Improving the Estimation and Communication of Ovarian Cancer Risk Among BRCA1/2 C

改善 BRCA1/2 C 人群卵巢癌风险的评估和沟通

• 批准号: 8380816
• 负责人: MARY Beryl DALY
• 金额: $ 34.36万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8380816
• 关键词: Age; Age of Onset; BRCA1 gene; BRCA2 gene; Breast; Communication; Complement; DNA Damage; Decision Aid; Decision Making; Development; Diagnosis; Epidemiology; Evaluation; Family; General Population; Genes; Genetic; Genetic Counseling; Genotype; Germ-Line Mutation; Goals; Hereditary Breast and Ovarian Cancer Syndrome; Incidence; Individual; Inherited; Instruction; Malignant Neoplasms; Malignant neoplasm of ovary; Menopause; Modality; Modeling; Morbidity - disease rate; Mutation; Nature; Online Systems; Operative Surgical Procedures; Oral Contraceptives; Ovariectomy; Pathway interactions; Patients; Pattern; Penetrance; Population; Prevalence; Prevention strategy; Process; Relative (related person); Risk; Risk Estimate; Risk Factors; Risk Management; Risk Reduction; Role; Salpingo-Oophorectomy; Screening procedure; Site; Testing; Time; Translating; Uncertainty; Woman; base; cancer prevention; cancer risk; cancer site; child bearing; cost; improved; malignant breast neoplasm; mutation carrier; non-genetic; ovarian cancer prevention; prophylactic; repaired; reproductive

Germline mutations in the BRCA1/2 genes are associated with significant risk of developing ovarian cancer. However, there is substantial interindividual variability in both the incidence rates and age at diagnosis in BRCA1/2 mutation carriers, implying that while germline mutations in BRCA1/2 may be necessary to explain the Mendelian pattern of cancer in some families, they may not be sufficient to completely describe interindividual variability in cancer risk. Although there is a wealth of epidemiologic information about exposure-related risk modifiers of ovarian cancer in the general population, their role in hereditary ovarian cancer is not well defined. Our current model of hereditary ovarian cancer risk prediction is based on prevalence estimates derived from small, selective populations, which compromises our ability to personalize ovarian cancer prevention strategies. Currently risk reducing salpingo-oophorectomy (RRSO) offers the highest degree of risk reduction (70-95%). Because of the younger age of onset of ovarian cancer in women with BRCA1/2 mutations, RRSO is recommended at age 35 or when childbearing is complete, often inducing surgical menopause and its associated short- and long-term morbidities. Without more specific estimates of the individual risk of developing ovarian cancer or the age of onset, women considering RRSO must weigh the pros and cons of undergoing surgery and consider the optimal timing of RRSO in the face of uncertainty, leading to significant numbers of women who choose not to undergo RRSO, or who delay the decision until they reach menopause. Evidence suggests that additional modifying factors influence cancer penetrance among BRCA1/2 mutation carriers. A better understanding of the pathways that modify both ovarian cancer incidence and its timing could lessen the uncertainty associated with ovarian cancer risk estimates and translate into more specific cancer prevention strategies for individual women, based on their personal modifier profile. We propose an enhancement of the current prevalence model through: 1) identification and quantification of reproductive and exposure-related risk factors involved in DNA damage recognition and repair pathways that influence 8RCA ¿//2-associated ovarian cancer risk; 2) exploration of their interaction with genotypes at other loci; and 3) development and evaluation of a web-based patient decision aid (PtDA) to complement the genetic counseling session and facilitate decision-making regarding hereditary ovarian cancer risk management. RELEVANCE (See instructions): Prophylactic oophorectomy offers the greatest degree of protection from ovarian cancer in women with mutations in BRCA1/2. However, the decision to undergo surgery is challenged by the uncertainties of individual risk and the adverse short- and long-term consequences of the surgery. The goal of this project is to investigate genetic and non-genetic factors which might provide more precise estimates of risk, and incorporate this personalized risk information into a decision aid to complement the testing process.

BRCA1/2基因中的种系突变与发生卵巢的重大风险有关 癌症。但是，事件率和年龄都存在很大的个体差异 BRCA1/2突变载体中的诊断，这意味着虽然BRCA1/2中的种系突变可能是 为了解释某些家庭的孟德尔癌模式所必需的，它们可能不足 完全描述癌症风险的个体变异性。虽然有很多流行病学 有关普通人群中卵巢癌风险改性剂的信息的信息，它们在 遗传性卵巢癌的定义不是很好。我们当前的遗传性卵巢癌风险预测模型 是基于从小的选择性种群中得出的普遍性估计值，这损害了我们的能力 个性化卵巢癌预防策略。目前有可能减少Salpingo-opophororcomto术的风险 （RRSO）提供最高的风险降低程度（70-95％）。因为年轻的发病率 BRCA1/2突变女性的卵巢癌，建议在35岁时或 生育是完整的，经常引起手术更年期及其相关的短期和长期 病态。没有对卵巢癌或年龄的个人风险进行更具体估计 发作，考虑RRSO的妇女必须权衡接受手术的利弊，并考虑 面对不确定性，RRSO的最佳时机，导致大量选择的女性 不要经历RRSO，或者谁推迟了决定直到到达绝经。有证据表明这一点 其他修饰因素会影响BRCA1/2突变载体之间的癌症外观。更好 了解改变卵巢癌事件及其时机的途径可以减少 与卵巢癌风险估计相关的不确定性并转化为更具体的癌症 根据个人修饰符的个人资料，为个别女性提供预防策略。我们建议一个 通过以下方式增强当前患病率模型：1）生殖的识别和数量 以及影响DNA损伤识别和维修途径的与暴露有关的风险因素 8RCA€// 2-相关的卵巢癌风险； 2）探索它们与其他基因座基因型的相互作用； 3）基于网络的患者决策援助（PTDA）的开发和评估以完成通用 咨询会议并促进有关遗传性卵巢癌风险管理的决策。 相关性（请参阅说明）： 预防性卵形切除术为患有卵巢癌提供了最大程度的保护 BRCA1/2中的突变。但是，进行手术的决定受到了不确定性的挑战 手术的个人风险和不利的短期和长期后果。这个项目的目标 是研究遗传和非遗传因素，这些因素可能会提供更精确的风险估计以及 将此个性化风险信息纳入决策援助以完成测试过程。