Do mutator mutations fuel tumorigenesis?

Abstract

The mutator phenotype hypothesis proposes that the mutation rate of normal cells is insufficient to account for the large number of mutations found in human cancers. Consequently, human tumors exhibit an elevated mutation rate that increases the likelihood of a tumor acquiring advantageous mutations. The hypothesis predicts that tumors are composed of cells harboring hundreds of thousands of mutations, as opposed to a small number of specific driver mutations, and that malignant cells within a tumor therefore constitute a highly heterogeneous population. As a result, drugs targeting specific mutated driver genes or even pathways of mutated driver genes will have only limited anticancer potential. In addition, because the tumor is composed of such a diverse cell population, tumor cells harboring drug-resistant mutations will exist prior to the administration of any chemotherapeutic agent. We present recent evidence in support of the mutator phenotype hypothesis, major arguments against this concept, and discuss the clinical consequences of tumor evolution fueled by an elevated mutation rate. We also consider the therapeutic possibility of altering the rate of mutation accumulation. Most significantly, we contend that there is a need to fundamentally reconsider current approaches to personalized cancer therapy. We propose that targeting cellular pathways that alter the rate of mutation accumulation in tumors will ultimately prove more effective than attempting to identify and target mutant driver genes or driver pathways.

MIPSTR: a method for multiplex genotyping of germline and somatic STR variation across many individuals

“…MIPSTR offers an approach to empirically test this hypothesis. Compared to single cell sequencing (Navin et al 2011;Baslan et al 2012), MIPSTR also offers a cost-and labor-efficient alternative for assessing the genetic heterogeneity of tumors, which is clinically relevant for disease treatment and prognosis (Schmitt et al 2012;Fox et al 2013).…”

Gene Fusion due to Chromosome Misconnection May Seriously Affect Your Health

“…For instance, patients with germline disruptions of RUNX1 may develop hematological malignancies later in life [Buijs et al, 2012]. In this way, the 'mutator hypothesis' of cancer development is extended to also include genomic rearrangements [Fox et al, 2013]. In addition, these findings appear to substantiate the hypothesis Boveri [1914] has put forward a century ago.…”

A Systems Biology Interpretation of Array Comparative Genomic Hybridization (aCGH) Data through Phylogenetics

“…This is especially valuable due to the heterogeneous nature of variation in cancer specimens and saves valuable time by focusing functional studies and pathway studies on the driver genes (clonal) rather than the passenger genes (nonexpanding) (Fox et al, 2013).…”