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Large-scale haplotyping for breast cancer susceptibility in Afric. Amer. and Wh.

非洲乳腺癌易感性的大规模单倍型分析。

基本信息

批准号：
8135444
负责人：
ROBERT C MILLIKAN
金额：
$ 27.28万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8135444
关键词：
Address Admixture African American Age American Anabolism Anti-Inflammatory Agents Anti-inflammatory BRCA1 gene BRCA2 gene Base Excision Repairs Bayesian Analysis Bayesian Method Biochemical Pathway Biological Process Biometry Blood specimen Breast Cancer Risk Factor Bypass CDK4 gene CDKN2A gene CHEK1 gene CHEK2 gene CYP11B2 gene CYP17A1 gene CYP19A1 gene CYP1A1 gene CYP1A2 gene CYP1B1 gene CYP2E1 gene CYP3A4 gene CYP3A5 gene CYP3A6 gene Candidate Disease Gene Carcinogen Metabolism Case Study Case-Control Studies Cell Cycle Regulation Cell Proliferation Cell Respiration Clupeidae Cohort Studies Collaborations Collection Complex Cytochrome c Reductase DNA DNA Damage DNA Repair DNA Repair Gene DNA Repair Pathway DNA-PKcs Data Data Analyses Disease Doctor of Medicine Double Strand Break Repair EPHX1 gene ERBB2 gene ERCC1 gene ERCC6 gene ESR1 gene Enrollment Environment Environmental Exposure Environmental Risk Factor Epidemiologic Studies Estrogen receptor negative Estrogen receptor positive Estrogens European Excision Exposure to Felis catus Frequencies Funding G22P1 gene GSTM1 gene GSTP1 gene GSTT1 gene Gene Cluster Gene Expression Profiling Gene-Modified Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Genome Genomics Genotype Geographic Locations Haplotypes Hormones In Situ Individual Investigation Ionizing radiation LIG4 gene Lead Link MDM2 gene MGMT gene MYBL2 gene Malignant Neoplasms Mammary Neoplasms Metabolism Methods Mitochondria Mitotic Modeling Molecular Profiling NBS1 gene National Cancer Institute Nonhomologous DNA End Joining North Carolina Norway Nucleotide Excision Repair Nucleotides OGG1 gene Odds Ratio PTGS2 gene Participant Pathway interactions Patients Peer Review Penetrance Pharmaceutical Preparations Polymerase Population Predisposition Prevalence Production Protocols documentation Publications RAD54L gene Radiation Reproduction spores Reproductive History Research Research Personnel Risk Role SOD2 gene STK6 gene Sampling Single Nucleotide Polymorphism Smoke Smoking Source Statistical Methods Stratification Testing Time Tumor Tissue UGT1A1 gene Validation Variant Vitamins Woman XPA gene XRCC1 gene XRCC2 gene XRCC3 gene XRCC4 gene XRCC5 gene alcohol effect base biobank cancer risk cohort gene environment interaction gene interaction gene repair genetic risk factor homologous recombination hormone biosynthesis hormone metabolism human APEX1 protein malignant breast neoplasm mitochondrial genome novel older women population based recombinational repair repaired simulation tumor

