Phenotype-based approach to find gene interactions underlying breast cancer risk

基于表型的方法寻找乳腺癌风险背后的基因相互作用

基本信息

批准号：
7386106
负责人：
AMANDA G PAULOVICH
金额：
$ 26.75万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-27 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7386106
关键词：
Alleles Antibody Therapy BRCA1 gene Biological Markers Breast Candidate Disease Gene Cell Line Chemoprevention Chromosome Mapping Condition DNA Damage DNA copy number Data Defect Disease Disease susceptibility Early identification Engineering Epithelial Cells Functional disorder Gamma Rays Gene Targeting Genes Genetic Genetic Epistasis Genetic Screening Genome Genotype Goals Homologous Gene Hormonal Human Individual Laboratories Liquid substance Malignant Neoplasms Mammalian Cell Mammary Neoplasms Mammary gland Measures Mediating Minor Molecular Mutation Numbers PTEN gene Phenotype Population Predisposition Prevention Prevention strategy Public Health Quantitative Trait Loci RNA Interference Relative (related person)Reverse Transcriptase Polymerase Chain Reaction Risk Saccharomyces cerevisiae Screening for cancer Screening procedure Series Standards of Weights and Measures Stratification Syndrome TEP1 gene Testing Treatment Protocols Tumor Suppressor Genes Tumor Suppressor Proteins Ultraviolet Rays Western Blotting Woman XRCC3 gene Yeasts base cancer risk cost deletion library design disorder risk gene interaction genetic association genetic linkage analysis human study innovation killings knock-down malignant breast neoplasm mutant programs response small hairpin RNA synergism therapeutic target vector yeast genetics

项目摘要

DESCRIPTION (provided by applicant): Identification of genes contributing to common (non-Mendelian) forms of breast cancer would enable early identification of individuals at risk and tailoring of prevention and treatment regimens. This is an extremely difficult problem since heritable risk for common forms of breast cancer is a result of multiple gene-gene interactions, with each individual gene making only a minor contribution to risk. Standard approaches (e.g. genetic association studies) are underpowered to detect the many gene-gene interactions underlying risk. We propose a phenotype-based approach to predict gene-gene interactions underlying risk for common forms of breast cancer. The approach is based on the observation that defects in the cellular DNA damage response (an intermediate phenotype for breast cancer susceptibility) are heritable, making it possible to map gene-gene interactions responsible for this phenotype. We hypothesize that gene-gene interactions governing sensitivity to DNA damage are conserved between yeast and humans. Our approach will be to: i) use the yeast S. cerevisiae to perform genome-wide screens for mutations that synergize with homologs of human breast cancer tumor suppressor genes to confer sensitivity to DNA damage, and ii) to screen amongst these identified synthetic interactions for those that are conserved in human mammary epithelial cells. Specific Aim 1: Perform genome-wide screens in S. cerevisiae to identify mutations that synergize with yeast homologs of human breast cancer tumor suppressor genes to produce sensitivity to DNA damage. Specific Aim 2: Using RNA interference, build human mammary epithelial cell lines that have stable knock- down of breast tumor suppressor genes. Specific Aim 3: Determine if genetic interactions discovered in yeast are conserved in human breast epithelial cells. PROJECT NARRATIVE: Determination of an individual's risk for developing cancer could have tremendous public health impact in several ways: i) identifying risk alleles for breast cancer will facilitate cost-effective cancer screening programs tailored to an individual's risk profile; ii) identifying risk alleles will allow identification of women who will most benefit from prevention strategies; iii) identifying risk alleles will elucidate the pathophysiology of the disease, leading to targeted therapeutics or chemoprevention agents such as existing targeted hormonal and antibody therapies.

描述（由申请人提供）：鉴定促成常见（非孟德尔）乳腺癌的基因将使人们能够尽早确定处于风险和预防和治疗方案的危险中。这是一个极其困难的问题，因为对乳腺癌的常见形式的遗传风险是多种基因相互作用的结果，每个基因仅对风险做出较小的贡献。标准方法（例如遗传关联研究）无法检测出许多基因相互作用的基础风险。我们提出了一种基于表型的方法来预测常见形式的乳腺癌风险的基因相互作用。该方法基于这样的观察结果，即细胞DNA损伤反应中的缺陷（乳腺癌易感性的中间表型）是可以遗传的，从而可以映射负责此表型的基因基因相互作用。我们假设酵母和人之间的基因基因相互作用是对DNA损伤的敏感性的。我们的方法将是：i）使用酵母S.酿酒酵母执行全基因组筛选，以与人类乳腺癌抑制基因的同源物协同的突变，以赋予对DNA损伤的敏感性，ii）在这些鉴定的合成相互作用中筛选对于那些在人类乳腺上皮细胞中保守的人。具体目标1：在酿酒酵母中进行全基因组筛查，以确定与人类乳腺癌抑制基因的酵母同源物协同的突变，以产生对DNA损伤的敏感性。特定目标2：使用RNA干扰，建立具有稳定的乳腺抑制基因的稳定敲门的人类乳腺上皮细胞系。特定目标3：确定在酵母中发现的遗传相互作用是否在人乳腺上皮细胞中保守。项目叙述：确定个人患癌症的风险可能会以多种方式产生巨大的公共卫生影响：i）确定乳腺癌的风险等位基因将促进量身定制的，旨在为个人的风险概况量身定制； ii）确定风险等位基因将允许识别将从预防策略中受益最大的妇女； iii）确定风险等位基因将阐明该疾病的病理生理，从而导致靶向治疗剂或化学预防剂，例如现有的靶向激素和抗体疗法。