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: 7687397
• 负责人: Thomas Louis LaFramboise
• 金额: $ 30.02万
• 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/7687397
• 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; MYCN gene; Malignant Neoplasms; Maps; Measurement; Methodology; Methods; Neuroblastoma; 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; genome-wide; 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(申请人提供)：体细胞和生殖系基因变异在癌症中都起作用。从躯体上看，基因组DNA的扩增是肿瘤获得竞争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。识别扩增子内的靶基因位点将使人们能够更好地了解推动肿瘤进展的遗传途径。然而，相对于重复扩增的数量，已发现的目标基因的数量很少。假设在肿瘤进化过程中，扩增子内的特定生殖系等位基因被积极选择，因此在扩增的(与未扩增的)染色体中实现了更高的等位基因频率。目的1采用种群和统计遗传学领域的原理来开发检验假设的方法学工具。AIM 2以系统的方式将这些工具应用于1900个肿瘤基因组，这些基因组已被广泛表征为扩增。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，以分离出实际选择的等位基因。这项研究的数据集的核心包含2000多个肿瘤和癌细胞系，涵盖多种组织类型。来自每个样本的DNA已经在Affymetrix芯片上进行了分析，发现了整个基因组中超过230,000个单核苷酸多态(SNPs)。这个平台允许跨生殖系(等位基因)和肿瘤(扩增)基因组的信息整合。统计学和群体遗传学技术在这个大而高分辨率的数据集上的新应用将有助于在正选择下发现扩增子内的特定区域。精确定位候选区域建议进行下游功能分析，这可以立即进行。研究与公共健康的相关性：肿瘤放大的特定靶点的确定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ERBB2)领域产生了深远的影响。这项拟议的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。有助于肿瘤存活和进展的基因和途径的发现将允许更精确的临床决策。