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Functional characterization of prostate cancer risk loci by high throughput sequencing

通过高通量测序对前列腺癌风险位点进行功能表征

基本信息

批准号：
10442619
负责人：
Liang Wang
金额：
$ 36.62万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442619
关键词：
Affect Aggressive behavior Alleles Benign Binding Binding Proteins Biological Biological Assay CRISPR interference CRISPR/Cas technology Cancer Etiology Cell Line Cell Proliferation Cells Characteristics Clinical Code Complex Data Set Databases Disease EMSA Gene Expression Genes Genetic Genetic Predisposition to Disease Genome Genomic DNA Genomic Segment Growth High-Throughput Nucleotide Sequencing Human Human Genome Immunoprecipitation Link Luciferases Malignant Neoplasms Malignant neoplasm of prostate Migration Assay Modeling Normal tissue morphology Nucleic Acid Regulatory Sequences Phenotype Play Prostate Proteins Regulatory Element Reporter Reporting Risk Role Single Nucleotide Polymorphism Site Susceptibility Gene Technology Testing Tissue-Specific Gene Expression Transcriptional Regulation Translations Tumor Tissue Untranslated RNA Validation Variant base cancer risk clinical practice clinically significant cohort differential expression disorder risk feasibility testing genome wide association study high throughput technology improved innovation innovative technologies knock-down loss of function matrigel novel overexpression population based prognostic prostate cancer cell line prostate cancer risk risk variant screening trait transcription factor

项目摘要

SUMMARY Although the causes of human cancers are attributable to many factors, there is substantial evidence that genetics likely plays a key role. Previous studies have used population-based approaches, such as genome- wide association studies (GWASs), to identify cancer-associated genetic susceptibility variants (single nucleotide polymorphisms or SNPs) in the human genome. Although GWASs have reported thousands of SNP loci associated with an increased cancer risk, functional effects of these risk-SNPs remain largely unknown. Because many of the risk-SNPs are located in genomic regions without known protein-coding genes and some reside several hundred kilobases from any nearby gene, it is believed that many, if not most, of these SNPs have regulatory effects on the genes that cause these cancers. To identify regulatory SNPs responsible for the disease risk, we propose to apply two novel high-throughput sequencing technologies to screen thousands of candidate SNPs at prostate cancer risk loci. Aim 1 is to determine SNP-dependent transcription factor (TF) binding differences at prostate cancer risk loci through IP-SNPs-seq. Aim 2 is to determine biological significance of SNP-dependent sequence variants at prostate cancer risk loci through CRISPRi-SNPs-seq. Aim 3 is to functionally characterize a set of selected SNPs and their target genes. Successful completion of the proposed study will gain further understanding of the functional role of GWAS-implicated SNPs. Characterization of the functional effects of cancer risk loci will facilitate the translation of population-based discovery into biological mechanisms and will eventually benefit clinical practice.

总结虽然人类癌症的原因可归因于许多因素，但有大量证据表明，遗传学可能起着关键作用。以前的研究使用了基于人群的方法，如基因组- 广泛关联研究（GWAS），以确定癌症相关的遗传易感性变体（单核苷酸多态性或SNP）。尽管GWAS已经报道了数千个SNP位点，与癌症风险增加相关，这些风险SNP的功能影响在很大程度上仍然未知。因为许多风险SNPs位于基因组区域，没有已知的蛋白质编码基因，如果从任何附近的基因中分离出数百个SNP，则相信这些SNP中的许多（如果不是大多数）具有对导致这些癌症的基因的调节作用。确定与疾病相关的调节性SNP 风险，我们建议应用两种新的高通量测序技术来筛选数千名候选人，前列腺癌风险基因座的SNP。目的1是确定SNP依赖的转录因子（TF）结合通过IP-SNPs-seq在前列腺癌风险位点的差异。目的2是确定通过CRISPRi-SNPs-seq在前列腺癌风险基因座的SNP依赖性序列变异目标3是功能上表征一组选定的SNP及其靶基因。圆满完成拟议的这项研究将进一步了解GWAS相关SNP的功能作用。表征癌症风险基因座的功能效应将有助于将基于人群的发现转化为生物学发现。并最终将有益于临床实践。