Multiple mutations and cancer

Abstract

Most human tumors are highly heterogenous. We have hypothesized that this heterogeneity results from a mutator phenotype. Our premise is that normal mutation rates are insufficient to account for the multiple mutations found in human cancers, and, instead, that cancers must exhibit a mutator phenotype early during their evolution. Here, we examine the current status and implications of the mutator phenotype hypothesis for the prognosis, treatment, and prevention of human cancers.

Figure 1

A mutator phenotype arising from genetic instability at the single nucleotide level is not detected in routine DNA sequencing. The DNA sequences of oligonucleotides containing clonal and random mutations are shown. Clonal nucleotide substitutions are in blue, and random substitutions are shown in red. The only substitutions observed by DNA sequencing are those present in the majority of molecules, i.e., the clonal mutations. In this example, random substitutions that constitute <10% of the nucleotides at each position are not detected. This level of detection approximates the sensitivity of routine DNA sequencing.