Genetic Susceptibility to Cancer

Abstract

Two recent publications have examined the role of heritable genetic factors in the cancer process and how genetic heterogeneity in cancer susceptibility might impact upon radiation protection practices. The International Commission on Radiological Protection (ICRP) report Genetic Susceptibility to Canceris the more extensive and begins with a comprehensive appraisal of radiation-induced DNA damage and repair processes. The misrepair of DNA double strand lesions leading to chromosome exchanges and deletions is considered characteristic of radiation exposure and the role of the XRCCand radfamilies of genes in this process is described. Ataxia telangiectasia is used as a model for elucidating the mechanisms involved in cancer proneness, with misrepair of DNA double strand breaks, disruption of signal transduction and impaired cell cycle checkpoint functions being implicated. Evidence is also presented for the role of recombinational processes in double strand break repair and the induction of deletion mutants as the prime mechanism for producing gene mutations by radiation. Experimental studies on the induction of genomic instability by radiation are reviewed, although it is concluded that the mechanistic basis for this phenomenon and its relationship with neoplastic development remains to be established. Although increased radiation-induced cellular lethality has been claimed for a range of genetic disorders, it is judged that only a minority show unambiguous evidence of cellular radiosensitivity. However, developments in chromosomal assays are thought to hold more promise for the discrimination of variations in radiosensitivity, with such studies leading to an understanding of how the low penetrance genes involved in this response may be related to cancer predisposition.