Identifying candidate modifier elements of a breast cancer risk associated allele

识别乳腺癌风险相关等位基因的候选修饰元素

基本信息

批准号：
8072142
负责人：
David J Samuelson
金额：
$ 29.79万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-08 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8072142
关键词：
Alleles Animal Model Anthracenes Area Automobile Driving BRCA1 gene BRCA2 gene Basic Research Breast Cancer Biological Assay Biological Models Breast Cancer Genetics Breast Cancer Model Breast Cancer Prevention Breast Carcinoma Candidate Disease Gene Cause of Death Chromosomes, Human, Pair 2 Chromosomes, Human, Pair 5 Complex DNA Resequencing Development Disease Elements Environmental Risk Factor Epigenetic Process Frequencies Functional RNA Genes Genetic Genetic Markers Genetic Models Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Genomics Goals Health Human Human Chromosomes In Vitro Inbred Strains Rats Inbreeding Incidence Individual Inherited Intercistronic Region Knowledge Lead Location Malignant Neoplasms Mammary Tumorigenesis Mammary gland Maps Modeling Molecular Genetics Molecular Target Nature PTPRJ gene Phenotype Population Predisposition Principal Investigator Quantitative Trait Loci Rat-1 Rattus Recombinants Research Research Project Grants Risk STAT5a Transcription Factor Single Nucleotide Polymorphism Staging Susceptibility Gene System Testing Transgenic Model Translating Transplantation Variant Woman Work abstracting aged anticancer research cancer prevention cancer risk candidate validation comparative comparative genomics congenic dimethylbenzanthracene disorder risk genetic analysis genetic element genome wide association study in vivo knockout gene malignant breast neoplasm mortality novel novel strategies rat genome research study

项目摘要

DESCRIPTION (provided by applicant): Identifying candidate modifier elements of a breast cancer risk associated allele Project Summary/Abstract: A woman's risk of developing breast cancer is influenced by genetic, epigenetic, and environmental factors. Up to 30-40% of the risk of developing breast cancer is likely to be inherited. Breast cancer genetics is complex. The factors controlling disease risk are high penetrant genes with risk alleles that are low in population frequency, and low penetrant modifier genes with risk associated alleles that are common in the population. Most of the genetic variation in breast cancer risk is unaccounted, and the majority of the genes influencing susceptibility to breast cancer are likely controlled by common genetic variation. The common single nucleotide polymorphism (SNP) rs889312 marks a low penetrant breast cancer risk associated allele on human chromosome 5 (Nature 447, 2007). The breast cancer risk associate gene and causal polymorphisms at this locus have not been identified. The human region is orthologous to rat mammary carcinoma susceptibility QTL, Mcs1b. The rat Mcs1b locus has been narrowed to 1.2 Mb using congenics. These experiments used the Wistar Furth (WF) strain, which is highly susceptible to 7,12- dimethylbenz[a]anthracene (DMBA)-induced mammary carcinomas, as the genetic background. The Mcs1b Copenhagen (COP) allele on a WF background conferred a 60% reduction in DMBA-induced mammary carcinoma development to WF.COP congenics that were COP-homozygous, and a 30% reduction to congenics that were COP/WF-heterozygous at Mcs1b. The objective of the proposed work is to use systems genetics in a model organism to identify quality candidate breast cancer risk genetic elements. This will be accomplished through the following specific aims: aim 1: fine map rat Mcs1b to a genomic interval less than 0.5 Mb by testing additional congenic lines carrying shorter segments of the Mcs1b locus as currently defined; aim 2: determine if the Mcs1b COP allele acts in an autonomous manner within the mammary gland by conducting rat mammary gland transplant experiments; and aim 3: identify and evaluate breast cancer candidate genes/genetic elements within rat Mcs1b by determining potential candidates and testing each to identify quality candidates. The final aim will be completed in stages that will incorporate comparative genomics, genetic and expression analyses, resequencing, and in vitro and in vivo validation of candidates. PUBLIC HEALTH RELEVANCE: Breast cancer is a complex disease, and the leading cause of death by cancer in US women aged 20- 59 years. Most common susceptibility genes and molecular genetic mechanisms contributing to breast cancer susceptibility are unknown. To work toward decreasing the incidence and mortality due to breast cancer, basic research toward better understanding of the genetic etiology of this complex disease is warranted. The proposed research uses a comparative genetic approach to accomplish this, and may also identify novel potential targets for breast cancer prevention.

描述（由申请人提供）：鉴定乳腺癌风险相关等位基因的候选修饰元件项目摘要/摘要：女性患乳腺癌的风险受到遗传、表观遗传和环境因素的影响。高达 30-40% 的乳腺癌风险可能是遗传性的。乳腺癌遗传学很复杂。控制疾病风险的因素是具有人群频率较低的风险等位基因的高渗透基因，以及具有人群中常见的风险相关等位基因的低渗透修饰基因。大多数乳腺癌风险的遗传变异都无法解释，并且大多数影响乳腺癌易感性的基因可能是由常见的遗传变异控制的。常见的单核苷酸多态性 (SNP) rs889312 标志着人类 5 号染色体上的低外显性乳腺癌风险相关等位基因 (Nature 447, 2007)。该基因座的乳腺癌风险关联基因和因果多态性尚未确定。人类区域与大鼠乳腺癌易感性 QTL、Mcs1b 是直系同源的。使用同源基因已将大鼠 Mcs1b 基因座缩小至 1.2 Mb。这些实验使用 Wistar Furth (WF) 菌株作为遗传背景，该菌株对 7,12-二甲基苯并[a]蒽 (DMBA) 诱导的乳腺癌高度敏感。 WF 背景上的 Mcs1b 哥本哈根 (COP) 等位基因使 COP 纯合子的 WF.COP 同系基因的 DMBA 诱导的乳腺癌发展减少 60%，而在 Mcs1b 上 COP/WF 杂合子的同系基因则减少 30% 。拟议工作的目标是在模型生物体中使用系统遗传学来识别优质候选乳腺癌风险遗传元件。这将通过以下具体目标来实现：目标 1：通过测试携带当前定义的 Mcs1b 基因座较短片段的其他同类系，将大鼠 Mcs1b 精细定位到小于 0.5 Mb 的基因组间隔；目标2：通过进行大鼠乳腺移植实验来确定Mcs1b COP等位基因是否在乳腺内以自主方式起作用；目标 3：通过确定潜在候选基因并测试每个候选基因以识别优质候选基因，来识别和评估大鼠 Mcs1b 内的乳腺癌候选基因/遗传元件。最终目标将分阶段完成，包括比较基因组学、遗传和表达分析、重测序以及候选者的体外和体内验证。公共卫生相关性：乳腺癌是一种复杂的疾病，是美国 20-59 岁女性癌症死亡的主要原因。导致乳腺癌易感性的最常见易感基因和分子遗传机制尚不清楚。为了努力降低乳腺癌的发病率和死亡率，有必要进行基础研究以更好地了解这种复杂疾病的遗传病因。拟议的研究使用比较遗传学方法来实现这一目标，并且还可能确定预防乳腺癌的新的潜在目标。