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: 7727488
• 负责人: MARY Beryl DALY
• 金额: $ 35.73万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-21 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727488
• 关键词: Address; Affect; Affective; Age; Age of Onset; BRCA1 gene; BRCA2 gene; Basic Science; Benefits and Risks; Bioinformatics; Biostatistics Core; Bone Density; Breast; Candidate Disease Gene; Characteristics; Classification; Clinical; Cognitive; Collaborations; Communication; Complement; Conflict (Psychology); DNA Damage; Data; Data Set; Decision Aid; Decision Making; Decision Support Systems; Development; Diagnosis; Disease; Distress; Environmental Exposure; Evaluation; Face; Family; Gene-Modified; General Population; Generic Drugs; Genes; Genetic; Genetic Counseling; Genotype; Germ-Line Mutation; Goals; Health; Hereditary Breast and Ovarian Cancer Syndrome; Hormone replacement therapy; Impairment; Incidence; Individual; Inherited; Instruction; Intervention; Knowledge; Level of Evidence; Life; Literature; Malignant Neoplasms; Malignant neoplasm of ovary; Menopause; Modality; Modeling; Modification; Morbidity - disease rate; Mutate; Mutation; National Cancer Institute; Nature; Online Systems; Operative Surgical Procedures; Oral Contraceptives; Osteoporosis; Outcome; Ovarian; Ovariectomy; Pathway interactions; Patients; Pattern; Penetrance; Phase; Population; Prevalence; Prevention strategy; Preventive Intervention; Process; Relative (related person); Reporting; Reproduction spores; Research; Resources; Risk; Risk Assessment; Risk Estimate; Risk Factors; Risk Management; Risk Reduction; Role; Salpingo-Oophorectomy; Science; Screening procedure; Site; Smoking; Support System; Symptoms; System; Testing; Time; Tissue Procurements; Translating; Translational Research Working Group; Translations; Uncertainty; Validation; Variant; Vasomotor; Woman; base; cancer prevention; cancer risk; cancer site; carcinogenesis; child bearing; cost; design; evidence base; experience; improved; innovation; malignant breast neoplasm; mortality; multidisciplinary; mutation carrier; non-genetic; ovarian cancer prevention; preference; primary outcome; prophylactic; prospective; protective behavior; repaired; reproductive; response; tumor; uptake

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基因的胚系突变与卵巢发育的显著风险相关 癌症。然而，无论是发病率还是年龄都有很大的个体差异。 BRCA1/2突变携带者的诊断表明，虽然BRCA1/2的种系突变可能是 有必要解释某些家族的孟德尔癌症模式，但它们可能不足以解释 完整描述癌症风险的个体间差异。尽管有丰富的流行病学研究 关于普通人群中与暴露相关的卵巢癌风险修饰物的信息，它们在 遗传性卵巢癌的定义并不明确。我们目前的遗传性卵巢癌风险预测模型 是基于来自少数有选择性的人群的流行率估计，这损害了我们的能力 使卵巢癌预防策略个人化。目前降低风险的输卵管卵巢切除术 (RRSO)提供最高程度的风险降低(70%-95%)。由于发病年龄较小， BRCA1/2突变女性中的卵巢癌，建议在35岁或以下时使用RRSO 生育是完全的，通常会导致手术绝经及其相关的短期和长期 病态。没有对个人患卵巢癌的风险或年龄进行更具体的估计 在发病时，考虑RRSO的女性必须权衡接受手术的利弊，并考虑 在面临不确定性的情况下，RRSO的最佳时机，导致大量女性选择 不接受RRSO，或将决定推迟到更年期。有证据表明 其他修饰因素影响BRCA1/2突变携带者的癌症外显率。更好的 了解改变卵巢癌发病率和发生时间的途径可能会减少 与卵巢癌风险评估相关的不确定性，并转化为更具体的癌症 针对个别妇女的预防策略，基于她们的个人修饰者档案。我们提出了一个 通过以下方式加强目前的流行模式：1)确定和量化生殖 以及影响DNA损伤识别和修复途径的暴露相关风险因素 8 RCA？//2与卵巢癌风险相关；2)探讨它们与其他基因座上的基因型的交互作用； 3)开发和评估基于Web的患者决策辅助工具(PtDA)，以补充遗传 咨询会议并促进关于遗传性卵巢癌风险管理的决策。 相关性(请参阅说明)： 预防性卵巢切除术为患有卵巢癌的妇女提供了最大程度的保护 BRCA1/2的突变。然而，接受手术的决定受到以下不确定性的挑战 个人风险和手术的不良短期和长期后果。这个项目的目标是 是调查遗传和非遗传因素，这些因素可能提供更准确的风险估计，以及 将这种个性化的风险信息合并到决策辅助中，以补充测试流程。