VARIATION IN DNA-REPAIR IS A FACTOR IN CANCER SUSCEPTIBILITY - A PARADIGM FOR THE PROMISES AND PERILS OF INDIVIDUAL AND POPULATION RISK-ESTIMATION

The repair of DNA damage protects the genome of the cell from the insu lts of cancer causing agents. This was originally demonstrated in indi viduals with the rare genetic disease, xeroderma pigmentosum, the prot otype of cancer genes, and subsequently in the relationship of mismatc h repair to colon cancer. Recent studies suggest that individuals with less dramatic reductions in the capacity to repair DNA damage are obs erved at polymorphic frequency and these individuals have an increased susceptibility to several types of cancer. Screening of individuals f or DNA sequence variation in the exons of 9 DNA repair genes has resul ted in identification of 15 different polymorphic amino acid substitut ion variants. Although the studies to relate these variants to reduced DNA repair capacity and cancer status have not been completed, the av ailable information is sufficient to suggest that DNA repair genes sho uld be incorporated into molecular epidemiology and cancer susceptibil ity studies. The availability of molecular epidemiology data presents exciting opportunities for refinement of risk estimation models and id entification of individuals at increased risk of disease, with resulta nt opportunities for effective surveillance and early intervention and treatment. The opportunities to acquire susceptibility data are assoc iated with possible perils for establishment of regulations for permis sible exposures to carcinogenic agents and also stigmatization of 'at risk' individuals that may result in decreased access to employment op portunities and health care. (C) 1998 Elsevier Science B.V. All rights reserved.