Recent advances in human cancer genetics have led to the identification of genes in which mutations in predispose to cancer. Tests for mutations in these cancer genes are becoming a part of routine clinical practice in cancer risk counseling. The benefits of cancer gene testing are countered by significant costs in emotional stress due to the inherent uncertainties of genetic risk data. Methods that provide individualized phenotypic information to reduce the degree of uncertainty in genetic test data would be beneficial to those at risk. Towards this goal, a new phenotypic marker for cancer risk assessment is presented. The new marker is based on new insights into the function of the p53 tumor suppressor gene. With high penetrance, germline p53 mutations predispose to multiple tumors or diverse tissues early in life. Recently, p53 has been shown to regulate the production of cellular guanine ribonucleotides (rGNPs). RGNPs function in growth factor signal transduction. They play a key role in regulating DNA replication and cell kinetics. Preliminary studies indicate that human germline p53 mutations are associated with a predicted increase in rGNP production. This phenotype is postulated to be an important factor in tumor development in cancer patients with germline p53 mutations. Due to related mechanisms, the same phenotype may also be at cause for cancers in patients with normal germline p53 genes. A proposal is made to develop a specific indicator of constitutional rGNP-production rate called the plasma to plasma uric acid concentration. An expanded study will be undertaken to investigate further an association detected between low PPR (indicating elevated rGNPO production) and mutant germline p53 genotype or ovarian cancer status. PPR will be evaluated retrospectively in additional members of families with inherited germline p53 mutations and in women in families at high risk for ovarian cancer, breast cancer, and other epithelial tumors. The breast cancer and ovarian cancer studies will evaluate PPR as a marker to identify women in high- risk cancer families who are at greatest risk for cancer. The proposed biomarker has potential as a general method to delineate individuals in clinically defined high-risk cancer populations who will benefit most from cancer prevention strategies.
