Precision Assessment and Delivery of Cancer Risks in BRCA 1/2 Mutation Cancers

项目摘要 在目前的风险评估和咨询实践中，所有检测结果为A阳性的女性 有害的BRCA1/2突变被引用为相同的卵巢癌风险和 得到了关于使用降低风险的跳伞鱼的相同建议- 卵巢切除术(RRSO)和其他预防措施。我们最近发表了一个模型 它报告了显著的和临床相关的风险差异，这取决于具体的 女性遗传的突变。特别是，我们最近已经证明了特定的突变 乳腺癌或卵巢癌的风险增加或发病年龄早于 对任何BRCA1/2突变进行的通用风险估计。此外，考虑到 以前接触过重要的风险因素(例如，生育史、口服避孕药的使用或 预防性手术)可能会对这一人群的癌症风险估计产生很大影响。 更准确的风险信息可能对女性做出最佳决策至关重要 考虑癌症预防策略。 基于这些初步观察，我们建议发展精确度绝对风险。 包含有关突变风险组信息的模型，将体外方法应用于 确定新的临床相关BRCA1/2突变并验证其致病能力， 为了更好地理解个人价值观如何影响女性个体的理解 并根据风险估计采取行动，以用于未来的决策辅助干预。因此，这项提议将 为BRCA1/2相关的癌症风险开发一种“精确预防”的方法，以降低 一名女性死于卵巢癌的可能性，并将对 携带BRCA1/2突变的女性。

Project Summary In current risk assessment and counseling practices, all women who test positive for a deleterious BRCA1/2 mutation are quoted the same general range of ovarian cancer risk and are given the same recommendation regarding utilization of risk reducing salpingo- oophorectomy (RRSO) and other preventive measures. We have recently published a model that reports substantial and clinically relevant differences in risk depending on the specific mutation a woman has inherited. In particular, we have recently shown that specific mutations confer an increased risk or earlier age of onset for breast or ovarian cancer compared with the generic risk estimates made for any BRCA1/2 mutation. In addition, risk estimates that consider previous exposure to important risk factors (e.g., reproductive history, oral contraceptive use, or preventive surgery use) may have a large impact on cancer risk estimates in this population. More precise risk information could be critical for optimal decision-making for women who are considering cancer prevention strategies. Based on these initial observations, we propose to develop precision absolute risk models that incorporate information about mutation risk group, to apply in vitro methods to identify new clinically relevant BRCA1/2 mutations and validate their capacity to cause disease, and to gain a better understanding of how personal values affect how individual women interpret and act on risk estimates, for use in a future decision aid intervention. Thus, this proposal will develop a “precision prevention” approach to BRCA1/2-associated cancer risk to lower the chances a woman will die from ovarian cancer, and will have immediate translational impact for women with BRCA1/2 mutations.