Integrative Genetic Epidemiologic Study of Breast Cancer Subtypes

描述（由申请人提供）： 乳腺癌是一种遗传异质性疾病，其表型表达在个体间存在很大差异。基于基因表达谱已经提出了几种乳腺癌亚型，并且这种方法在预测临床结果方面的实用性已得到证实。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改变，为识别癌症相关基因提供了线索。单核苷酸多态性（SNP）阵列已被用作鉴定染色体改变的有效方法，并且其在全基因组关联研究中的使用正在增加。我们的长期目标是通过识别易患不同亚型乳腺癌的遗传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，整合基因表达谱，SNP阵列为基础的染色体变异分析，关联研究。具体目标是：（1）确定基因表达定义的乳腺癌亚型之间杂合性丢失和拷贝数改变的模式;（2）检查乳腺癌亚型的生殖系决定因素。这种互补的方法将有助于将新的候选基因缩小到小的基因组区域，并且来自两个特定目标的发现的交叉验证将有效地降低假阳性率。乳腺癌是女性中最常见的癌症，乳腺癌由几种“亚型”组成，具有不同的病因和对治疗的不同反应，这一点并没有被广泛接受。本研究的重点是确定乳腺癌亚型，特别是基底细胞样亚型之间的肿瘤在大的染色体变化和小的遗传变异方面的差异。我们将研究这些补充数据，以确定乳腺癌发展和进展的遗传决定因素，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.