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：
8250466
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/8250466
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）：确定乳腺癌风险相关等位基因项目摘要/摘要的候选修饰符元素：妇女患乳腺癌的风险受遗传，表观遗传和环境因素的影响。多达30-40％的乳腺癌风险可能是遗传的。乳腺癌遗传学很复杂。控制疾病风险的因素是高渗透基因，其风险等位基因的人口频率低，而渗透性修饰剂基因低，具有与风险相关的等位基因相关的等位基因。乳腺癌风险中的大多数遗传变异都没有被指责，并且影响乳腺癌易感性的大多数基因可能受到常见遗传变异的控制。常见的单核苷酸多态性（SNP）RS889312标志着人类5号染色体上的渗透乳腺癌风险低（自然447，2007）。尚未确定该基因座的乳腺癌风险相关基因和因果多态性。人类区域与大鼠乳腺癌易感性QTL直源，MCS1B。大鼠MCS1B基因座已使用友善者缩小为1.2 MB。这些实验使用了Wistar furth（WF）菌株，该菌株高度易受7,12-二甲基苯甲酸[A]蒽（DMBA）诱导的乳腺癌，作为遗传背景。在WF背景上，MCS1B哥本哈根（COP）等位基因赋予DMBA诱导的乳腺癌发育降低60％，降低了COP-HOMOZYGOUS的wf.cop Encenics，减少了30％的MC/WF/WF杂质者，在MCS1B的MCS1B中降低了30％。拟议工作的目的是在模型生物体中使用系统遗传学来鉴定候选乳腺癌风险遗传因素。这将通过以下特定目的来完成：AIM 1：细MAP RAT MCS1B到小于0.5 MB的基因组间隔，通过测试当前定义的MCS1B基因座的较短段的其他先天线； AIM 2：通过进行大鼠乳腺移植实验，确定MCS1B COP等位基因是否在乳腺内部起作用。 AIM 3：通过确定潜在的候选者并测试每个人以识别质量候选者，确定和评估大鼠MCS1B中乳腺癌的基因/遗传因素。最终目标将分阶段完成，其中将结合比较基因组学，遗传和表达分析，重新定制以及在体外以及对候选者的体内验证。公共卫生相关性：乳腺癌是一种复杂的疾病，是20至59岁的美国妇女癌症的主要死亡原因。最常见的敏感性基因和导致乳腺癌易感性的分子遗传机制尚不清楚。为了降低由于乳腺癌而引起的发病率和死亡率，有必要更好地理解这种复杂疾病的遗传病因。拟议的研究使用了一种比较遗传方法来实现这一目标，还可以确定预防乳腺癌的新型潜在靶标。