A Genetic Approach to Genome-scale Analysis of Cancers

癌症的发展是由影响许多基因功能的遗传改变引起的。要了解其分子机制，就必须彻底寻找受影响的基因。在这个分阶段的创新项目中，将开发一种高效和具有成本效益的癌症基因组规模分析遗传方法。在第一阶段，将开发高通量多重基因分型系统的能力和灵敏度，以便每个检测可包括300个标记物，灵敏度为使用1200个石蜡存档组织细胞。在第二阶段，12，000个由单核苷酸多态性组成的遗传标记将被纳入该基因分型系统，因此，只需40次检测就足以对这些标记进行分型。该系统将用于鉴定可能完全含有肿瘤抑制基因的染色体区域，并用于揭示乳腺癌中可能含有原癌基因的至少部分区域。为了获得高分辨率，将分析1，000个癌样本和200个转移样本以及浸润样本中的配对样本。结果将用于在鉴定区域中选择一小组鉴定的标记。所选择的标记物将被纳入高通量基因分型系统中，以便将来的研究需要一个或很少的检测，这些研究覆盖了大多数（如果不是全部的话）可能含有TSG的染色体区域和一些含有原癌基因的区域。该项目的成功将使高通量技术可用于癌症的基因组规模分析。这将使许多大规模的遗传学研究，如果使用单标记-碱基测定，可能需要数百年才能完成，而使用这种高通量方法，只需几年或几年。该项目的成功还将产生高度简化和负担得起的乳腺癌基因组规模分析实验程序，目前这在技术上具有挑战性，许多实验室负担不起。

Cancer development is caused by genetic alterations affecting the function of a number of genes. To understand the molecular mechanisms, it is necessary search for the affected genes exhaustively. In this phased innovation project, a highly efficient and cost effective genetic approach to genome scale analysis of cancers will be developed. In phase I, the capacity and sensitivity of a high-throughput multiplex genotyping system will be developed so that each assay may include 300 markers with a sensitivity of using 1200 cells from paraffin-archive tissue. In phase II, 12,000 genetic markers consisting of single nucleotide polymorphisms will be incorporated into this genotyping system so that as few as 40 assays will be sufficient for typing these markers. This system will be used for identifying chromosomal regions that may harbor tumor suppressor genes exhaustively and for revealing at least part of the regions that may contain protooncogenes in breast cancer. To obtain a high resolution, 1,000 carcinoma specimens and 200 metastatic specimens with paired specimens with paired specimens with paired specimens among the invasive specimens will be analyzed. The results will be used to select a small set of markers in the identified in the identified regions. The selected markers will be incorporated in to the high-throughput genotyping system so that one or very few assays will be needed for the future studies covering most, if not all, chromosomal regions that may harbor TSGs and some of the regions containing protooncogenes. Success of this project will make the high-throughput techniques available for genome-scale analysis of cancers. This will make many large-scale genetic studies that may need hundreds of years to complete if the single marker-base assays is used,, but only or few years with this high-throughput approach. The success of the project will also generate highly simplified and affordable experimental procedures for genome-scale analysis of breast cancer, which currently is technically challenging and not affordable for many of the laboratories.