Finding Genes for Human Prostate Cancer

寻找人类前列腺癌的基因

• 批准号: 10267096
• 负责人: elaine ostrander
• 金额: $ 25.83万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10267096
• 关键词: 8q24; Affect; African; African American; Age; BRCA2 gene; Benign; Biological Markers; Cancer Patient; Case-Control Studies; Catalogs; Cessation of life; Clinic; Collaborations; Custom; DNA; DNA Methylation; Data; Data Analyses; Data Set; Development; Diagnosis; Disease; Event; Family; Family Cancer History; Family Study; Family history of; Frequencies; Gene Expression Regulation; Genes; Genome; Gleason Grade for Prostate Cancer; Haplotypes; Histologic; Hospitals; Human; KLK3 gene; Laboratories; Localized Disease; MSMB gene; Malignant neoplasm of prostate; Manuscripts; Maps; Metastatic to; Methylation; Mutation; Neoplasm Metastasis; Oncogenes; Pathogenicity; Patients; Population; Population Study; Predisposition; Preparation; Prostate-Specific Antigen; Prostatic Neoplasms; Publishing; Quantitative Trait Loci; Radical Prostatectomy; Recurrence; Regulation; Reporting; Risk; Role; Sampling; Screening for Prostate Cancer; Sum; Testing; The Cancer Genome Atlas; Time; Training; Transcript; Tumor stage; Variant; base; cancer genome; case control; design; exome; exome sequencing; genetic variant; genome sequencing; genome wide association study; high risk; improved; men; mortality; novel; patient stratification; predictive modeling; prostate cancer risk; risk variant; tumor; whole genome

Prostate Cancer Studies Prostate Cancer in Men of African Ancestry Although men of African ancestry have a high risk of prostate cancer (PCa), few genes or mutations have been identified that contribute to familial clustering of PCa in this population. This collaboration investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (Darst et al., 2020). In men of African ancestry, the relevant variant accounts for 32% of the total familial risk explained by all known PCa risk variants, suggesting that African American men would benefit from guidance about prostate cancer screening and this variant. Prostate Cancer Risk and Prediction In this collaboration the role of DNA methylation in expression quantitative trail loci (eQTL) regulation was investigated (Dai et al., 2020). Specifically, this collaboration identifies and compares eQTLs and CpG methylation quantitative trait loci (meQTLs) among 147 established PrCa risk SNPs in primary prostate tumors (n = 355 from a Seattle-based study and n = 495 from The Cancer Genome Atlas, TCGA) and tumor-adjacent, histologically benign samples (n = 471 from a Mayo Clinic study). The study provides a comprehensive catalog of eQTLs, meQTLs and putative cancer genes for known PCa risk SNPs. We observe that a substantial portion of germline eQTL regulatory mechanisms are maintained in the tumor development, despite somatic alterations in the tumor genome. Finally, our analyses illuminates the likely intermediary role of CpG methylation in eQTL regulation of gene expression. In a separate collaboration (Schaid et al., 2020), we sought to understand the role of family history and more aggressive PCa. A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls. Frequencies of genetic variants were compared between cases and controls. Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). This approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease. Metastatic Lethal Prostate Cancer It is well know that, with the exception of Gleason score, few factors accurately identify the subset of prostate cancer (PCa) patients at high risk for metastatic progression (Wang et al., 2020). In this collaboration we tested if copy number alterations (CNAs), assessed using CpG methylation probes could identify primary prostate tumors with potential to develop metastatic progression. The study shows that CNAs can be reliably detected in tumor data. There are 11 recurrent CNAs showing association with metastatic-lethal events following radical prostatectomy, thus improving prediction over Gleason score. Genes affected by these CNAs may functionally relate to tumor aggressiveness and metastatic progression. An additional collaboration investigated if a four gene transcript score could be used to predict metastatic lethal progression in men original treated for localized disease (Cheng et al., 2019). Based on a previously published panel of 23 gene transcripts that distinguished patients with metastatic progression, the collaboration constructed a prediction model using independent training and testing datasets. Thirteen of 23 previously identified gene transcripts that stratified patients with aggressive PCa were validated in the training dataset. These biomarkers plus Gleason Score were used to develop a four-gene (CST2, FBLN1, TNFRSF19, and ZNF704) transcript (4GT) score that was significantly higher in patients who progressed to metastatic-lethal disease compared to those without recurrence. In aggregate, these studies show a role for transcript score in predicting which men originally treated for relatively moderate disease, will go on to get metastatic disease.

