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COMPLETE VARIANT PROFILING OF ALL KNOWN BREAST CANCER GENES

所有已知乳腺癌基因的完整变异分析

基本信息

批准号：
8630707
负责人：
MARY-CLAIRE KING
金额：
$ 62.68万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8630707
关键词：
Affect Age Alleles BARD1 gene BRCA1 gene BRCA2 gene Bar Codes Bioinformatics Biological Assay Biopsy Specimen Blood Breast CDH1 gene CHEK1 gene CHEK2 gene Candidate Disease Gene Code Custom DNA DNA Damage DNA Repair Exons Family Family Study Fanconi Anemia-BRCA Pathway Frequencies Gene Frequency Gene Targeting Genes Genetic Predisposition to Disease Genomics Genotype Germ-Line Mutation Goals Information Technology Inherited Intercistronic Region Introns Lead Libraries Loss of Heterozygosity Missense Mutation Modality Modeling Mutation Nonsense Mutation Oncogenes Operative Surgical Procedures PPM1D gene PTEN gene Patient Care Patients RAD51C gene RNA RNA Splicing Recording of previous events Relative Risks Reverse Transcriptase Polymerase Chain Reaction Risk STK11 gene Sample Size Sampling Side TP53 gene Testing Translations Variant Woman XRCC2 gene Yeasts base case control clinical care effective therapy enzyme activity gene function genetic variant loss of function mutation malignant breast neoplasm premature public health relevance response screening tool tumor

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to identify and characterize clinically actionable mutations in all known breast cancer genes so that they can be incorporated into clinical care. DNA samples from 3000 cases and 2000 ancestry matched controls will be sequenced for all known breast cancer genes. Germline mutations will be evaluated with respect to function and relative risk of breast cancer. The discovery and characterization of clinically actionable variants in breast cancer genes involves three aims. In AIM 1, we will sequence all 18 known breast cancer genes in DNA samples from 3000 women with breast cancer and 2000 ancestry-matched controls. In parallel, we will similarly evaluate 6 new candidate genes for inherited breast cancer that have emerged from our independent family studies. For all characterizations, we will use our recently developed approach for simultaneous capture and multiplexed sequencing, to >300-fold median coverage, of exons, introns, regulatory, and flanking intergenic regions of breast cancer genes. In AIM 2, we will identify all variants predicted to lead to loss of gene function, including truncating mutations (whether nonsense, frameshifts, disrupting CNV and so on), complete genomic deletions, and putatively damaging missense mutations. We will assess all variants for effect on gene function using bioinformatics tools. Variants with possible splice effects will be evaluated by RT-PCR of patient RNA and ex vivo minigenes. The most promising missense alleles will be tested experimentally for DNA damage response, loss of enzyme activity and other functional assays as appropriate. In AIM 3, we will test the strength of association of breast cancer with each of the 24 genes, based on the combined frequency of unambiguous loss-of-function mutations in cases vs controls. Relative risks will be estimated for each gene. The challenge of integrating genomics into clinical care is timely now for inherited predisposition to breast cancer, because multiple causal genes are known, specialized breast screening modalities are available, risk- reducing surgery is effective, and treatment of breast cancer is influenced by the patient's genotype. The goal of this project is to provide the information and technology necessary for this translation.

描述（由申请人提供）：该项目的目标是识别和表征所有已知乳腺癌基因中的临床可行突变，以便将其纳入临床护理。将对3000例病例和2000例血统匹配对照的DNA样本进行所有已知乳腺癌基因的测序。生殖系突变将在乳腺癌的功能和相对风险方面进行评价。发现和表征乳腺癌基因中临床上可操作的变体涉及三个目标。在AIM 1中，我们将对来自3000名乳腺癌患者和2000名祖先匹配的对照的DNA样本中的所有18个已知乳腺癌基因进行测序。与此同时，我们将同样评估6个新的遗传性乳腺癌候选基因，这些基因是从我们的独立家族研究中出现的。对于所有表征，我们将使用我们最近开发的方法，用于同时捕获和多重测序，以>300倍的中值覆盖率，乳腺癌基因的外显子、内含子、调控和侧翼基因间区域。在AIM 2中，我们将鉴定所有预测会导致基因功能丧失的变体，包括截短突变（无论是无义突变、移码突变、破坏CNV等）、完全基因组缺失和致突变性错义突变。我们将使用生物信息学工具评估所有变体对基因功能的影响。将通过患者RNA和离体小基因的RT-PCR评价具有可能剪接效应的变体。将对最有希望的错义等位基因进行DNA损伤反应、酶活性损失和其他适当功能测定的实验测试。在AIM 3中，我们将根据病例与对照组中明确的功能丧失突变的组合频率来测试乳腺癌与24个基因中的每一个的关联强度。将估计每个基因的相对风险。将基因组学整合到临床护理中的挑战对于乳腺癌的遗传易感性来说是及时的，因为已知多种致病基因，可以使用专门的乳腺筛查模式，降低风险的手术是有效的，并且乳腺癌的治疗受患者基因型的影响。该项目的目标是提供翻译所需的信息和技术。