10 Telomere Dynamics and Genome Instability in Human Cancer

Abstract

TELOMERE LOSS AND THE ACQUIRED INSTABILITY OF TUMOR GENOMES
More than 80 years ago, Boveri (1914) proposed that chromosome non-disjunction can cause malignant transformation of human cells. Anecdotes about anomalous behavior of cancer chromosomes have accumulated since. For instance, epidemiologists calculated that some human malignancies evolve through the combined effects of five or six independent mutations. Since the mutation rate in normal human cells is too low to account for all these changes, it appears that cancer cells have acquired the ability to deconstruct their DNA (Nowell 1976). Observations reviewed here suggest that this mutator phenotype may in part be caused by the loss of chromosomal telomeres during tumorigenesis.

To a great degree, the instability of tumor genomes can be blamed on changes in the regulation of the cell cycle and loss of cell cycle checkpoints (Hartwell and Kastan 1994). For instance, the recognition of the tumor suppressor gene p53 as part of both a DNA damage checkpoint and a spindle checkpoint explains why p53⁻ tumors tolerate genotypic changes (Hartwell and Kastan 1994; Cross et al. 1995). But what is the source of the DNA damage in these cells? Some of the mutations are probably inherent mistakes in the normal process of genome maintenance, as suggested by increased genome instability in normal cells from p53^−/− mice (Livingstone et al. 1992; Cross et al. 1995). Second, environmental assaults are a likely source of chromosomal lesions.

Third, the genotypic changes in human tumors may betray the malfunction of (repair) genes that normally...