The role of chromosomal instability in tumor initiation

Abstract

Chromosomal instability (CIN) is a defining characteristic of most human cancers. Mutation of CIN genes increases the probability that whole chromosomes or large fractions of chromosomes are gained or lost during cell division. The consequence of CIN is an imbalance in the number of chromosomes per cell (aneuploidy) and an enhanced rate of loss of heterozygosity. A major question of cancer genetics is to what extent CIN, or any genetic instability, is an early event and consequently a driving force for tumor progression. In this article, we develop a mathematical framework for studying the effect of CIN on the somatic evolution of cancer. Specifically, we calculate the conditions for CIN to initiate the process of colorectal tumorigenesis before the inactivation of tumor suppressor genes.

Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer

“…The role of genomic instability as a mechanism to initiate or promote this genetic variation is still controversial [15][16][17][18] , as is the question of whether there is a distinctive difference between different tumor types depending on whether the initiating event is a mutation leading to loss of function of tumor suppressor genes 19 or deregulation or fusion of genes as a consequence of …”

Does age influence loss of heterozygosity?

“…This has led to the hypothesis that one of the early steps in cancer progression is a genetic change causing a switch to a higher than normal rate of mutation, creating a 'mutator phenotype' that increases the likelihood of subsequent genetic events (Loeb, 1991) (Loeb and Loeb, 2003) (Nowak et al, 2002). The relationship between advanced age and the incidence of cancer also raises the question: does aging lead to a higher than normal rate of mutation?…”

Adaptive dynamics of unstable cancer populations: The canonical equation

“…Many mathematical models have provided interesting points into this topic, with the introduction of relevant ideas such as the mutator phenotype (Loeb, 2001) and several multi‐step models of mutation acquisition (see e.g., Komarova et al., 2002; Nowak et al., 2002) that have investigated the possible scenarios of correlation between instability and cancer progression.…”