DNA Polymerase Beta and Breast Cancer

描述(申请人提供)：几项小规模研究表明，到目前为止，在所检查的189个肿瘤中，至少有30%表达DNA聚合酶β(POLβ)基因的变异，这些突变都不是常见的多态。这表明POLβ基因突变与癌症之间存在联系。我们实验室的初步数据显示，癌症来源的I260M、K289M和E295K Polβ突变体在小鼠细胞中的表达会导致细胞转化。我们还表明，K289M结肠癌相关突变酶和I260M前列腺癌相关Polβ突变酶的DNA合成会导致突变的诱导。这些结果表明，POLβ癌症相关突变体具有功能表型。由于POLβ是碱基切除修复途径中的一个关键酶，我们的结果表明由POLβ酶变异体引起的异常碱基切除修复与人类癌症有关。这些研究为确定POLβ基因突变是否对人类癌症有重大贡献提供了动力。由于乳腺癌是女性癌症相关死亡的第二大原因，我们将重点放在这种疾病上。这项拟议研究的长期目标是确定POLβ是否在高频率的人类乳腺肿瘤中发生突变，确定这些肿瘤中POLβ突变的类型，并确定我们确定的POLβ突变是否具有功能表型。这些研究将通过确定300个乳腺肿瘤的POLβ基因的DNA序列并将其与正常对照组进行比较来进行，以获得携带POLβ变异的肿瘤的百分比。结果将与结果数据进行比较。我们获得的变异将在遗传和生化分析中进行表征，以确定它们是否具有与癌症病因学一致的表型。

DESCRIPTION (provided by applicant): Several small-scale studies suggest that at least thirty percent of the 189 tumors examined to date express variants of DNA polymerase beta (Pol beta) gene and none of these mutations are common polymorphisms. This suggests that there is a link between mutations in Pol beta and cancer. Preliminary data from our laboratory shows that expression of the cancer-derived I260M, K289M, and E295K Pol beta mutants in mouse cells results in cellular transformation. We have also shown that DNA synthesis by the K289M colon cancer-associated and I260M prostate cancer-associated Pol beta mutant enzymes results in the induction of mutations. These results demonstrate that Pol beta cancer- associated mutants have functional phenotypes. Because Pol beta is a key enzyme in the base excision repair pathway, our results suggest that abnormal base excision repair by Pol beta enzyme variants contributes to human cancers. These studies provide the impetus to determine whether mutations in the Pol beta gene make a significant contribution to human cancer. Because breast carcinoma is the second leading cause of cancer-related death in women, we are focusing on this disease. The broad long-term objectives of the proposed research are to determine if Pol beta is mutated in a high frequency of human breast tumors, to identify the types of Pol beta mutations in these tumors, and to determine if the Pol beta mutations we identify have a functional phenotype. These studies will be performed by determining the DNA sequences of the Pol beta gene from 300 breast tumors and comparing them to normal controls, to obtain the percentage of tumors that harbor Pol beta variants. The results will be compared to outcome data. The variants we obtain will be characterized in genetic and biochemical assays to determine if they have phenotypes that are consistent with cancer etiology.