Genetic Epidemiology of Breast Cancer: BRCA1 and BRCA2

描述（申请人提供）：携带BRCA 1和BRCA 2（BRCA 1/2）突变的女性患乳腺癌和卵巢癌的风险显著增加。诊断时的年龄以及乳腺癌和卵巢癌的相对发病率存在相当大的差异，即使在具有相同突变的女性中也是如此，这表明额外的风险因素改变了年龄特异性风险。我们提出了一个全面的分析基因在胰岛素样生长因子（IGF）信号通路，一条通路整体参与细胞增殖。我们将使用强大的新方法，将联合收割机多个连锁变异体结合在一个基因中形成单倍型，并允许在一个单一的机制途径中评估多个基因。我们将利用我们的多中心队列的资源，该队列目前包括2,000名白人和76名非洲裔美国人BRCA 1/2女性突变携带者，收集工作正在进行中。很少有研究在非洲裔美国人中进行，即使他们经常患有更具侵袭性的乳腺癌，出现在更年轻的年龄，并具有BRCA 1肿瘤的组织病理学特征。我们的总体目标是确定改变乳腺癌风险的遗传风险因素。我们的具体目标是：目的1）对100名无关的白种人和非裔美国人的IGF 1、IGF 1 R、IGFBP 1、IGFBP 3、IRS 1和SHBG单核苷酸多态性（SNPs）进行基因分型，并通过连锁不平衡分析确定单倍型块。将选择SNP子集（单倍型标记SNP和具有已知功能的SNP）用于目标3。目的2）：继续招募BRCAI/2突变携带者，以扩大我们的队列。这包括扩大先前登记的携带突变的家庭;继续登记和筛查患有乳腺癌的非洲裔美国妇女，扩大携带有害突变的家庭;并从我们的多中心队列中获得突变携带者。目的3：对目标1中选择的SNP的受影响（病例）和未受影响（匹配对照）的BRCAI/2突变携带者进行基因分型。目的4：分析基因型在乳腺癌发生、诊断年龄和分期中的作用。我们的重点是BRCA 1/2突变携带者，因为他们在早期患癌症的风险更高，是这些结果适用的群体。这些信息可用于协助妇女及其医生进行个人风险评估，并根据妇女的遗传风险因素，针对妇女采取具体的预防或治疗战略。

DESCRIPTION (provided by applicant): Women who carry mutations in BRCA1 and BRCA2 (BRCA1/2) have a substantially increased risk of developing breast and ovarian cancers. There is considerable variability in age at diagnosis and relative incidence of breast and ovarian cancers, even among women with the same mutation, suggestive that additional risk factors modify the age-specific risk. We propose a comprehensive analysis of genes in the insulin-like growth factor (IGF) signaling pathway, a pathway integrally involved in cellular proliferation. We will use powerful new approaches that combine multiple linked variants in a single gene to form haplotypes and that allow evaluation of multiple genes in a single mechanistic pathway. We will utilize the resources of our multi-center cohort, which currently includes 2,000 Caucasian and 76 African-American BRCA1/2 female mutation carriers, and for which collection is ongoing. Few studies have been conducted in African Americans, even though they often have more aggressive breast cancer, present at a younger age, and have histopathology characteristic of BRCA1 tumors. Our overall objective is to identify genetic risk factors that modify breast cancer risk. Our specific aims are: Aim 1) to genotype Single Nucleotide Polymorphisms (SNPs) in IGF1, IGF1R, IGFBP1, IGFBP3, IRS1, and SHBG in 100 unrelated Caucasian and African Americans and identify haplotype blocks by linkage disequilibrium analysis. A subset of SNPs (haplotype-tagging SNPs and SNPs with known function) will be selected for Aim 3. Aim 2): to continue enrolling BRCAI/2 mutation carriers in order to expand our cohort. This includes extending previously enrolled families carrying mutations; continuing to enroll and screen African-American women with breast cancer and expanding families with deleterious mutations; and obtaining mutation carriers from our multi-center cohort. Aim 3: to genotype affected (cases) and unaffected (matched controls) BRCAI/2 mutation carriers for SNPs selected in Aim 1. Aim 4: to perform analyses to evaluate the role of the genotypes in breast cancer development, age at diagnosis and stage. Our focus is BRCA1/2 mutation carriers, who because of their higher risk of developing cancer at an early age, are the group for whom these results would be applied. This information can be used to assist women and their physicians in individual risk assessment, as well as to target women for specific prevention or treatment strategies based on their genetic risk factors.