Genetic instability and cancer

Abstract

It is well known that defects in some aspects of DNA metabolism including telomere maintenance, nucleotide excision repair and mismatch repair contribute to tumor development. However, to account for the multiple mutations observed in cancer cells, the new fields of DNA metabolism that maintain genome integrity must be determined. I will show four new aspects of genetic instability that have recently emerged which helps toward the understanding of the links between defects in genome integrity and tumor development. First, mutations in DNA helicase genes cause rare genetic instability syndromes, suggesting that defects in DNA helicase activities are responsible for predispositions to cancers. Second, mutations of the gene for ataxia-telangiectasia in sporadic leukemias suggest that genes involved in rare syndromes are paradigms for understanding the mechanism underlying the genesis of sporadic tumors. Third, since the emergence of a link between breast cancer susceptibility gene products and RAD51, great interest has been shown in recombinational repair. Finally, a mutator phenotype is conditional in some mismatch-repair deficient cells, proposing that cancer arises under restrictive conditions even though stability genes are mutated.