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

基本信息

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
项目类别：
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

项目摘要

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）：研究培训计划将在癌症生物学和遗传流行病学领域发展博士后候选者的技能。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。候选人将参加课程并参加与生物统计学，癌症生物学，遗传流行病学和表观遗传学有关的研讨会。特定的研究项目候选人将领导的领导涉及研究肥胖症的遗传易感性是否会改变雌性BRCA1和BRCA2突变携带者的乳腺癌风险。在BRCA1和BRCA2基因突变的女性载体中，乳腺癌的风险很高。但是，在BRCA1/2载体中，乳腺癌风险存在很大个体间差异。 BRCA1/2突变类别（例如，功能丧失或部分保留的正常功能），BRCA1/2突变的位置（“乳腺癌群集区域”或“卵巢癌簇区”）以及其他遗传和环境因素已被证明可以改变BRCA1/2携带者中乳腺癌风险。肥胖是一种可修改的危险因素，与绝经后妇女的乳腺癌风险增加有关。提出的研究将解决三个具体目标。 AIM 1将确定肥胖症的遗传敏感性是否会改变大量BRCA1/2载体样本中的乳腺癌风险。 AIM 2将确定BRCA1/2突变类别以及BRCA1/2突变的位置是否与乳腺癌风险相对于肥胖的遗传易感性相互作用。 AIM 3将确定遗传对肥胖症的敏感性是否会差异增加雌激素受体阳性或雌激素受体阴性乳腺癌的风险。回顾性队列研究设计将用于解决这些目标。女性参与者是通过研究诊所招募的，所有参与者均被筛选以进行BRCA1/2突变。拟议的研究中包括的队列将包括雌性BRCA1/2载体，18岁以上，在确定之前没有任何癌症，并且在5年内没有乳腺癌，并且在确定性的3年内均不在卵巢癌。通过全基因组关联研究发现的肥胖易感基因中的变体已经对参与者进行了基因分型。通过求和携带的风险等位基因数量，将为每个参与者创建累积肥胖敏感性评分。此外，将为每个肥胖敏感性基因座进行单倍型关联。 COX比例危害模型使用加权方法来说明高风险女性的采样，将用于统计分析。该研究提出的潜力有可能识别BRCA1/2载体中乳腺癌的重要修饰剂，该修饰者可以通过影响能量平衡的能量干预措施而成为目标。公共卫生相关性：BRCA1和BRCA2突变的女性承运人患乳腺癌的风险增加；但是，BRCA1/2携带者之间的乳腺癌风险存在很大的个体间差异。拟议的研究将研究遗传易感性是否会改变BRCA1/2载体中乳腺癌的风险。这项研究可能会确定BRCA1/2载体的重要乳腺癌危险因素，该携带者可能通过精力充沛的干预措施来靶向。