项目摘要

The Carolina Breast Cancer Study (CBCS) is a comprehensive, interdisciplinary investigation into the causes of breast cancer in African American and white women. CBCS focuses on understanding how genetic and environmental factors interact to cause breast cancer. From 1993-2001, CBCS enrolled 2311 cases of in- situ and invasive breast cancer and 2022 frequency-matched controls from a defined geographic region of eastern and central North Carolina. 40% of CBCS participants are African-American. Over 70 peer-review publications have resulted. During the last SPORE funding cycle (2001-2006), we used previously collected DMA samples to conduct genotyping for polymorphisms in DMA repair genes. Genotypes at multiple genetic loci were combined to create "pathway" genotypes. We observed interactions between combinations of single nucleotide polymorphisms (SNPs) in the double strand break DNA repair pathway and radiation exposure, and combined genotypes in the nucleotide excision DNA repair pathway and smoking. The data rich CBCS attracted biostatistics collaborators who developed statistical methods to estimate haplotypes at the individual level and to use haplotypes to evaluate gene-gene and gene-environment interactions. We propose to expand our previous investigations by conducting a comprehensive study of haplotypes in genes involved in DNA repair, damage recognition, cell cycle control and cellular proliferation, hormone biosynthesis and metabolism, and oxidative metabolism. The advent of multiplex genotyping and identification of haplotype-tagging SNPs now makes it possible to capture the principal sources of genetic variation in the candidate genes in African Americans and whites. With newly-developed statistical methods, haplotypes will be used to evaluate gene-gene as well as gene-environment interactions. Monte Carlo simulation and applied Bayesian analysis will be used to address multiple hypothesis testing. We will also genotype 100 SNPs that serve as ancestry informative markers in order to adjust for population stratification. We used tumor blocks from CBCS cases to determine the prevalence of specific subtypes of breast cancer. The subtypes were codified using gene expression profiling. In the CBCS, the estrogen-receptor positive forms of breast cancer, Luminal A and B, were found at highest frequency in white women and older African American women, while the estrogen-receptor negative forms, including Basal-like breast cancer, were at highest frequency in younger African American women. CBCS patients with Basal-like breast cancer had lower disease-specific survival than patients with Luminal A or B. Our preliminary data suggest that combinations of genetic and environmental exposures lead to increased risk of specific subtypes of breast cancer. We will expand our investigation of genetic susceptibility to candidate genes for breast cancer subtypes, including newly-discovered polymorphisms in genes that show differential expression in breast cancer subtypes. Positive findings (including main effects and associations with breast cancer subtypes) will be repeated using DNA samples collected from a large population-based study in Norway.

卡罗莱纳乳腺癌研究（CBCS）是一项全面的、跨学科的研究，非裔美国人和白色妇女的乳腺癌发病率。CBCS侧重于了解遗传和环境因素相互作用导致乳腺癌。1993-2001年，CBCS共纳入2311例，原位和浸润性乳腺癌和2022个频率匹配的对照，来自一个定义的地理区域，北卡罗来纳州东部和中部。40%的CBCS参与者是非洲裔美国人。超过70个同行评审出版物产生了。在上一个SPORE资助周期（2001-2006年），我们使用了以前收集的 DMA样本进行DNA修复基因多态性的基因分型。多基因型将基因座组合以产生“途径”基因型。我们观察到的组合之间的相互作用双链断裂DNA修复途径中的单核苷酸多态性与辐射暴露，以及核苷酸切除DNA修复途径和吸烟中的组合基因型。数据丰富的CBCS吸引了生物统计学合作者，他们开发了统计方法来估计个体水平的单元型并使用单元型来评估基因-基因和基因-环境交互.我们建议扩大我们以前的调查，进行全面研究，涉及DNA修复、损伤识别、细胞周期控制和细胞增殖的基因的单倍型，激素生物合成和代谢以及氧化代谢。多重基因分型的出现，单倍型标记SNP的鉴定现在使得捕获遗传学的主要来源成为可能。非裔美国人和白人的候选基因变异。通过新开发的统计方法，单倍型将用于评估基因-基因以及基因-环境相互作用。蒙特卡罗模拟和应用贝叶斯分析将用于解决多重假设检验。我们还将基因型100个SNP作为祖先信息标记，以调整人口分层。我们使用来自CBCS病例的肿瘤块来确定乳腺癌特定亚型的患病率。使用基因表达谱对亚型进行编码。在CBCS中，雌激素受体阳性在白色妇女和非洲老年人中，发现Luminal A和B型乳腺癌的发病率最高而雌激素受体阴性形式，包括基底细胞样乳腺癌，在年轻的非洲裔美国女性中发病率最高。基底细胞样乳腺癌的CBCS患者疾病特异性生存率低于Luminal A或B患者。我们的初步数据显示，遗传和环境暴露的组合导致特定亚型乳腺癌的风险增加癌我们将扩大对乳腺癌候选基因遗传易感性的调查亚型，包括新发现的基因多态性，在乳腺癌中显示差异表达，癌症亚型。阳性结果（包括主要影响和与乳腺癌亚型的关联）将使用从挪威的一项大规模人口研究中收集的DNA样本进行重复。