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: 8203414
• 负责人: Jonathan Andrew Mitchell
• 金额: $ 6.23万
• 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/8203414
• 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. PUBLIC HEALTH RELEVANCE: Female carriers of BRCA1 and BRCA2 mutations have an increased risk of breast cancer; however, there is a high inter-individual variance in breast cancer risk among BRCA1/2 carriers. The proposed research will investigate if genetic susceptibility to obesity modifies breast cancer risk in BRCA1/2 carriers. This study may identify an important breast cancer risk factor for BRCA1/2 carriers, which can potentially be targeted through energetic interventions.

描述（由申请人提供）：研究培训计划将发展博士后候选人在癌症生物学和遗传流行病学领域的技能。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有关的课程和研讨会。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BRCA 1和BRCA 2突变携带者的乳腺癌风险。 BRCA 1和BRCA 2基因突变的女性携带者患乳腺癌的风险很高。然而，BRCA 1/2携带者之间的乳腺癌风险存在很高的个体间差异。BRCA 1/2突变的类型（例如，BRCA 1/2基因突变（乳腺癌聚集区或卵巢癌聚集区）、BRCA 1/2基因突变（乳腺癌聚集区或卵巢癌聚集区）的位置以及其他遗传和环境因素已被证明可以改变BRCA 1/2携带者患乳腺癌的风险。肥胖是一个可改变的风险因素，与绝经后妇女乳腺癌风险增加有关。拟议的研究将针对三个具体目标。目标1将确定肥胖的遗传易感性是否会改变大样本BRCA 1/2携带者的乳腺癌风险。目的2将确定BRCA 1/2突变的类型和BRCA 1/2突变的位置是否与肥胖的遗传易感性在乳腺癌风险方面相互作用。目标3将确定肥胖的遗传易感性是否差异性地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实现这些目标。女性参与者通过研究诊所招募，所有人都接受BRCA 1/2突变筛查。拟纳入本研究的队列将包括女性BRCA 1/2携带者，年龄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肥胖易感基因内的变异进行基因分型。通过对携带的风险等位基因数量进行求和，为每位参与者创建累积肥胖易感性评分。此外，将对每个肥胖易感性基因座进行单倍型关联。将使用考克斯比例风险模型进行统计分析，该模型使用加权方法解释高危女性的抽样情况。这项研究有可能确定BRCA 1/2携带者中乳腺癌的一种重要修饰剂，可以通过影响能量平衡的能量干预来靶向。 公共卫生关系：BRCA 1和BRCA 2突变的女性携带者患乳腺癌的风险增加;然而，BRCA 1/2携带者患乳腺癌的风险存在很高的个体间差异。这项拟议中的研究将调查肥胖的遗传易感性是否会改变BRCA 1/2携带者患乳腺癌的风险。这项研究可能会确定BRCA 1/2携带者的一个重要乳腺癌风险因素，这可能是通过积极干预的目标。