Use of elderly tumor-free subjects as a "supercontrol" for cancer epidemiological studies: pros and cons

Search for cancer-predisposing single-nucleotide gene polymorphisms is complicated due to weakness of expected associations. We introduced a novel design for molecular epidemiological study, which relies on selection of highly demonstrative cases and controls. It is assumed that patients with clinical features of hereditary predisposition (e.g., cancer bilaterality, or young onset, or presence of family history, etc.) are more likely to accumulate at-risk alleles than randomly recruited cases. Furthermore, subjects with characteristics of cancer tolerance, e.g., elderly tumor-free smokers, may serve as a "supercontrol" for the rapid assessment of polymorphic candidates. The utility of the "comparison of extremes" design has already been exemplified in a series of reports. However, the use of elderly subjects for cancer case-control studies may possess a bias; for example, factors contributing to cancer predisposition may nevertheless be advantageous for the overall longevity, as they could compensate age-related decline of tissue maintenance and renewal. For example, there is some evidence for a dual role of the apoptosis-deficient Pro/Pro genotype of p53 gene, which may simultaneously increase both cancer risk and survival. Comprehensive studies on distribution of cancer-related gene polymorphisms in elderly population remain to be done.