GENETIC PREDISPOSITION TESTING IN COLORECTAL CANCER

基因技术的爆炸性增长使识别癌症风险增加的个人成为可能，并创造了针对癌症筛查和预防努力的可能性。然而，基因易感性检测实际上是一种有效和具有成本效益的临床策略的情况尚不确定。最近描述的APC基因I1307K密码子的低外显率胚系突变似乎增加了德系犹太人患结直肠癌的风险，这突显了批判性评估何时以及如何将基因检测策略纳入临床癌症预防的必要性。我们建议对患有结直肠癌和息肉的德裔患者进行遗传流行病学研究，以评估I1307K APC突变的意义。我们的发现将被用来构建一个决策分析模型，该模型为预测这一点以及其他结肠癌易感基因的预测性测试的临床重要性和政策含义提供了一个全面的框架。实现这些目标的具体目标是：1.确定在以医院为基础的美国和以色列德系犹太人结直肠癌或腺瘤性息肉患者队列中遗传的I1307K APC突变的意义。通过评估基因频率和外显率，这项分析将评估遗传的I1307K APC突变增加癌症风险的程度，以及突变相关肿瘤是否具有特定的预后特征。2.评估基因检测对遗传性结直肠癌易感性的有效性(以寿命年和质量调整寿命年衡量)和成本效益。特别是，我们将研究基因外显率、基因频率、年龄、家族史、测试特征、相关成本和知识驱动的筛查遵从性对基因测试策略的成本效益的影响。达纳-法伯癌症研究所人口科学部的教师赞助商将为候选人提供关键的指导，以实现这些目标，并作为一名专注于评估基因技术在癌症预防中的应用的研究人员获得独立。

The explosion of genetic technology makes identification of individuals with increased cancer risks possible and creates the potential to target cancer screening and prevention efforts. However, the circumstances where genetic predisposition testing is actually an effective and cost-effective clinical strategy are uncertain. A recently described low-penetrance germline mutation in codon I1307K of the APC gene that appears to increase colorectal cancer risk among Ashkenazi Jews underscores the need to critically evaluate when and how genetic testing strategies should be incorporated into clinical cancer prevention. We propose a genetic epidemiologic study among Ashkenazi patients with colorectal cancer and polyps that evaluates the significance of I1307K APC mutations. Our findings will be used to construct a decision analysis model that provides a comprehensive framework for predicting the clinical importance and policy implications of predictive testing for this as well as for other colon cancer predisposing genes. The specific aims to accomplish these goals are: 1. To determine the significance of inherited I1307K APC mutations in a hospital-based cohort of American and Israeli Ashkenazi Jews with colorectal cancer or adenomatous polyps. By evaluating gene frequency and penetrance, this analysis will assess the extent to which inherited I1307K APC mutations increase cancer risk and whether mutation-associated tumors have particular prognostic features. 2. To assess the effectiveness, measured in life-years and quality-adjusted life years, and the cost-effectiveness, of genetic testing for inherited colorectal cancer susceptibility. In particular, we will examine the impact of gene penetrance, gene frequency, age, family history, test characteristics, associated costs, and knowledge motivated screening compliance on the cost-effectiveness of genetic testing strategies. Faculty sponsors in the Division of Population Sciences at the Dana-Farber Cancer Institute will provide the candidate with the guidance critical to accomplishing these aims and to attaining independence as an investigator focused on evaluating the application of genetic technologies to cancer prevention.