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

BRCA 1/2基因的生殖系突变与卵巢癌的发生风险相关 癌然而，在发病率和年龄方面存在很大的个体差异， BRCA 1/2突变携带者的诊断，这意味着虽然BRCA 1/2的生殖系突变可能是 虽然这对于解释某些家族中的孟德尔癌症模式是必要的，但它们可能不足以解释 完全描述了癌症风险的个体间差异。尽管有大量的流行病学研究， 关于一般人群中卵巢癌的风险因素的信息，它们在 遗传性卵巢癌的定义不明确。我们目前的遗传性卵巢癌风险预测模型 是基于对小规模、有选择的人群的流行率估计，这损害了我们的能力。 个性化的卵巢癌预防策略。目前风险降低输卵管卵巢切除术 （RRSO）提供了最高程度的风险降低（70-95%）。由于发病年龄较小， BRCA 1/2突变的女性卵巢癌，RRSO建议在35岁或 分娩是完全的，通常会导致手术绝经及其相关的短期和长期 病态如果没有更具体的估计个体患卵巢癌的风险或年龄， 考虑RRSO的女性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，导致大量女性选择 不接受RRSO，或者推迟决定直到更年期。证据表明 其他修饰因子影响BRCA 1/2突变携带者的癌症发病率。更好的 了解改变卵巢癌发病率和发病时间的途径可以减少 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 根据妇女的个人修饰特征，为妇女个人制定预防战略。我们提出了一个 通过以下方式加强目前的流行模式：1）确定和量化生殖健康状况， 与DNA损伤识别和修复途径相关的风险因素， 8 RCA <$//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; 和3）开发和评估基于网络的患者决策辅助工具（PtDA），以补充遗传 咨询会议和促进决策有关遗传性卵巢癌的风险管理。 相关性（参见说明）： 预防性卵巢切除术可最大程度地保护患有卵巢癌的女性， BRCA 1/2突变。然而，接受手术的决定受到以下不确定性的挑战： 个人风险以及手术的短期和长期不良后果。这个项目的目标 是调查遗传和非遗传因素，这可能提供更精确的风险估计， 将这种个性化的风险信息纳入决策辅助工具，以补充测试过程。

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.