The Multiplicity of Mutations in Human Cancers

Abstract

Human cancer cells contain large numbers of mutations. These can be observed as alterations in chromosomal numbers (gains or losses) and structural integrity, by an analysis of the lengths of microsatellite sequences and mutations in oncogenes and tumour-suppressor genes. The question is how and when these mutations originate, what the consequences of these mutations are, and most importantly, whether they drive tumour progression. In order to account for the disparity between the infrequency of spontaneous mutations in normal somatic human cells and the large number of mutations in human cancers, we formulated the hypothesis that cancer cells express a mutator phenotype. The hypothesis states that an increase in mutation rate is an early step during tumorigenesis. As a result, random mutations are generated throughout the genome. Some of these mutations occur in genes that normally function to guarantee the accurate transfer of genetic information during each cell division. Among the many mutations produced, some are ones that impart a growth advantage and result in invasion and metastasis, the hallmarks of cancer. In this chapter we will focus on the multiple mutations in human tumours, postulated sources for these mutations, and the arguments, for and against, the mutator phenotype hypothesis.