Obesity susceptibility loci and breast cancer risk in BRCA1 and BRCA2 mutation ca

BRCA1 和 BRCA2 突变中的肥胖易感位点与乳腺癌风险

• 批准号: 8366278
• 负责人: Jonathan Andrew Mitchell
• 金额: $ 5.39万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-13 至 2014-09-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8366278
• 关键词: 18 year old; Accounting; Address; Adipose tissue; Age; Alleles; Area; Aromatase; BRCA1 Mutation; BRCA1 gene; Biological; Biometry; Breast; Breast Cancer Detection; Breast Cancer Risk Factor; Cancer Biology; Cancer Cluster; Cell Differentiation process; Chronic Disease; Clinic; Cohort Studies; Cox Proportional Hazards Models; DNA Repair; Environmental Risk Factor; Epigenetic Process; Estrogen receptor negative; Estrogen receptor positive; Estrogens; Fatty acid glycerol esters; Female; Female Breast Carcinoma; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Goals; Haplotypes; Heritability; High Risk Woman; Individual; Inflammatory; Insulin; Intervention; Investigation; Knowledge; Lead; Link; Location; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Mediator of activation protein; Mutation; Nonsense-Mediated Decay; Obesity; Other Genetics; Participant; Patient Self-Report; Penetrance; Postmenopause; Predisposition; Premenopause; Production; Progesterone; Public Health; Recruitment Activity; Research; Research Design; Research Personnel; Research Project Grants; Research Training; Risk; Risk Factors; Sampling; Serum; Signal Transduction; Sum; Susceptibility Gene; Training Programs; Variant; Weight; Woman; base; cancer genetics; cancer risk; cohort; energy balance; genetic epidemiology; genome wide association study; infancy; insulin signaling; loss of function; malignant breast neoplasm; modifiable risk; mutation carrier; prevent; protein function; skills

DESCRIPTION (provided by applicant): The research training program will develop the skills of a postdoctoral candidate in the areas of cancer biology and genetic epidemiology. The candidate aspires to become an independent researcher in the field of genetic epidemiology to investigate and prevent cancer and other chronic diseases. The candidate will take courses and attend seminars related to biostatistics, cancer biology, genetic epidemiology and epigenetics. The specific research project the candidate will lead involves investigating if genetic predisposition to obesity modifies breast cancer risk in female BRCA1 and BRCA2 mutation carriers. The risk of breast cancer is high among female carriers of mutations in the BRCA1 and BRCA2 genes. However, there is high inter-individual variance with regard to breast cancer risk among BRCA1/2 carriers. Classes of BRCA1/2 mutations (e.g., loss of function or partially preserved normal function), the location of the BRCA1/2 mutations ("breast cancer cluster region'" or "ovarian cancer cluster region"), and other genetic and environmental factors have been shown to modify breast cancer risk in BRCA1/2 carriers. Obesity is a modifiable risk factor that has been associated with increased breast cancer risk in postmenopausal women. The research proposed will address three specific aims. Aim 1 will determine if genetic susceptibility to obesity modifies breast cancer risk in a large sample of BRCA1/2 carriers. Aim 2 will determine if the class of BRCA1/2 mutations and location of BRCA1/2 mutations interact with genetic susceptibility to obesity with regard to breast cancer risk. Aim 3 will determine if genetic susceptibility to obesity differentially increases the risk of estrogen receptor positive or estrogen receptor negative breast cancer. A retrospective cohort study design will be used to address these aims. Female participants were recruited through research clinics and all are screened for BRCA1/2 mutations. The cohort to be included in the proposed study will comprise female BRCA1/2 carriers, 18+ years old, free from any cancer before ascertainment, and free from breast cancer within 5-years and ovarian cancer within 3-years of ascertainment. Participants have been genotyped for variants within obesity susceptibility genes that were identified through genome-wide association studies. A cumulative obesity susceptibility score will be created for each participant by summing the number of risk alleles carried. In addition, haplotype associations will be conducted for each obesity susceptibility loci. Cox proportional hazard models, using a weighted approach to account for the sampling of high-risk women, will be used for the statistical analyses. The research proposed has the potential to identify an important modifier of breast cancer in BRCA1/2 carriers that can be target through energetic interventions that influence energy balance.

描述（由申请人提供）：研究培训计划将培养癌症生物学和遗传流行病学领域的博士后候选人的技能。候选人渴望成为遗传流行病学领域的独立研究人员，以调查和预防癌症和其他慢性疾病。候选人将参加与生物统计学、癌症生物学、遗传流行病学和表观遗传学相关的课程和研讨会。该候选人将领导的具体研究项目包括调查肥胖的遗传易感性是否会改变女性BRCA1和BRCA2突变携带者患乳腺癌的风险。携带BRCA1和BRCA2基因突变的女性患乳腺癌的风险很高。然而，BRCA1/2携带者患乳腺癌的风险存在较高的个体间差异。BRCA1/2突变的类别（如功能丧失或部分保留的正常功能）、BRCA1/2突变的位置（“乳腺癌聚集区”或“卵巢癌聚集区”）以及其他遗传和环境因素已被证明可以改变BRCA1/2携带者患乳腺癌的风险。肥胖是一个可改变的风险因素，与绝经后妇女患乳腺癌的风险增加有关。拟议的研究将涉及三个具体目标。目的1将确定肥胖的遗传易感性是否会改变BRCA1/2携带者的乳腺癌风险。目的2将确定BRCA1/2突变的类别和BRCA1/2突变的位置是否与乳腺癌风险中肥胖的遗传易感性相互作用。目的3将确定肥胖的遗传易感性是否会增加雌激素受体阳性或雌激素受体阴性乳腺癌的风险。将采用回顾性队列研究设计来解决这些问题。女性参与者通过研究诊所招募，所有人都进行了BRCA1/2突变筛查。拟纳入研究的队列将包括女性BRCA1/2携带者，18岁以上，确诊前无任何癌症，确诊后5年内无乳腺癌，3年内无卵巢癌。参与者已通过全基因组关联研究确定了肥胖易感基因变异的基因分型。通过将携带的风险等位基因的数量相加，将为每个参与者创建一个累积的肥胖易感性评分。此外，将对每个肥胖易感位点进行单倍型关联。Cox比例风险模型将用于统计分析，该模型使用加权方法来考虑高风险妇女的抽样。提出的研究有可能确定BRCA1/2携带者乳腺癌的重要修饰因子，可以通过影响能量平衡的能量干预作为目标。