'Hide-then-hit' to explain the importance of genotypic polymorphism of DNA repair genes in determining susceptibility to cancer.

Interindividual variations in DNA repair capacity/efficiency linked to the presence of polymorphisms in DNA repair-related genes have been suggested to account for different risk of developing cancers. In this review article, on the basis of breast cancer formation as a model, we propose a 'hide-then-hit' hypothesis indicating the importance of escaping checkpoint surveillance for sub-optimal DNA repair variants to cause cancer. Therefore, only cells with subtle defects in repair capacity arising from low-penetrance variants of DNA repair genes would have the opportunity to grow and accumulate the genetic changes needed for cancer formation, without triggering cell-cycle checkpoint surveillance. Furthermore, distinct from high-penetrance alleles, these polymorphic alleles of DNA repair genes would predispose carriers to a higher risk of developing cancer but would not necessarily cause cancer. To examine this, we simultaneously genotyped multiple SNPs of cell-cycle checkpoint genes and the DNA repair genes. Support for the hypothesis came from observations that breast cancer risk associated with variant genotypes of DNA repair genes became more significant in the subgroups of women with specific genotypic statuses of checkpoint genes. This 'hide-then-hit' hypothesis is certainly needed to be confirmed by biological evidence in which a cause-effect relationship has to be established. However, based on this, possible gene-gene interaction is considered to play an important role in modifying the cancer risk associated with genotypic polymorphism of DNA repair gene in different study populations.