A genomic survey of allele-specific selection in tumor amplicons

肿瘤扩增子等位基因特异性选择的基因组调查

• 批准号: 7527126
• 负责人: Thomas Louis LaFramboise
• 金额: $ 32.19万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7527126
• 关键词: Alleles; Automobile Driving; Biological Assay; Cancer cell line; Cataloging; Catalogs; Cells; Chromosome Mapping; Chromosomes; Classification; Clinical; Clinical Oncology; Computational Biology; DNA; Data Set; Decision Making; Development; ERBB2 gene; Evolution; Gene Frequency; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Techniques; Genome; Genomics; Genotype; Goals; Grant; Growth; Heart; Histocompatibility Testing; Localized; MYCN gene; Malignant Neoplasms; Maps; Measurement; Methodology; Methods; Neuroblastoma; Numbers; Pathway interactions; Play; Population; Population Genetics; Public Health; Recurrence; Relative (related person); Research; Resolution; Role; Sampling; Single Nucleotide Polymorphism; Site; Solutions; Surveys; Testing; Therapeutic; Validation; Variant; density; gene discovery; genetic variant; lens; malignant breast neoplasm; novel; prognostic; statistics; tool; trait; tumor; tumor progression

DESCRIPTION (provided by applicant): Somatic and germline genetic variants both play a role in cancer. Somatically, amplification of genomic DNA is a common mechanism exploited by a tumor to gain a competitive growth advantage. Regions of amplification tend to span considerable distances and encompass many genes. Identification of the target loci within the amplicon will enable a refined understanding of the genetic pathways driving tumor progression. The number of target genes that have been revealed relative to the number of recurrent amplifications, however, is low. The hypothesis is that particular germline alleles within an amplicon are positively selected for during tumor evolution and therefore achieve a higher allele frequency among amplified (versus non-amplified) chromosomes. Aim 1 adapts principles from the fields of population and statistical genetics to develop the methodological tools to test the hypothesis. Aim 2 applies these tools in a systematic fashion across 1,900 tumor genomes that have been extensively characterized for amplifications. Lastly, in Aim 3, promising candidate regions will be subjected to fine mapping and validation to isolate the actual allele under selection. The heart of the dataset for this study contains over 2,000 tumors and cancer cell lines, encompassing multiple tissue types. DNA from each sample has already been profiled on Affymetrix chips for over 230,000 single nucleotide polymorphisms (SNPs) across the genome. This platform allows for integration of information across the germline (alleles) and tumor (amplifications) genomes. The novel application of statistical and population genetic techniques to this large and high-resolution dataset will facilitate the discovery of specific regions within an amplicon under positive selection. Pinpointing candidate regions suggests downstream functional assays, which can be immediately pursued. Relevance of research to public health: The identification of the specific targets of tumor amplification has already had a profound effect on the prognostic (MYCN in neuroblastoma) and therapeutic (ERBB2 in breast cancer) realms of clinical oncology. The proposed research aims to perform a genome wide survey to systematically delineate the target genes in regions of copy number gain in multiple tumor types. Discovery of the genes and pathways contributing to tumor survival and progression will allow for more refined clinical decision-making.

描述（由申请人提供）：体细胞和生殖系遗传变异都在癌症中发挥作用。在体细胞方面，基因组DNA的扩增是肿瘤利用以获得竞争性生长优势的常见机制。扩增区域往往跨越相当大的距离，并包含许多基因。扩增子内靶基因座的鉴定将使得能够精确理解驱动肿瘤进展的遗传途径。然而，相对于重复扩增的数量，已经揭示的靶基因的数量是低的。该假设是扩增子内的特定种系等位基因在肿瘤演变期间被积极选择，因此在扩增的（相对于非扩增的）染色体中实现更高的等位基因频率。目的1适应原则，从人口和统计遗传学领域发展的方法学工具，以测试的假设。目标2以系统的方式将这些工具应用于1，900个肿瘤基因组，这些基因组已被广泛表征用于扩增。最后，在目标3中，将对有希望的候选区域进行精细定位和验证，以分离选择中的实际等位基因。该研究数据集的核心包含超过2，000种肿瘤和癌细胞系，涵盖多种组织类型。来自每个样本的DNA已经在Affytechnic芯片上进行了分析，以获得整个基因组中超过230，000个单核苷酸多态性（SNP）。该平台允许跨种系（等位基因）和肿瘤（扩增）基因组整合信息。将统计和群体遗传技术应用于这一大型高分辨率数据集将有助于发现正选择下扩增子内的特定区域。精确定位候选区域表明可以立即进行下游功能测定。研究与公共卫生的相关性：确定肿瘤扩增的特定靶点已经对临床肿瘤学的预后（神经母细胞瘤中的MYCN）和治疗（乳腺癌中的ERBB 2）领域产生了深远的影响。该研究旨在进行全基因组调查，以系统地描绘多种肿瘤类型中拷贝数增加区域的靶基因。发现有助于肿瘤生存和进展的基因和途径将允许更精确的临床决策。