Genetic basis of susceptibility to melanoma - PubMed (original) (raw)

Review

Genetic basis of susceptibility to melanoma

M W Piepkorn. J Am Acad Dermatol. 1994 Dec.

Abstract

The search for candidate genes involved in the genesis of common cancers has traditionally been hampered by ambiguities in the process of determining by reliable, clinical criteria which persons harbor the genetic lesion that confers malignant susceptibility. In the case of cutaneous melanoma, the existence of genetic susceptibility has long been evident from its tendency to cluster in families, but it has been unclear until recently whether the genetic basis of familial melanoma derives from the concerted interaction of multiple genes or from a major locus with properties of a tumor suppressor gene. The original strategy used to circumvent difficulties in identifying those who harbor the genetic defect exploited a proposed melanoma precursor lesion, the dysplastic nevus, as the phenotypic marker from which the presence of the melanoma-associated genotype was inferred. That strategy in genetic linkage studies provided the first indication of a major gene for melanoma and assigned the locus to the short arm of chromosome 1. In part because the criteria for the dysplastic nevus have been neither well-defined nor generally agreed upon, multiple independent attempts to confirm the assignment of a gene to that location have failed. The probable map position of a major gene became clear when the most frequently deleted region of the human genome in melanoma tumors was localized to chromosome 9p. The significance of this assignment was established when genetic linkage studies of multiple melanoma kindreds subsequently evaluated the correlated inheritance between melanoma gene carriers, as assigned by a history of melanoma, and molecular markers for DNA polymorphisms near the 9p candidate region; this analysis provided strong statistical evidence of linkage to a melanoma susceptibility locus. Once this candidate tumor suppressor gene) as well as other relevant suppressor loci that may exist is actually cloned and characterized, rapid advances can be expected in our understanding of the pathophysiologic basis for development of melanoma. This will provide opportunities for exploring the mechanisms underlying defects in the gene and the molecular consequences of its loss of function. It will then be possible to identify precisely those persons with a genetic risk for melanoma; as a result, surveillance efforts can be more appropriately focused than has heretofore been possible.

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