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发挥作用。就体细胞而言，基因组 DNA 扩增是肿瘤利用其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。扩增子内目标位点的识别将有助于深入了解驱动肿瘤进展的遗传途径。然而，相对于重复扩增的数量，已揭示的靶基因数量很低。假设是，扩增子内的特定种系等位基因在肿瘤进化过程中被积极选择，因此在扩增（与非扩增）染色体中实现更高的等位基因频率。目标 1 采用人口和统计遗传学领域的原理来开发检验假设的方法工具。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，有希望的候选区域将接受精细绘图和验证，以分离出选择下的实际等位基因。本研究数据集的核心包含 2,000 多种肿瘤和癌细胞系，涵盖多种组织类型。每个样本的 DNA 均已在 Affymetrix 芯片上进行了基因组中超过 230,000 个单核苷酸多态性 (SNP) 的分析。该平台允许整合种系（等位基因）和肿瘤（扩增）基因组的信息。统计和群体遗传技术在这个大型高分辨率数据集中的新颖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：肿瘤扩增特定靶点的识别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。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。发现有助于肿瘤生存和进展的基因和途径将有助于做出更精细的临床决策。

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.