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

TP53种系突变家族癌症风险预测的统计方法和工具

• 批准号: 9902384
• 负责人: Wenyi Wang
• 金额: $ 42.02万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902384
• 关键词: Accounting; Affect; Assessment tool; BRCA1 gene; Bioinformatics; Cancer Center; Cancer Etiology; Clinic; Clinical; Clinical Management; Computer software; Counseling; Country; Data; Data Set; Decision Making; Disease; Early Diagnosis; Education; Epidemiologist; Epithelial; Epithelium; Evaluation; Extended Family; Family; Family history of; Family member; Frequencies; Future; Genetic; Genetic Counseling; Germ-Line Mutation; Hereditary Breast and Ovarian Cancer Syndrome; High-Risk Cancer; Human; Individual; Inherited; International; Li-Fraumeni Syndrome; Life; Malignant Neoplasms; Medical; Modeling; Mutation; National Cancer Institute; Oncogenes; Organ; Outcome; Outcomes Research; Pattern; Pediatrics; Penetrance; Physicians; Population; Probability; Public Health; Recording of previous events; Research; Risk; Risk Assessment; Screening for cancer; Site; Software Tools; Statistical Methods; Syndrome; TP53 gene; Testing; Tissues; Tumor Suppressor Genes; University of Texas M D Anderson Cancer Center; cancer diagnosis; cancer genetics; cancer risk; cancer site; cancer type; clinical practice; early onset; genetic counselor; improved; indexing; large datasets; lifetime risk; malignant breast neoplasm; mathematical model; member; mortality; mutation carrier; open source; programs; receptor; risk prediction model; screening; screening program; software development; tool

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.

项目摘要 复杂的风险预测建模极大地改善了遗传性癌症的筛查和测试 综合征，例如乳腺癌中的BRCA1/2突变。这样的定量风险预测模型迫切地是 证明减少后，需要早期检测到Li-Fraumeni综合征（LFS） 该综合征的监视测试死亡率。 LFS主要来自TP53的种系突变 肿瘤抑制基因，其特征是癌症在生命早期相对较早发生，通常反复在 生命周期，影响与其他癌症综合症重叠的多个部位，特别是 遗传性乳腺癌和卵巢癌综合征。我们的目标是改善 通过开发数学模型来评估早期发作癌症家族史的人1） TP53测试之前的种系突变携带者概率和2）发展的绝对终生风险 患有TP53突变的个体的癌症。我们的理由是我们的高级模型将使 遗传性TP53突变家庭的系统和全面的风险评估，以便遗传 辅导员和医生可以提供更有效的辅导和筛查，这些个人携带TP53 鉴于这些个体的癌症型结局的高频和多样性，种系突变。我们将 通过以下特定目标来实现我们的研究目标。 1）表征特定的发作 有LFS风险的个体的癌症类型：a）通过通过 使用MD Anderson癌症中心（MDACC）和外部诊所的扩展家庭数据的癌症类型； b）开发LFSProcs以结合癌症特异性的外观，并验证这些模型 预测未来的风险； c）富含LFSPRO，并具有其他癌症风险的修饰符，例如HER2状态 乳腺癌; 2）表征有LFS风险的个体的主要癌症的数量：a）估计 使用扩展家庭数据的主要癌症数量的渗透性； c）开发LFSpromp和 LFSPROMP+CS融合了新的渗透率并验证这些模型； 3）开发软件和 将其传播在癌症诊所中。我们的重要贡献是开发高级 定量风险评估工具将提供更准确的风险量化，并提供一般性的风险评估工具 统计框架将来包括其他癌症部位和癌症基因进行风险评估。 相关的软件套件LFSPRO将很快传播到MDACC Li-Fraumeni教育中 以及早期检测（铅）筛查计划以及全国其他筛查研究。 LFSPRO是 已经集成到贝叶斯山和癌症套件中，这些软件包被广泛用于风险评估和 高危癌症诊所的咨询，特别是乳腺癌诊所。随着我们的高级 模型，这些软件工具将继续在临床环境下为新人群带来LFS咨询 并吸引更多受TP53突变影响的家庭。