11 Heritable Cancer and Tumor Suppressor Genes: A Tentative Connection

Abstract

I. INTRODUCTION
In several of the foregoing chapters, the dominant expression and action of cellular oncogenes has been emphasized. Studies of these oncogenes have clearly indicated that they act as positive regulators of cell proliferation. In the early stages of the research on oncogenes, it was thought that activation of a single oncogene was sufficient for the neoplastic transformation of a normal cell. It rapidly became apparent that this was not the case, and further studies indicated the need for two or more cooperating oncogenes to be expressed for the neoplastic transformation of normal rodent cells to ensue. Further detailed analysis of oncogene-mediated transformation revealed that other, as yet unidentified, genetic changes were required in addition to oncogene activation in order for cells to acquire tumor-forming properties. Data derived from somatic cell hybrid experiments together with cytogenetic and polymorphic allele analysis of human tumors have indicated that one frequent and often essential genetic alteration occurring during tumor development is the inactivation or loss of function of one or more genes. This phenomenon of loss of function suggests that these genes, when intact, play a negative regulatory role in the control of cell proliferation. In this chapter, we examine the evidence for negative regulatory elements and their possible role in the development of neoplasia.

II. SOMATIC CELL GENETICS OF TUMORIGENESIS
A. Tumor Suppression Is Demonstrated
Historically, the first attempts at a genetic analysis of malignancy utilized the technique of somatic cell hybridization. A simple question was asked: Upon fusion of a...