ANALYSIS OF COMMON CANCER ASSOCIATED MUTATIONS IN ASHKENAZI JEWS

在过去的十年里，许多成功的识别 导致人类疾病的突变相对来说 以简单孟德尔遗传的罕见疾病 模式.近年来，人们的注意力转向了试图 阐明与常见疾病相关的遗传改变， 如癌症、糖尿病和各种神经退行性疾病。 一些证据表明，这种突变可能是 以高频率出现，具有低反射率， 不同的基因在不同的个体具有相似的表型。 此外，可能的是，多个之间的上位相互作用 遗传和环境因素将需要在疾病之前 发展起来的作为一个实际问题， 基因同质群体中的突变类型。一旦 这些群体是东欧和中欧德系犹太人 起源虽然没有证据表明他们有一个全面的 比其他群体更大的遗传疾病负担，常见 最有可能是由于奠基者效应和遗传漂变引起的突变， 以相对较高的频率被检测到。最近的一项研究 检查BRCA 1中常见创始者突变的突变率 和BRCA 2，两个与遗传性乳腺癌相关的基因， 癌症，导致收集DNA样本和家庭 从大约5000名德系犹太人的样本中， 巴尔的摩-华盛顿地区的犹太人这些宝贵 资源提供了强大的工具， 常见的DNA序列变异可能与 癌症的发展。四个基因的突变， 潜在的疾病相关等位基因将被调查， 在上述队列中， 德系犹太人已经开发了一种多重PCR检测方法， 允许同时扩增DNA产物， APC基因在家族性腺瘤病中发生突变（6%携带者 频率），BLM，在Bloom综合征中突变（1%携带者 频率），FACC，在范可尼贫血中突变， 互补组C（1%载频）和MTHFR， 亚甲基四氢叶酸还原酶，一种参与 细胞内叶酸代谢（约40%载体 频率）。癌症的相对风险（特别是结肠癌） APC和MTHFR病例）， 非携带者将允许估计每个突变的突变率。 该项目的APC部分于1998年完成。

Over the past decade many successes in identifying mutations responsible for human illness have been for relatively uncommon diseases which are inherited in simple mendelian patterns. More recent years have seen attention turn to attempts to elucidate genetic alterations associated with common diseases such as cancer, diabetes and a variety of neurodegenerative disorders. Several lines of evidence suggest that such mutations might be present at high frequencies, have low penetrance and involve distinct genes in different individuals with similar phenotypes. Further, it is likely, that epistatic interactions between multiple genetic and environmental factors will be required before disease develops. As a practical matter, it is often easiest to identify these types of mutations in genetically homogeneous populations. Once such group are Ashkenazi Jews of eastern and middle European origin. Although there is no evidence that they have an overall greater burden of genetic illness than other groups, common mutations most likely due to founder effect and genetic drift have been detected at a comparatively high frequency. A recent study examining the penetrance of common founder mutations in BRCA1 and BRCA2, two genes associated with inherited forms of breast cancer, resulted in the collection of DNA samples and family histories of cancer from a sample of approximately 5000 Ashkenazi Jews from the Baltimore-Washington area. These valuable resources provide powerful tools for the characterization of common DNA sequence variations potentially associated with the development of cancer. Mutations in four genes with common, potentially disease- associated alleles will be investigated for increased cancer risk in the above-mentioned cohort of Ashkenazim. A multiplex PCR assay has been developed that will allow simultaneous amplification of DNA products from portions of APC, the gene mutated in familial adenomatosis (6% carrier frequency), BLM, which is mutated in Bloom syndrome (1% carrier frequency), FACC, which is mut ated in Fanconi anemia, complementation group C (1% carrier frequency) and MTHFR, methylene tetrahydrofolate reductase, an enzyme involved in intracellular folate metabolism (approximately 40% carrier frequency). The relative risk of cancer (in particular colon cancer in the cases of APC and MTHFR) among relatives of carriers and non-carriers will allow estimation of penetrance of each mutation. The APC portion of this project was completed in 1998.