Hereditary adenomatosis of the colon and rectum: relevance to cancer promotion and cancer control in humans

Abstract

We propose that SF derived from normal-appearing biopsies of ACR gene carriers exist in an initiated state as the result of a dominant mutation. Based on our studies with the ACR cell system, we further suggest that, although an initiated state is essential to cancer development, not all initiated cells necessarily develop into cancerous cells. The genetic makeup of an initiated cell has been established through linkage between abnormal phenotypic markers and pedigree profiles and through cell hybridization, including initial analysis of gene products. We believe that it is consistent with an autosomal dominant trait. In contrast, cells from patients who are homozygous for chromosomal breakage syndromes, including those with xeroderma pigmentosum, represent an experiment of nature which presumably underlies factors associated with cancer promotion in humans. We have demonstrated that ACR cells can be differentially transformed by oncogenic viruses, a carcinogen (MNNG), and gamma-ray irradiation, and that they can proliferate in vitro after exposure to a tumor promoter (TPA. This simple experimental model provides a novel system for the study of tumor promotion in vitro. We further suggest that, through the use of TPA, various stages associated with cancer development in humans, i.e., initiation through promotion and progression, can be identified in vitro. Attempts to apply these results in vivo are currently in progress. The apparent susceptibility of ACR cells to further transformation by oncogenic viruses and chemical and physical agents indicates that genetic information residing within these cells, probably in the form of a relatively limited and specific number of DNA sequences associated with the ACR mutation, renders them more sensitive to these three distinct classes of carcinogens. We submit that, through our tests on SF, and ACR gene carriers within recognized ACR clusters can be diagnosed at present with sufficient certainty to warrant immediate action. In addition, it seems that the time has arrived for a major undertaking to screen for persons who are likely to be at increased risk of cancer, perhaps through walk-in clinics. An underlying assumption in these studies is that predisposition to cancer, in general, is associated with an autosomal dominant trait in obligatory heterozygote gene carriers.