Integrative Genetic Epidemiologic Study of Breast Cancer Subtypes

描述(由申请人提供)： 项目概述乳腺癌在遗传上是异质性的，在疾病的表型表达上有很大的个体间差异。基于基因表达谱，已经提出了几种乳腺癌亚型，这种方法在预测临床结果方面的有效性已经得到证明。遗传和环境风险因素也可能因乳腺癌的分子亚型而异，但这方面的数据有限。肿瘤细胞中的染色体改变，包括杂合性丢失和拷贝数变化，为识别癌症相关基因提供了线索。单核苷酸多态(SNP)阵列已经被用作识别染色体改变的有效方法，并且它们在全基因组关联研究中的使用越来越多。我们的长期目标是通过识别易患不同亚型乳腺癌的基因变异来改善乳腺癌的预防和治疗。在这项研究中，我们提出了一种创新的方法，整合了基因表达谱、基于SNP阵列的染色体改变分析和关联研究。其具体目的是：(1)确定由基因表达定义的乳腺癌亚型中杂合性丢失和拷贝数变化的模式；(2)检查乳腺癌亚型的种系决定因素。这种互补的方法将有助于将新的候选基因缩小到较小的基因组区域，并且对这两个特定目标的发现进行交叉验证将有效地降低假阳性率。项目简介乳腺癌是女性中最常见的癌症，人们并不广泛接受乳腺癌由几个不同病因和不同治疗反应的“亚型”组成。这项研究的重点是确定乳腺癌亚型，特别是基底细胞样亚型的肿瘤在大染色体变化和小遗传变异方面的差异。我们将询问这些互补的数据，以确定乳腺癌发生和发展的基因决定因素，并反过来为其预防和治疗提供新的知识。

DESCRIPTION (provided by applicant): Project Summary Breast cancer is genetically heterogeneous and there is substantial inter-individual variability in phenotypic expression of the disease. Several breast cancer subtypes have been proposed based on gene expression profiling and the utility of this approach has been demonstrated in predicting clinical outcomes. Genetic and environmental risk factors may also vary by molecular subtypes of breast cancer but there is limited data in this regard. Chromosome alterations, including loss of heterozygosity and copy number change, in tumor cells provide clues for identifying cancer related genes. Single nucleotide polymorphism (SNP) arrays have been used as an efficient approach to identifying chromosome alterations and their use in whole-genome association studies is increasing. Our long-term goal is to improve the prevention and treatment of breast cancer by identifying genetic variants predisposing to different subtypes of breast cancer. In this study, we propose an innovative approach to integrating gene expression profiling, SNP array-based chromosome alteration analysis, and association study. The specific aims are: (1) To determine the pattern of loss of heterozygosity and copy number alterations across breast cancer subtypes defined by gene expression; (2) to examine germline determinants of to breast cancer subtypes. This complementary approach will help narrow down novel candidate genes to small genomic regions and cross-validation of the findings from the two specific aims will effectively reduce false positive rate. Project narrative Breast cancer is the most common cancer among women and it is not widely accepted that breast cancer consists of several "subtypes" with different etiology and differential response to therapies. This study focuses on identifying the differences both in large chromosome changes and small genetic variations between tumors of breast cancer subtypes, in particular the basal-like subtype. We will interrogate these complementary data to pinpoint the genetic determinants of breast cancer development and progression, and, in turn, provide new knowledge for its prevention and treatment.