Chapter 20 - Tumour Suppressor Genes and Inherited Susceptibility to Cancer

Summary

INTRODUCTION

The discovery of proto-oncogenes, which function as promoters of cellular proliferation, was a highlight in molecular medicine, providing insight into the mechanisms regulating growth control and leading to the idea that a distinct group of ‘anti-oncogenes’ may oppose their effects. This proved to be the case and over the past 20 years many such genes, known as tumour suppressor genes, have been identified. Proto-oncogenes are genes that encode proteins which activate proliferation and survival in normal cells; these proteins include growth factors, receptors, signal transduction proteins, transcription factors, positive cell-cycle regulatory proteins and cell survival factors. Tumour suppressor genes, on the other hand, encode proteins that normally suppress cell proliferation and promote cell death; they slow down cell division, activate apoptosis and repair DNA. The actions of proteins encoded by proto-oncogenes and tumour suppressor genes are finely coordinated to maintain a dynamic balance between growth stimulation and inhibition. When this balance is disrupted cells may become cancerous. Mutations of proto-oncogenes, which increase their activity, may con - tribute to cancer, whereas tumour development is associated with the inactivation of tumour suppressor gene function.

Mutation of a single copy of a protooncogene can have a dominant growth promoting effect on a cell. The oncogene can therefore be detected by its effect when it is added, by DNA transfection or through infection with a viral vector, to the genome of a suitable type of cell. In contrast, both copies of the normal tumour suppressor gene must be removed or inactivated in the diploid somatic cell before an effect is seen – the cancer-causing mutations are recessive (see Figure 1). This calls for a different approach to discover what is missing – one cannot, for instance, use a cell transformation assay to identify something that is simply not there.

The existence of tumour suppressor genes was demonstrated by showing that somatic cell hybrids, created in vitro by fusing a cancer cell with a non-cancerous one, most often took on the characteristics of the cancer-free parent. The identification of specific genes, however, was initially the result of studies of inherited cancers, such as hereditary retinoblastoma and Wilms’ tumour.