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基因改变引起的。为了了解分子机制，有必要详尽地寻找受影响的基因。在这个分阶段的创新项目中，将开发一种高效且具有成本效益的基因方法来进行癌症的基因组规模分析。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，以便每个分析可能包括300个标记，其灵敏度为使用来自石蜡存档组织的1200个细胞。在第二阶段，由单核苷酸多态性组成的12,000个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包含肿瘤抑制基因的染色体区域，并用于揭示乳腺癌中可能包含原癌基因的至少部分区域。为了获得高分辨率，我们将分析侵袭性标本中1000例癌标本和200例具有配对标本的转移标本，配对标本与配对标本。该结果将用于在识别区域中选择识别的一小部分标记。所选择的标记将被纳入高通量基因分型系统，以便在未来的研究中需要进行一次或很少的检测，覆盖大多数（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。这将使得许多大规模的基因研究可能需要数百年才能完成，如果使用单标记基分析，而使用这种高通量方法只需要几年。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，目前这在技术上是具有挑战性的，对许多实验室来说也是负担不起的。

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.