (Norris 1820) who arrived at the conclusion that melanoma is a hereditary disease. In his 1820 manuscript, Norris wrote: ‘it is remarkable that this gentleman’s father...died of a similar disease. This tumor...originated in a mole and it is also worth mentioning that, not only my patient and his children had many moles..., but also his own father and brothers....These facts, together with a case that has come under my notice, rather similar, would incline me to believe that this disease is hereditary.’ This prescient statement is all the more striking by the fact that it was made nearly half of a century before the genetic paradigm was articulated by Gregor Johann Mendel in The Transactions of the Brunn Natural History Society in 1866 and 1869 (see Hecht 1989). Today, cancer biologists stand resolute in the concept that melanoma has strong genetic underpinnings. This position has been strengthened by the identification of genomic hot spots (and their resident genes) in which structural alteration correlates with the genesis and/or progression of melanoma. More recent efforts to understand the biological impact of these melanoma-associated genetic lesions have yielded a series of scientific observations that has captured center stage in the field of cancer genetics. These new molecular insights are indeed welcome because they come at a time when melanoma has emerged as a true health crisis. As a cancer type, incidence of melanoma is rising at a rate second only to lung cancer in women and, on its present course, the lifetime risk will reach 1 in 75 Caucasians in the US by the year 2000 (Rigel et al. 1996). In contrast to many other cancer types, it is notable that melanoma affects a much younger population and is notorious for its propensity to metastasize early in the course of the disease and for its poor response to current therapeutic modalities (Herlyn 1993). The purpose of this review is to provide a current view of the key genetic lesions associated with the development of melanoma including those involving the INK4a/ARF tumor suppressor locus, the ras family oncogenes, and the receptor tyrosine kinases and their ligands. These pathways in particular are emphasized here because their pathogenetic roles in melanoma have been verified on several experimental levels. This review will not attempt to catalog the vast number of genetic and gene expression changes observed in melanoma; several comprehensive reports have capably summarized such information (Albino 1995; Greene 1997; Welch and Goldberg 1997; Haluska and Hodi 1998).