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

• 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
• 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

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 尽管人类癌的原因归因于许多因素，但有大量证据表明 遗传学可能起关键作用。先前的研究使用了基于人群的方法，例如基因组 - 广泛的关联研究（GWASS），以鉴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GWASS报告了成千上万的SNP基因座 与癌症风险增加有关，这些风险SNP的功能效应在很大程度上未知。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，有些居住 来自附近任何基因的几百千碱基，据信，这些SNP中有许多（如果不是大多数） 对引起这些癌症的基因的调节作用。确定负责该疾病的监管SNP 风险，我们建议将两种新型的高通量测序技术应用于筛选数千名候选人 前列腺癌风险基因座的SNP。目标1是确定依赖SNP的转录因子（TF）结合 通过IP-SNPS-SEQ，前列腺癌风险基因座的差异。目标2是确定生物学意义 通过CRISPRI-SNPS-SEQ，前列腺癌风险位点的SNP依赖性序列变体。目标3是 在功能上表征一组选定的SNP及其靶基因。成功完成拟议的 研究将进一步了解GWAS刺激性SNP的功能作用。表征 癌症风险基因座的功能效应将促进基于人群的发现转化为生物学 机制，最终将受益于临床实践。

项目成果

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