Genes, environment and breast cancer risk: The 15 year follow-up of the Prof-SC

描述(申请人提供)：BRCA1和BRCA2的发现导致了乳腺癌预防和筛查策略的更适当的目标。正在进行的中等风险突变基因的发现，以及具有常见低风险相关变异的多个基因座的发现，意味着将有更多具有实质性遗传风险的女性被识别出来。尽管基因组医学取得了这些进展，但对于高危女性来说，仍有一些重大问题尚未得到解答，她们中的大多数都没有携带任何目前已确定的易感基因突变：1)我患乳腺癌的绝对风险是多少？2)有没有可修改的因素可以降低我的风险？3)对于以前患有乳腺癌的女性，我能做些什么来降低我患新癌症的风险吗？这些问题的答案是改善临床护理的基础，早该回答了。我们对这些重要问题缺乏答案，因为许多研究未能捕捉到家族史的复杂性，也缺乏衡量风险的长期跟踪数据。通常在非专科诊所使用的乳腺癌风险预测模型通常仅基于一级家族史来捕捉风险。没有乳腺癌预测模型是建立在高危女性的大量预期队列的基础上的，也没有得到验证。研究了BRCA1和BRCA2突变携带者的潜在风险修饰物，采用了回溯性设计，包括对疾病幸存者进行过抽样的流行癌症。为了解决这些差距，我们建议对30,563名女性进行积极的随访，其中2,597名女性是BRCA1和BRCA2突变携带者。这些女性来自自1995年以来在美国、加拿大和澳大利亚招募和跟踪的9739个家庭。我们收集了这些女性相同的基线流行病学、多代谱系和基因数据。我们的前瞻性家庭研究丰富了乳腺癌易感性增加的女性，她们的潜在家庭风险谱(FRP)差异很大，可以使用多代谱系和基因数据进行估计。我们将使用两个独立的队列(18,530名未受影响的女性和12,033名受影响的女性)，根据他们估计的FRP、可修改的风险因素以及BRCA1和BRCA2突变状态来估计特定年龄的乳腺癌的绝对和相对风险。到随访结束时，我们估计，在未受影响的女性中，1,427人和基线上受影响的1,359人将被诊断为新的乳腺癌。这些新病例中有15%-17%将是BRCA1或BRCA2突变携带者。我们将利用我们的发现，通过结合来自多代家族史、测量的基因变异和风险因素的信息来增强预测模型。临床实践在建议高危女性，特别是突变携带者，关于潜在的生活方式改变以降低风险方面一直是保守的，这一建议是基于对中等风险女性的研究。相反，我们建议为妇女各种风险建立更准确的预测模型，用于制定更有效的预防策略。 与公共卫生相关：尽管基因组医学取得了进展，但关于高危妇女的绝对和相对风险仍然存在重大悬而未决的问题，她们中的大多数人目前没有携带任何目前已确定的易感基因突变。我们建议对30,563名女性进行积极的随访，其中2,597名是BRCA1和BRCA2突变携带者。这些妇女来自自1995年以来在美国、加拿大和澳大利亚招募和跟踪的9,739个家庭，我们收集了这些妇女相同的广泛基线流行病学、多代谱系和基因数据。我们建议为妇女各种风险建立更准确的预测模型，用于制定更有效的预防和治疗策略。

DESCRIPTION (provided by applicant): The discovery of BRCA1 and BRCA2 has resulted in more appropriate targeting of preventive and screening strategies for breast cancer. The on-going discovery of genes with moderate-risk mutations, and of multiple loci with common low-risk associated variants, means that more women at substantial genetic risk will be identified. Despite these advances in genomic medicine, there remain major unanswered questions for high risk women, the majority of whom do not carry mutations in any currently identified susceptibility genes: 1) What is my absolute risk of breast cancer?; 2) Are there modifiable factors that might lower my risk?; and, for women with prior breast cancer, 3) Can I do anything to lower my risk of a new cancer? Answers to these questions are fundamental to improving clinical care, and are long overdue. We lack answers to these important questions because many studies fail to capture the complexity of family history and lack long-term follow-up data to measure risk. Breast cancer risk prediction models commonly used at non-specialist clinics often capture risk based on only first-degree family history. No breast cancer prediction models have been based on, nor validated with, large prospective cohorts of high risk women. Studies that have examined potential modifiers of risk for BRCA1 and BRCA2 mutation carriers have used a retrospective design and included prevalent cancers over-sampled for disease survivors. To address these gaps, we propose to conduct active follow-up of 30,563 women of whom 2,597 are BRCA1 and BRCA2 mutation carriers. These women come from 9,739 families recruited and followed since 1995 in the U.S., Canada, and Australia. We collected the same extensive baseline epidemiologic, multigenerational pedigree, and genetic data for these women. Our prospective family study is enriched with women at increased susceptibility for breast cancer who vary widely in underlying Familial Risk Profile (FRP), which can be estimated using multigenerational pedigree and genetic data. We will estimate age-specific absolute, and relative, risks of breast cancer using two separate cohorts (18,530 women unaffected and 12,033 women affected at baseline), as a function of their estimated FRP, modifiable risk factors, and by BRCA1 and BRCA2 mutation status. By the end of follow-up, we estimate 1,427 of the women unaffected and 1,359 women affected at baseline will be diagnosed with a new breast cancer. 15-17% of these new cases will be in BRCA1 or BRCA2 mutation carriers. We will use our findings to enhance prediction models by incorporating information from multigenerational family history, measured gene variants, and risk factors. Clinical practice has been conservative in advising high risk women, particularly mutation carriers, about potential lifestyle modifications to reduce risk, basing this advice on studies of average-risk women. Instead, we propose to build more accurate prediction models for women across the spectrum of risk that can be used to tailor more effective prevention strategies. PUBLIC HEALTH RELEVANCE: Despite advances in genomic medicine, there remain major unanswered questions about absolute and relative risks for high risk women, the majority of whom do not carry mutations in any currently identified susceptibility genes. We propose to conduct active follow-up of 30,563 women of whom 2,597 are BRCA1 and BRCA2 mutation carriers. These women come from 9,739 families recruited and followed since 1995 in the U.S., Canada, and Australia of whom we collected the same extensive baseline epidemiologic, multigenerational pedigree and genetic data for these women. We propose to build more accurate prediction models for women across the spectrum of risk that can be used to tailor more effective prevention and treatment strategies.