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: 8196169
• 负责人: JOHN L HOPPER
• 金额: $ 208.15万
• 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/8196169
• 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. 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.

描述（由申请人提供）：BRCA1 和 BRCA2 的发现使得乳腺癌的预防和筛查策略更加合适。具有中等风险突变的基因以及具有常见低风险相关变异的多个位点的持续发现意味着将识别出更多具有重大遗传风险的女性。尽管基因组医学取得了这些进展，但对于高危女性来说，仍然存在一些未解答的重大问题，其中大多数女性在任何目前已确定的易感基因中都不携带突变：1）我患乳腺癌的绝对风险是多少？ 2) 是否存在可以降低我的风险的可改变因素？对于既往患有乳腺癌的女性，3) 我可以做些什么来降低患新癌症的风险吗？这些问题的答案对于改善临床护理至关重要，而且早就应该得到答案。我们缺乏这些重要问题的答案，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随访数据。非专科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。目前还没有乳腺癌预测模型基于大型前瞻性高风险女性群体，也没有经过其验证。研究检查了 BRCA1 和 BRCA2 突变携带者风险的潜在修饰因素，采用回顾性设计，并包括对疾病幸存者的流行癌症进行过度采样。为了解决这些差距，我们建议对 30,563 名女性进行积极随访，其中 2,597 名是 BRCA1 和 BRCA2 突变携带者。这些女性来自 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。我们为这些女性收集了同样广泛的基线流行病学、多代谱系和遗传数据。我们的前瞻性家庭研究丰富了乳腺癌易感性较高的女性，她们的潜在家族风险状况 (FRP) 差异很大，可以使用多代谱系和遗传数据进行估计。我们将使用两个单独的队列（18,530 名未受影响的女性和 12,033 名基线时受影响的女性）来估计年龄特定的乳腺癌绝对和相对风险，作为其估计的 FRP、可改变的风险因素以及 BRCA1 和 BRCA2 突变状态的函数。到随访结束时，我们估计基线时未受影响的 1,427 名女性和受影响的 1,359 名女性将被诊断出患有新的乳腺癌。这些新病例中有 15-17% 是 BRCA1 或 BRCA2 突变携带者。我们将利用我们的发现，通过整合多代家族史、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（尤其是突变携带者）有关潜在的生活方式改变以降低风险方面一直持保守态度，该建议基于对平均风险女性的研究。相反，我们建议为女性建立更准确的预测模型，涵盖各种风险，可用于制定更有效的预防策略。 公共卫生相关性：尽管基因组医学取得了进展，但关于高危女性的绝对和相对风险仍然存在重大未解答的问题，其中大多数女性在目前已确定的易感基因中不携带突变。我们建议对 30,563 名女性进行积极随访，其中 2,597 名是 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 9,739 个家庭，我们为这些女性收集了同样广泛的基线流行病学、多代谱系和遗传数据。我们建议为女性建立更准确的风险预测模型，可用于制定更有效的预防和治疗策略。