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

卡罗莱纳乳腺癌研究(CBCS)是一项对病因的全面、跨学科的调查 非裔美国人和白人女性患乳腺癌的风险。CBCS的重点是了解基因和 环境因素相互作用导致乳腺癌。在1993-2001年间，CBCS登记了2311起案件-- 来自确定的地理区域的原位和浸润性乳腺癌和2022个频率匹配的对照 北卡罗来纳州东部和中部。40%的CBCS参与者是非洲裔美国人。70多个同行评议 结果是出版了各种出版物。在上一个孢子资助周期(2001-2006)，我们使用了以前收集的 对DNA修复基因进行基因分型。多基因的基因分型 基因座结合在一起创造了“途径”的基因类型。我们观察到两种组合之间的相互作用 DNA双链断裂修复途径中的单核苷酸多态与辐射 暴露，以及在核苷酸切除DNA修复途径中的联合基因型和吸烟。 数据丰富的CBCs吸引了生物统计学的合作者，他们开发了统计方法来估计 在个体水平上的单倍型，并利用单倍型评估基因-基因和基因-环境 互动。我们建议扩大以往的调查范围，全面研究 参与DNA修复、损伤识别、细胞周期控制和细胞增殖的基因单倍型， 激素的生物合成和代谢，以及氧化代谢。多重基因分型的出现和 单倍型标记SNPs的鉴定现在使捕捉遗传的主要来源成为可能 非裔美国人和白人候选基因的变异。利用新开发的统计方法， 单倍型将被用来评估基因-基因以及基因-环境的相互作用。蒙特卡洛 模拟和应用贝叶斯分析将被用来解决多重假设检验。我们还将 作为祖先信息标记的100个SNP基因，以适应人口分层。 我们使用CBCS病例中的肿瘤块来确定特定亚型乳腺癌的患病率。 利用基因表达谱对亚型进行编码。在CBCs中，雌激素受体阳性 A型和B型乳腺癌在白人妇女和老年非洲人中发病率最高 美国女性，而雌激素受体阴性的形式，包括基底样癌，在 在年轻的非裔美国女性中频率最高。基底细胞样乳腺癌的CBCS患者 我们的初步数据表明，与Lumina A或B患者相比，特定疾病的存活率更低 遗传和环境暴露的组合导致特定亚型乳房的风险增加 癌症。我们将扩大对乳腺癌候选基因的遗传易感性的研究 亚型，包括新发现的乳房差异表达基因的多态性 癌症亚型。阳性发现(包括主要影响和与乳腺癌亚型的关联)将 使用从挪威一项大规模人口研究中收集的DNA样本进行重复。

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.