DNA polymorphisms as modulators of genotoxicity and cancer.

Cancer arises as a result of several factors, including multiple genes and environmental exposures. It is generally accepted that genetic polymorphisms are associated with most common disorders like cancer. The majority of polymorphisms are single nucleotide polymorphisms (SNPs) which occur with a frequency of 10(-6). Susceptibility-conferring alleles are not sufficient to cause disease, but modulate the risk in combination with other alleles and environmental exposures, except in the extreme case of Mendelian cancer syndromes (e.g. FAP, HNPCC, Rb). The Environmental Genome Project identifies, among others, two lines of research along which we have been working and are the topic of the present paper, namely (i) allele-disease associations and (ii) functional studies of allelic variants. Case-control association studies conducted by us and others showed that polymorphism at a single site could increase risk-predictability by a factor < 2. It is known, however, that the individual risk predictability increases by associating multiple genetic polymorphisms as was demonstrated for breast, renal and thyroid cancer. Functional genomics of the putative susceptibility-alleles involved in cancers can improve substantially the strength of association studies. This calls for cell-systems capable of tracking different gene activities, which may clarify the possible role of allelic variants in certain cancers. This endeavour is likely to be met by the bacterial tester strain, MTC, described here.