Premalignant lesion and cancer: etiology and prospects for genetic mapping

It has long been recognized that a nonmalignant structure in the body might be a precursor forming the basis from which a malignancy might arise. This research investigates the importance of studying such premalignant lesions for understanding the genetic predisposition to cancer. Pedigree data have been examined for evidence of a cosegregation of lesions and their related malignancy in the case of two common cancers: colorectal cancer and melanoma. Evidence for a genetically inherited susceptibility to premalignant lesions and the associated cancer was favored over environmental or nongenetic models. The evidence for both cancer sites studied suggests a single autosomal gene locus with dominant inheritance of a common susceptibility allele. In the case of colorectal cancer, evidence of an inherited susceptibility was found in pedigrees that were selected for clusters of colorectal cancers, as well as in those pedigrees selected for random colorectal polyps, suggesting the susceptibility allele may be responsible for most, if not all, adenomatous polyps. The results for melanoma suggest that a susceptibility allele is responsible for most observed clusters of melanoma, but not for commonly observed nevi or moles. Since the eventual goal of such family studies is the identification of the gene or genes responsible for the inherited susceptibility, the potential for mapping such susceptibility loci has been estimated in the presence of confounding factors that may exist in the etiology of these lesions. This set of questions has been approached through simulation studies, as appropriate family data are not available. The results are promising for linkage analysis and suggest that the presence of a linked marker can be recognized in the presence of very high levels of confounding evidence if larger sample sizes are used. These studies support the suggested biological model for cancer that suggests that cancers are caused by a dominantly inherited predisposition in a target cell that transforms to a cellular recessive when an allele for normal cellular control is lost.