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 尽管非洲血统的男性患有前列腺癌（PCA）的风险很高，但很少发现基因或突变会导致该人群中PCA的家族性聚类。这项合作调查了非洲祖先特异性的PCA风险变体在8q24，Rs72725854 rs72725854是否在9052例患有PCA家族史的男性中富含9052案例的男性，143例高风险家庭和8595个非洲祖先的控制权。我们发现，风险等位基因与诊断时更早的年龄，更具侵略性疾病的年龄显着相关，并且在具有PCA家族史的男性中富含（Darst等，2020）。在非洲血统的男性中，相关变体占所有已知PCA风险变异的总家族风险的32％，这表明非洲裔美国男性将从有关前列腺癌筛查和这种变体的指导中受益。 前列腺癌风险和预测 在这种合作中，研究了DNA甲基化在表达定量轨迹基因座（EQTL）调节中的作用（Dai等，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).这项研究为已知的PCA风险SNP提供了全面的EQTL，MEQTL和假定的癌症基因目录。我们观察到，尽管肿瘤基因组发生了体细胞改变，但尽管肿瘤的发展仍在肿瘤发育中保持了很大一部分的种系EQTL调节机制。最后，我们的分析阐明了CpG甲基化在基因表达的EQTL调节中的可能中介作用。 在另一次合作（Schaid等，2020）中，我们试图了解家族史和更具侵略性的PCA的作用。 使用了两阶段的设计。在第一阶段，使用全外观测序来确定患有疾病家族史或更具侵略性疾病（491例和429例对照）的受影响男性的潜在风险等位基因。侵略性疾病基于格里森评分，节点状态，转移，肿瘤阶段，前列腺特异性抗原的分数，诊断，全身复发和PCA死亡时间。在第二阶段中鉴定出的基因在第二阶段使用定制捕获设计在2917个病例和1899年对照组中进行了筛选。比较病例和对照之间的遗传变异频率。 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和THAP3）。这种方法证明了基因测序在寻找与PCA相关的遗传变异方面的优势以及对具有疾病家族史或侵略性疾病家族史的患者进行采样的好处。 转移性致命前列腺癌 众所周知，除了格里森评分外，很少有因素准确地确定前列腺癌（PCA）患者的子集高风险转移性进展（Wang等，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变化（CNA）是否可以鉴定出具有转移性进展潜力的原发性前列腺肿瘤。研究表明，在肿瘤数据中可以可靠地检测到CNA。有11个复发性的CNA显示了从根治性前列腺切除术后转移性致命事件的关联，从而改善了格里森评分的预测。受这些CNA影响的基因在功能上可能与肿瘤侵袭性和转移性进展有关。 是否可以使用四个基因转录物评分来预测原始疾病治疗的男性的转移性致命进展（Cheng等，2019）。基于先前发表的23个基因转录本的小组，该小组以转移性进展的患者区分出来，该协作使用独立的培训和测试数据集构建了一个预测模型。在训练数据集中验证了23个先前鉴定出对侵袭性PCA患者进行分层患者的基因转录本中的13个。这些生物标志物加上格里森评分用于开发四基因（CST2，FBLN1，TNFRSF19和ZNF704）转录本（4GT）评分，该评分与没有复发的患者相比，该患者在转移性致命疾病的患者中的较高。总体而言，这些研究表明了转录本评分在预测哪些最初接受相对中度疾病治疗的男性中的作用，将继续患上转移性疾病。