Mutator phenotype in cancer: Origin and consequences

Abstract

The concept that cancers express a mutator phenotype was formulated eons ago1. Its origin stems from observations that within each tumor there are many different chromosomal alterations in each malignant cell and the shape and structure of these cells are strikingly heterogeneous. We surmised that many human cancers harbor large numbers of mutations and hypothesized that these multiple mutations could not be accounted for by the exceptional accuracy of DNA replication in normal cells. Instead, we postulated that many cancers accumulate mutations in DNA polymerases and in proteins functioning in DNA repair and replication and mutations in these genes render DNA synthetic processes error-prone, resulting in genetic instability. With each generation, more and more mutations occur, some of which are in other genes that are required to maintain the genetic stability of normal cells. As tumors grow, there are repetitive rounds of selection for mutants that allow the tumors to invade and metastasize, ultimately killing the host. The genetic heterogeneity within a tumor is advantageous for overcoming environmental growth impediments and constitutes a repository of different mutant cells that allows for the rapid emergence of resistance to treatment with chemotherapeutic agents.