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

基本信息

批准号：
8113868
负责人：
Thomas Louis LaFramboise
金额：
$ 28.97万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8113868
关键词：
Alleles Automobile Driving Biological Assay Cancer cell line Cataloging Catalogs Cells Chromosome Mapping Chromosomes Clinical Oncology Computational Biology DNA Data Set 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 clinical decision-making density gene discovery genetic variant genome-wide lens malignant breast neoplasm novel prognostic statistics tool trait tumor tumor progression

项目摘要

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）：体细胞和种系遗传变异都在癌症中起作用。从体面上讲，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。放大区域倾向于跨越相当大的距离并包含许多基因。鉴定扩增子内的靶基因座将使人们能够对驱动肿瘤进展的遗传途径有完善的理解。但是，相对于复发扩增的数量，靶基因的数量很少。假设是在肿瘤演化过程中积极选择扩增子内的特定种系等位基因，因此在扩增（与未扩增的）染色体中获得更高的等位基因频率。 AIM 1适应了人群和统计遗传学领域的原则，以开发方法学工具来检验该假设。 AIM 2在1,900个肿瘤基因组中以系统的方式应用了这些工具，这些工具已广泛特征用于扩增。最后，在AIM 3中，有希望的候选区域将经过精细的映射和验证，以隔离所选择的实际等位基因。该研究的数据集的心脏包含超过2,000个肿瘤和癌细胞系，其中包括多种组织类型。每个样品的DNA已经在整个基因组上的230,000多个单核苷酸多态性（SNP）上分析了Affymetrix芯片上。该平台允许在整个种系（等位基因）和肿瘤（扩增）基因组中整合信息。统计和人口遗传技术在这个大型和高分辨率数据集中的新应用将促进在阳性选择下在扩增子内发现特定区域。精确的候选区域建议下游功能分析，可以立即进行。研究与公共卫生的相关性：鉴定肿瘤扩增的特定靶标已经对临床肿瘤学的预后（神经母细胞瘤中的MYCN）和治疗（ERBB2）产生了深远的影响。拟议的研究旨在进行基因组广泛的调查，以系统地描述多种肿瘤类型的拷贝数增益区域中的靶基因。发现导致肿瘤存活和进展的基因和途径将允许更精致的临床决策。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Losing balance: Hardy-Weinberg disequilibrium as a marker for recurrent loss-of-heterozygosity in cancer.

失去平衡：哈迪-温伯格不平衡作为癌症中反复出现的杂合性丧失的标志。

DOI：
10.1093/hmg/ddr422
发表时间：
2011
期刊：
Human molecular genetics
影响因子：
3.5
作者：
Wilkins,Katherine;LaFramboise,Thomas
通讯作者：
LaFramboise,Thomas

An optimization framework for unsupervised identification of rare copy number variation from SNP array data.

用于从 SNP 阵列数据中无监督识别罕见拷贝数变异的优化框架。

DOI：
10.1186/gb-2009-10-10-r119
发表时间：
2009
期刊：
GENOME BIOLOGY
影响因子：
12.3
作者：
Yavas, Goekhan;Koyutuerk, Mehmet;Oezsoyoglu, Meral;Gould, Meetha P.;LaFramboise, Thomas
通讯作者：
LaFramboise, Thomas

Accurate estimation of short read mapping quality for next-generation genome sequencing.