Statistical methods and tools for cancer risk prediction in families with germline mutations in TP53

项目摘要 复杂的风险预测模型极大地改善了遗传性癌症的筛查和检测 乳腺癌中BRCA 1/2突变等综合征。这样一个定量的风险预测模型， 需要在证明减少的LFS后早期发现Li-Fraumeni综合征（LFS）。 死亡率与监测测试该综合征。LFS主要由TP 53中的种系突变引起。 肿瘤抑制基因，其特征是癌症发生在生命的相对早期，经常反复超过一个月。 寿命，并影响与其他癌症综合征重叠的多个部位，特别是 遗传性乳腺癌和卵巢癌综合征。我们的目标是改善临床管理， 具有早发性癌症家族史的个体，通过开发数学模型来评估1） TP 53检测前的生殖系突变携带者概率和2）发展为 TP 53基因突变的癌症。我们的理由是，我们的先进模式将使 对遗传性TP 53突变的家庭进行系统和全面的风险评估， 咨询师和医生可以为携带TP 53的个体提供更有效的咨询和筛查 生殖系突变，考虑到这些个体的高频率和不同的癌症类型结果。我们将 通过以下具体目标实现我们的研究目标。1)描述特定的 具有LFS风险的个体的癌症类型：a）通过以下方法估计TP 53突变相关癌症的发生率： 癌症类型，使用MD安德森癌症中心（MDACC）和外部诊所的大家族数据; B）开发LFSPROCS以纳入癌症类型特异性的转录因子，并在 c）用癌症风险的其他修饰因子（如HER 2状态）丰富LFSPRO， 乳腺癌; 2）表征处于LFS风险中的个体的原发性癌症的数量：a）估计 使用大家族数据确定原发性癌症的数量; c）开发LFSPROMP， LFSPROMP+CS，以纳入新的系统并验证这些模型;以及3）开发软件， 在癌症遗传诊所中传播。我们的重大贡献将是开发一种先进的 定量风险评估工具，将提供更准确的风险量化，并提供一个通用的 统计框架，以纳入未来风险评估的其他癌症部位和癌症基因。 相关的软件套件LFSPRO将迅速传播到MDACC Li-Fraumeni教育 和早期检测（LEAD）筛查计划，以及全国其他筛查研究。LFSPRO是 已经集成在BayesMendel和CancerGene软件包中，广泛用于风险评估， 在高危癌症诊所，特别是乳腺癌诊所提供咨询。随着我们先进的 这些软件工具将继续在临床环境下为新人群提供LFS咨询 帮助更多受TP 53突变影响的家庭。

Project Summary Sophisticated risk prediction modeling has greatly improved screening and testing for inheritable cancer syndromes such as BRCA1/2 mutations in breast cancer. Such a quantitative risk prediction model is urgently needed for the early detection of the Li-Fraumeni syndrome (LFS) following the demonstration of reduced mortality with surveillance testing for that syndrome. LFS primarily arises from germline mutations in the TP53 tumor suppressor gene and is characterized by cancer occurring relatively early in life, often repeatedly over a lifetime, and affecting multiple sites that overlap with those of other cancer syndromes, in particular the hereditary breast and ovarian cancer syndrome. Our objective is to improve the clinical management of individuals with a family history of early-onset cancers by developing mathematical models to assess 1) germline mutation carrier probability prior to TP53 testing and 2) the absolute lifetime risk of developing cancers in individuals with TP53 mutations. Our rationale is that our advanced models will enable the systematic and comprehensive risk evaluation of families with inherited TP53 mutations so that genetic counselors and physicians can provide more effective counseling and screening of individuals who carry TP53 germline mutations, given the high frequency and varied cancer-type outcomes in these individuals. We will accomplish our research objective through the following Specific Aims. 1) Characterize the onset of specific cancer types for individuals at risk of LFS: a) Estimate the penetrance of TP53 mutation-associated cancers by cancer type, using extended-family data from MD Anderson Cancer Center (MDACC) and from external clinics; b) Develop LFSPROCS to incorporate cancer-type-specific penetrances, and validate these models in predicting future risk; c) Enrich LFSPRO with additional modifiers of cancer risk, such as HER2 status for breast cancer; 2) Characterize the number of primary cancers for individuals at risk of LFS: a) estimate the penetrance for the number of primary cancers using extended-family data; c) Develop LFSPROMP and LFSPROMP+CS to incorporate new penetrances and validate these models; and 3) Develop software and disseminate it among cancer genetic clinics. Our significant contribution will be to develop an advanced quantitative risk assessment tool that will provide more accurate risk quantification, and to provide a general statistical framework for including additional cancer sites and cancer genes for risk assessment in the future. The associated software suite LFSPRO will be quickly disseminated into the MDACC Li-Fraumeni Education and Early Detection (LEAD) screening program, as well as other screening studies in the nation. LFSPRO is already integrated in BayesMendel and CancerGene packages, which are widely used for risk assessment and counseling at high-risk cancer clinics, in particular breast cancer clinics. With the addition of our advanced models, these software tools will continue to bring LFS counseling to new populations under clinical settings and reach more families that are affected by TP53 mutations.