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

基因、环境和乳腺癌风险：Prof-SC 的 15 年随访

• 批准号: 8461709
• 负责人: JOHN L HOPPER
• 金额: $ 185.07万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461709
• 关键词: Address; Affect; Age; Alcohol consumption; Australia; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Behavior Therapy; Body mass index; Breast; CHEK2 gene; Canada; Categories; Characteristics; Clinic; Clinical; Complex; Counseling; Data; Diagnosis; Disease; Environment; Epidemiology; Exogenous Hormone Therapy; Family; Family Study; Family history of; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genomics; Genotype; Hereditary Breast Carcinoma; High Risk Woman; Knowledge; Lactation; Mails; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Medical; Medicine; Modeling; Mutation; Ovariectomy; Physical activity; Predisposition; Pregnancy; Prevention; Prevention strategy; Preventive screening; Public Health; Questionnaires; RAD51C gene; Radiation; Recording of previous events; Recruitment Activity; Relative (related person); Relative Risks; Reproductive History; Research; Risk; Risk Factors; Sampling; Selective Estrogen Receptor Modulators; Single Nucleotide Polymorphism; Specialist; Survivors; Susceptibility Gene; Telephone; Test Result; Testing; Time; Update; Variant; Vital Status; Woman; base; breast cancer family registry; cancer risk; cigarette smoking; clinical care; clinical practice; cohort; design; follow-up; gene discovery; genetic pedigree; genetic variant; genome wide association study; high risk; improved; malignant breast neoplasm; modifiable risk; mutation carrier; non-genetic; prospective; treatment strategy

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.

描述（由申请人提供）：发现BRCA1和BRCA2的发现导致更合适的靶向乳腺癌的预防和筛查策略。持续发现具有中等风险突变的基因以及具有共同低风险相关变体的多个基因座，这意味着将发现更多具有实质性遗传风险的女性。尽管在基因组医学方面取得了这些进步，但对于高风险妇女仍存在重大问题，其中大多数在任何当前确定的敏感性基因中都没有突变：1）我患乳腺癌的绝对风险是什么？ 2）是否有可改变的因素可以降低我的风险？而且，对于患有先前乳腺癌的女性，3）我可以做任何事情以降低我的新癌症风险吗？这些问题的答案对于改善临床护理至关重要，早就应该了。我们缺乏对这些重要问题的答案，因为许多研究未能捕获家族史的复杂性，并且缺乏长期的随访数据来衡量风险。非专业诊所常用的乳腺癌风险预测模型通常仅根据一级家族史来捕获风险。没有乳腺癌预测模型基于或通过大量高风险女性的大量前瞻性人群进行了验证。研究了BRCA1和BRCA2突变携带者的潜在风险修饰符的研究使用了回顾性设计，并包括过度采样过采样疾病幸存者。为了解决这些差距，我们建议对30,563名妇女进行积极随访，其中2,597名是BRCA1和BRCA2突变携带者。这些妇女来自1995年以来在美国，加拿大和澳大利亚招募并紧随其后的9,739个家庭。我们为这些女性收集了相同广泛的基线流行病学，多代谱和遗传数据。我们的前瞻性家庭研究富含对乳腺癌易感性增加的女性，这些乳腺癌在基本的家族风险概况（FRP）方面差异很大，可以使用多代谱系和遗传数据来估算这些风险。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）估算特定年龄的绝对和相对风险，这是其估计的FRP，可修改的危险因素以及BRCA1和BRCA2突变状态的函数。随访结束时，我们估计未受影响的女性中有1,427名在基线时受到1,359名妇女的影响，将被诊断出患有新的乳腺癌。这些新病例中有15-17％将用于BRCA1或BRCA2突变载体。我们将使用我们的发现来通过合并来自多代家族史，测量基因变异和风险因素的信息来增强预测模型。临床实践一直是保守的，在向高风险妇女（尤其是突变携带者）的建议方面提供了有关降低风险的潜在生活方式修改的建议，并将这种建议基于对平均风险妇女的研究。取而代之的是，我们建议在风险范围内为女性建立更准确的预测模型，以量身定制更有效的预防策略。