Deregulation of Control of Growth and Apoptosis Occurs with Age or Exposure to Certain Mutagens in Normal Human Cells; A Possible Predictive Test for Cancer Risk

The identification of sub populations at increased risk from carcinogenic agents in the workplace or environment is a major healthcare goal. General screening is costly and reduction of risk to negligible levels is impractical if not impossible. Attempts to categorise people on the basis of predisposition have only worked in a few cases where an inherited cancer syndrome exists. Recent advances in our understanding of initial events in cancer however, now point to growth deregulation in response to DNA damage as a fundamental event in cancer and in culture systems designed to study carcinogenesis. This is thought to occur instead of apoptosis which is designed to eliminate damaged cells. In this study epithelial tissue from adults and children under two was cultured and exposed to radiation or a chemical carcinogen. The cultures were then tested for expression of cmyc, p53 and bcl-2 The results show that the paediatric tissue has low levels off these gene products and that these increase after carcinogen exposure. In the adult series some deviation from the paediatric status can be seen in the controls and up to 40% of adults fail to demonstrate a normal apoptotic response to serious DNA damage. Nitrosamines, at non toxic levels, blocked the apoptotic response normally seen after exposure to radiation. The most significant correlation between DNA damage and gene expression was the relationship between the bcl-2/cmyc ratio and the ability of DNA damaged cells to grow in culture. bcl-2/cmyc ratio <1 correlated significantly with radio sensitivity and apoptosis while ratios>1 correlated with increased growth rate and induction of a repair process. The test can be done on biopsy sized specimens and may provide a means of cheaply assessing cancer predisposition in large numbers of people.