前列腺癌研究 非洲血统男性的前列腺癌 尽管非洲裔男性患前列腺癌的风险很高，但在这一人群中，几乎没有发现导致前列腺癌家族聚集性的基因或突变。这项合作调查了位于8q24的非洲血统特有的PCa风险变量rs72725854是否在9052例有PCa家族史、143例来自高危家族和8595名非洲血统对照的男性中丰富。我们发现，风险等位基因与确诊时年龄较早、更具侵袭性的疾病显著相关，并在有前列腺癌家族史的男性中丰富(Darst等人，2020年)。在非洲裔男性中，相关变异占所有已知PCA风险变异所解释的总家族风险的32%，这表明非洲裔美国男性将受益于前列腺癌筛查和该变异的指导。 前列腺癌的风险和预测 在这项合作中，研究了DNA甲基化在表达定量TRAIL基因座(EQTL)调控中的作用(Dai等人，2020)。具体地说，这项合作在147个已建立的PrCa风险SNPs中识别和比较了eQTL和CpG甲基化数量性状基因座(n=355来自西雅图的研究，n=495来自癌症基因组图谱TCGA)和肿瘤邻近的组织良性样本(n=471来自Mayo诊所的研究)。这项研究提供了已知的PCA风险SNPs的eQTL、meQTL和可能的癌症基因的全面目录。我们观察到，尽管肿瘤基因组发生了体细胞变化，但很大一部分胚系eQTL调控机制在肿瘤的发展过程中保持不变。最后，我们的分析阐明了CpG甲基化在eQTL基因表达调控中的可能中介作用。 在另一项单独的合作中(Schaid等人，2020)，我们试图了解家族史和更具侵略性的PCA的作用。采用两阶段设计。在第一阶段，使用全外显子组测序在有强烈家族病史或有更多侵袭性疾病的受影响男性中识别潜在的风险等位基因(491例患者和429名对照)。侵袭性疾病基于Gleason评分、结节状态、转移、肿瘤分期、确诊时的前列腺特异性抗原、全身复发和PCa死亡时间的总和。在第一阶段确定的基因在第二阶段使用定制捕获设计在2917个病例和1899个对照的独立集合中进行筛选。比较病例组和对照组的基因变异频率。共检测到11个与前列腺癌相关的基因(ATM、BRCA2、HOXB13、FAM111A、EMSY、HNF1B、KLK3、MSMB、PCAT1、PRSS3和TERT)，以及另外10个新基因(PABPC1、QK1、FAM114A1、MUC6、MYCBP2、RAPGEF4、RNASE-2B、ULK4、XPO7和THAP3)。这种方法证明了基因测序在寻找与前列腺癌相关的遗传变异方面的优势，以及对有强烈家族病史或侵袭性疾病形式的患者进行抽样的好处。 转移性致死性前列腺癌 众所周知，除了Gleason评分外，很少有因素能准确识别前列腺癌(PCA)患者的高危转移进展(Wang等人，2020)。在这项合作中，我们测试了使用CpG甲基化探针评估的拷贝数改变(CNA)是否可以识别具有潜在转移进展的原发性前列腺癌。研究表明，在肿瘤数据中可以可靠地检测到CNA。有11例复发的CNA显示与根治性前列腺切除术后的转移-致死事件有关，因此改善了对Gleason评分的预测。受这些CNA影响的基因可能在功能上与肿瘤的侵袭性和转移进展有关。 另一项合作调查了四基因转录本评分是否可以用于预测最初接受局部疾病治疗的男性的转移性致死进展(程等人，2019年)。基于之前发表的一个由23个基因转录本组成的小组来区分转移进展的患者，合作小组使用独立的训练和测试数据集构建了一个预测模型。先前识别的23个基因转录本中的13个在训练数据集中得到验证，这些转录本对侵袭性前列腺癌患者进行分层。这些生物标记物加上Gleason评分被用来开发四个基因(CST2、FBLN1、TNFRSF19和ZNF704)转录本(4GT)评分，与未复发的患者相比，进展为转移性致命性疾病的患者显著更高。总体而言，这些研究表明，记录分数在预测哪些男性最初接受相对中度的疾病治疗后将继续患上转移性疾病方面发挥了作用。