PLASMA PURINE RATIO--A NEW BIOMARKER FOR CANCER RISK

人类癌症遗传学的最新进展已导致鉴定出其中突变易患癌症的基因。对这些癌症基因突变的检测正在成为癌症风险咨询中常规临床实践的一部分。癌症基因检测的好处被由于遗传风险数据固有的不确定性而导致的情绪压力的巨大成本所抵消。提供个体化表型信息以降低基因检测数据不确定性程度的方法将对那些有风险的人有益。为了实现这一目标，一个新的表型标记癌症风险评估。新的标记物是基于对p53肿瘤抑制基因功能的新见解。生殖系p53突变具有高突变率，在生命早期易患多种肿瘤或多种组织。最近，p53已被证明可以调节细胞鸟嘌呤核糖核苷酸（rGNP）的产生。RGNP在生长因子信号转导中起作用。它们在调节DNA复制和细胞动力学中起关键作用。初步研究表明，人类生殖系p53突变与预测的rGNP产量增加有关。这种表型被认为是生殖系p53突变的癌症患者肿瘤发展的重要因素。由于相关的机制，相同的表型也可能是正常生殖系p53基因患者癌症的原因。建议开发一种称为血浆尿酸浓度的体质rGNP生产率的具体指标。将进行一项扩展研究，以进一步研究低PPR（表明rGNPO产生升高）与突变生殖系p53基因型或卵巢癌状态之间的相关性。PPR将在具有遗传性生殖系p53突变的家庭成员和卵巢癌、乳腺癌和其他上皮性肿瘤高风险家庭中的女性中进行回顾性评价。乳腺癌和卵巢癌研究将评估PPR作为一种标志物，以确定高危癌症家庭中患癌症风险最大的妇女。提出的生物标志物有可能作为一种通用方法来描绘临床定义的高风险癌症人群中的个体，这些个体将从癌症预防策略中获益最多。

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.