Genome-Wide Allelic Imbalances in Colon Cancer

结肠癌的全基因组等位基因失衡

• 批准号: 6926856
• 负责人: JAMES M. FORD
• 金额: $ 13.5万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6926856
• 关键词: alleles; bioinformatics; biomarker; carcinoma; cell line; clinical research; colorectal neoplasms; diagnosis design /evaluation; gene frequency; genetic disorder diagnosis; genetic mapping; genetic screening; genome; high throughput technology; human subject; molecular probes; neoplasm /cancer diagnosis; neoplasm /cancer genetics; neoplasm /cancer relapse /recurrence; neoplastic cell; patient oriented research; prognosis; single nucleotide polymorphism

DESCRIPTION (provided by applicant): Colorectal carcinoma is a major health issue in developed western countries. Currently, clinical staging is the most commonly used predictor of overall prognosis but remains relatively poor in predicting recurrence. Specific genomic instability events such as allelic imbalances in chromosomes have potential utility as prognostic biomarkers. While there is an urgent need for better biomarkers that utilize genomic instability events, current technologies to measure this phenomenon have significant limitations. Better technologies are required with improved reproducibility and prognostic potential in clinical studies. We describe the molecular inversion probe (MIP) technology and its application in genome-wide detection of gene copy number changes and allelic imbalances (1). For genomics-based biomarker discovery, molecular inversion probes (MIPs) have many advantages over current high-throughput technologies, including high reproducibility, the ability to interrogate gene copy number at a large number of designated, unrestricted positions across the entire genome and simultaneous genotyping of SNP alleles quantitatively. We propose to design a large number (2,000) molecular inversion probes set that will cover all human chromosomes and 320 known major cancer-related genes important in colorectal tumorigenesis and other cancers. To validate the application of MIPs for quantifying gene copy number and allelic imbalance analysis, we will analyze a panel of colorectal cancer cell lines, normal cell lines and other tumor cell lines containing known genomic instability events. We have implemented the bioinformatics necessary to design the probes, will optimize the parameters of the MIPs assay and refine the bioinformatics for data analysis. The cancer MIP probes will be used to analyze clinical colorectal cancer sample and identify particular gene copy number or allelic imbalance events that can distinguish different types of genomic instability.

描述（由申请人提供）：结直肠癌是西方发达国家的一个主要健康问题。目前，临床分期是最常用的总体预后预测指标，但在预测复发方面仍然相对较差。特定的基因组不稳定事件，例如染色体中的等位基因不平衡，具有作为预后生物标志物的潜在用途。虽然迫切需要更好的生物标志物来利用基因组不稳定事件，但目前测量这种现象的技术存在很大的局限性。临床研究中需要更好的技术来提高可重复性和预后潜力。我们描述了分子倒置探针 (MIP) 技术及其在基因拷贝数变化和等位基因失衡的全基因组检测中的应用 (1)。对于基于基因组学的生物标志物发现，分子倒置探针 (MIP) 比当前的高通量技术具有许多优势，包括高重现性、能够在整个基因组中大量指定、不受限制的位置询问基因拷贝数，以及同时对 SNP 等位基因进行定量基因分型。我们建议设计大量（2,000）个分子倒置探针组，涵盖所有人类染色体和 320 个已知的主要癌症相关基因，这些基因在结直肠肿瘤发生和其他癌症中很重要。为了验证 MIP 在量化基因拷贝数和等位基因失衡分析中的应用，我们将分析一组包含已知基因组不稳定事件的结直肠癌细胞系、正常细胞系和其他肿瘤细胞系。我们已经实施了设计探针所需的生物信息学，将优化 MIP 测定的参数并完善数据分析的生物信息学。癌症MIP探针将用于分析临床结直肠癌样本并识别特定的基因拷贝数或等位基因失衡事件，从而区分不同类型的基因组不稳定性。