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：
10659186
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/10659186
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 Invaded 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 cancer risk candidate selection clinical practice clinically significant cohort differential expression disorder risk feasibility testing genome wide association study high throughput technology improved innovation innovative technologies knock-down lentivirally transduced 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.

概括尽管人类癌症的病因有多种因素，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，例如基因组广泛关联研究（GWAS），以确定与癌症相关的遗传易感性变异（单核苷酸人类基因组中的多态性或SNP）。尽管 GWAS 已报告了数千个 SNP 位点尽管与癌症风险增加相关，但这些风险 SNP 的功能影响仍然很大程度上未知。因为许多风险 SNP 位于没有已知蛋白质编码基因的基因组区域，有些位于数百个碱基来自任何附近的基因，据信这些 SNP 中的许多（如果不是大多数）都具有对导致这些癌症的基因的调节作用。确定导致疾病的监管 SNP 风险，我们建议应用两种新颖的高通量测序技术来筛选数千个候选者前列腺癌风险位点的 SNP。目标 1 是确定 SNP 依赖性转录因子 (TF) 结合通过 IP-SNPs-seq 发现前列腺癌风险位点的差异。目标 2 是确定生物学意义通过 CRISPRi-SNPs-seq 发现前列腺癌风险位点的 SNP 依赖性序列变异。目标 3 是对一组选定的 SNP 及其靶基因进行功能表征。顺利完成拟议的研究将进一步了解 GWAS 相关的 SNP 的功能作用。的表征癌症风险位点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机制，最终将有益于临床实践。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Clinical Applications of Liquid Biopsy in Prostate Cancer: From Screening to Predictive Biomarker.

DOI：
10.3390/cancers14071728
发表时间：
2022-03-29
期刊：
Cancers
影响因子：
5.2
作者：
Ionescu F;Zhang J;Wang L
通讯作者：
Wang L

Extensive germline-somatic interplay contributes to prostate cancer progression through HNF1B co-option of TMPRSS2-ERG.

DOI：
10.1038/s41467-022-34994-z
发表时间：
2022-11-28
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Giannareas, Nikolaos;Zhang, Qin;Yang, Xiayun;Na, Rong;Tian, Yijun;Yang, Yuehong;Ruan, Xiaohao;Huang, Da;Yang, Xiaoqun;Wang, Chaofu;Zhang, Peng;Manninen, Aki;Wang, Liang;Wei, Gong-Hong
通讯作者：
Wei, Gong-Hong