Genome-Wide Allelic Imbalances in Colon Cancer

描述（由申请人提供）：结直肠癌是西方发达国家的主要健康问题。目前，临床分期是最常用的总体预后的预测因子，但在预测复发方面仍然相对较差。特定的基因组不稳定性事件，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效用。虽然迫切需要利用基因组不稳定性事件的更好的生物标志物，但目前测量这种现象的技术具有显著的局限性。需要更好的技术，提高临床研究的重现性和预后潜力。我们描述了分子倒置探针（MIP）技术及其在全基因组检测基因拷贝数变化和等位基因失衡中的应用（1）。对于基于基因组学的生物标志物发现，分子倒置探针（MIP）具有许多优于当前高通量技术的优点，包括高再现性、在整个基因组中的大量指定的、不受限制的位置处询问基因拷贝数的能力以及定量地对SNP等位基因进行同时基因分型。我们建议设计大量（2，000）分子倒置探针集，其将覆盖所有人类染色体和320个已知的在结直肠肿瘤发生和其他癌症中重要的主要癌症相关基因。为了验证MIP用于定量基因拷贝数和等位基因不平衡分析的应用，我们将分析一组包含已知基因组不稳定性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测定的参数并完善用于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品，并鉴定特定的基因拷贝数或等位基因不平衡事件，从而可以区分不同类型的基因组不稳定性。

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.