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前列腺癌 (PCa) 的风险很高，但已发现很少有基因或突变导致该人群中 PCa 家族聚集。这项合作调查了 8q24 rs72725854 的非洲血统特异性 PCa 风险变异是否在 9052 例有 PCa 家族史的男性、来自高风险家庭的 143 例以及 8595 名非洲血统对照患者中富集。我们发现风险等位基因与早期诊断年龄、更具侵袭性的疾病显着相关，并且在有 PCa 家族史的男性中丰富（Darst 等人，2020）。在非洲血统的男性中，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%，这表明非裔美国男性将受益于有关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 甲基化在表达定量轨迹基因座 (eQTL) 调控中的作用 (Dai et al., 2020)。具体来说，这项合作鉴定并比较了原发性前列腺肿瘤中 147 个已确定的 PrCa 风险 SNP 中的 eQTL 和 CpG 甲基化数量性状位点 (meQTL)（n = 355 来自西雅图的研究，n = 495 来自癌症基因组图谱 (TCGA)），肿瘤邻近、组织学良性样本（n = 471，来自 Mayo Clinic 研究）。该研究提供了已知 PCa 风险 SNP 的 eQTL、meQTL 和推定癌症基因的综合目录。我们观察到，尽管肿瘤基因组发生了体细胞改变，但生殖系 eQTL 调控机制的很大一部分在肿瘤发展过程中得以维持。最后，我们的分析阐明了 CpG 甲基化在 eQTL 基因表达调控中可能的中介作用。 在一项单独的合作中（Schaid 等人，2020），我们试图了解家族史和更具侵袭性的 PCa 的作用。 使用了两阶段设计。在第一阶段，全外显子组测序用于识别具有强烈疾病家族史或患有更具侵袭性疾病的受影响男性（491 例病例和 429 例对照）中的潜在风险等位基因。侵袭性疾病基于格里森评分、淋巴结状态、转移、肿瘤分期、诊断时前列腺特异性抗原、全身复发和前列腺癌死亡时间的评分总和。在第一阶段确定的基因在第二阶段使用定制捕获设计在一组独立的 2917 个病例和 1899 个对照中进行筛选。比较病例和对照之间的遗传变异频率。检测到 11 个先前报道与 PCa 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, RNA酶H2B, 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，以及对具有强烈疾病家族史或侵袭性疾病的患者进行采样的好处。 转移性致死性前列腺癌 众所周知，除了格里森评分之外，很少有因素能够准确识别转移进展高风险的前列腺癌 (PCa) 患者亚群 (Wang et al., 2020)。在这次合作中，我们测试了使用 CpG 甲基化探针评估的拷贝数改变 (CNA) 是否可以识别具有发生转移进展潜力的原发性前列腺肿瘤。研究表明，CNA 可以在肿瘤数据中可靠地检测到。有 11 个复发性 CNA 显示与根治性前列腺切除术后的转移致死事件相关，从而改善了对格里森评分的预测。受这些 CNAs 影响的基因可能在功能上与肿瘤侵袭性和转移进展相关。 另一项合作研究了四基因转录评分是否可用于预测最初接受局部疾病治疗的男性的转移致死进展（Cheng 等人，2019）。基于之前发布的区分转移进展患者的 23 个基因转录本组，该合作使用独立的训练和测试数据集构建了一个预测模型。先前确定的 23 个对侵袭性 PCa 患者进行分层的基因转录本中有 13 个在训练数据集中得到了验证。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，与未复发的患者相比，进展为转移性致死性疾病的患者显着更高。总的来说，这些研究表明转录评分在预测哪些男性最初接受相对中等疾病治疗后将继续患上转移性疾病方面发挥着重要作用。