Maryland Prostate Cancer Case-Control Study

马里兰州前列腺癌病例对照研究

• 批准号: 10702364
• 负责人: Stefan Ambs
• 金额: $ 68.51万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/10702364
• 关键词: Affect; African; African American; African American population; African ancestry; Age; American; Amphotericin B; Area; Aspirin; Award; Baltimore; Biological; Blood; Cancer Etiology; Cancer Patient; Case/Control Studies; Cell Line; Cessation of life; Chemotaxis; Child; Chronic; Cities; Cohort Studies; Collaborations; Collection; Colon Carcinoma; Communities; Control Groups; DNA Methylation; Data; Databases; Development; Diabetes Mellitus; Diagnosis; Diet; Dietary Factors; Disease; Disease Marker; Disease Outcome; Disease Progression; Enrollment; Environmental Risk Factor; European; Female; Freezing; Frequencies; Gene Expression; Genotype; Ghana; Gleason Grade for Prostate Cancer; Goals; Guidelines; Hereditary Malignant Neoplasm; Hospitals; Household; Human; Immune; Immune response; Individual; Infection; Inflammation; Investigation; Laboratories; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Maryland; Measures; Medical; Medical History; Medical Records; Medical center; Metastatic Prostate Cancer; Minor; Molecular; Molecular Profiling; Motor Vehicles; Mutation Spectra; National Comprehensive Cancer Network; Native American Ancestry; Neighborhoods; Nigerian; Occupational; Operative Surgical Procedures; Outcome; PSA level; Paraffin Embedding; Participant; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Penetrance; Pharmaceutical Preparations; Phase; Pilot Projects; Poverty; Procedures; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Proteins; Protocols documentation; Public Assistance; Race; Recording of previous events; Records; Recurrence; Reporting; Research; Risk; Risk Factors; Risk Reduction; Role; Secure; Sexually Transmitted Diseases; Smoker; Socioeconomic Status; Specimen; Study Subject; Surveys; Susceptibility Gene; TNM; Time; Tissue Sample; Tissues; Tobacco use; Tumor Biology; Tumor Immunity; Tumor Markers; Tumor Suppression; Unemployment; United States Department of Veterans Affairs; Universities; Update; Urine; Virus Diseases; Work; advanced disease; base; bead chip; cancer diagnosis; cancer health disparity; case control; cigarette smoking; cohort; cooking; database of Genotypes and Phenotypes; deprivation; design; disease diagnosis; disorder risk; ethnic difference; follow-up; gene environment interaction; genetic risk factor; genetic signature; genetic variant; high risk; indexing; inflammatory marker; male; men; metabolome; mortality; mouse model; population based; precision medicine; prostate cancer risk; protective effect; recruit; risk sharing; smoking exposure; survival disparity; systemic inflammatory response; tumor

Our study was implemented in two phases. The first phase, which started in April of 2005, constituted a pilot study to evaluate recruitment procedures. This phase was successful, and the full study was initiated with minor changes to the protocol in April of 2006. The full study was completed in 2015 [976 cases (489 African American and 487 European American) and 1034 population-based controls (486 African American and 548 European American)]. We collected blood and urine from all individuals and paraffin-embedded and fresh-frozen tissue specimens form 135 prostatectomy surgeries. Cases are from two Baltimore hospitals, the Veterans Affairs Medical Center and the University of Maryland Medical Center. Cases have pathologically confirmed prostate cancer. They had a disease diagnosis within the last two years prior to recruitment and presented with prostate cancer at all stages of the disease. One-hundred and thirty-eight cases had advanced stage disease (n = 79 with T3 and n = 59 with T4 disease). Cases were also assigned to National Comprehensive Cancer Network risk groups, based on the patients' TNM stage, Gleason score, Gleason pattern, and PSA level at diagnosis according to the guidelines, for prostate cancer, version 2.2021. They were classified into low, intermediate, high, and very high risk based on the likelihood of their disease to progress to lethal prostate cancer. Lastly, we have secured current information on overall and disease-specific survival from National Death Index records for the cases. The most recent update brought the number to 247 deaths from all causes with 66 of them being reported as a prostate cancer-specific mortality. The median survival follow-up time for the cohort is now 8.4 years. We will continue to collect this information for both cases and controls. More recently, we were able to determine PSA values at recruitment for 888 men from the control group. Sixteen of them had PSA 4 at time of recruitment ( 2%). Furthermore, we defined 823 patients as incident cases (422 African American, 401 European American) when they were recruited into the study within one year after the disease diagnosis, having an average interval between diagnosis and enrollment into our study of 4.8 months (4.4 months for African American and 5.2 months for European-American men). The population-based controls were identified through the Maryland Department of Motor Vehicles database and were frequency-matched by age and race to cases. The study involved the administration of a survey and collection of blood and urine from all study subjects. Tumor specimens were obtained from cancer patients if they were available after prostatectomy. Our survey evaluates tobacco use, medication use, occupational history, diet, medical and sexual history, familial cancer history, and socioeconomic status. Current activities in this study include the collection of additional data from pathology and medical records to have clinicopathology for all cases and information on disease recurrence as available. We continue to characterize the study participants and performed ancestry-typing in collaboration with the Kittles laboratory (City of Hope). Participants were evaluated for their West African, European, and Native American ancestry using 105 ancestry informative markers. The genotyping data showed that self-identified African American participants have an average West African ancestry of 75.5% among cases and 72.1% among controls whereas the European ancestry in the self-identified European American participants ranged from an average 85.8% among cases to 89.9% among the controls. For a subset (83%) of the cases and controls, we obtained additional West African ancestry estimates using the Infinium HumanOmni5-Quad BeadChip array (genotyping data for 706 cases and 744 controls were submitted to dbGaP). West African ancestry estimates using the two approaches were highly similar (r=0.98). In 2021, we completed a multi-year effort to link neighborhood measures of poverty to participants in our studies. A neighborhood deprivation index was generated following the guidelines by Messer at al. Our index contains the following variables: percent (%) households in poverty, % female headed households with dependent children, % households on public assistance, % households earning under $30,000/year, % households with no car, and % males and females unemployed. Our study is aimed at identifying differences in risk factor exposure and tumor biology between African American and European American men. Molecular work will be used to examine race/ethnic differences in tumor biology. Our research is also aimed at identifying environmental and inherited factors (e.g., infections and immune response, smoking exposure, ancestry-related factors, low penetrance susceptibility loci) that promote the development of an aggressive disease and specifically contribute to the survival disparity between African American and European American men. A major research focus is the role of tumor and systemic inflammation in disease progression because of our previous observation that tumors of African American patients contain a prominent immune-inflammation gene signature. Additionally, we have been examining the role of cigarette smoking in the development of metastatic prostate cancer with the analysis of human tumors and the use of cell lines and a mouse model of metastatic prostate cancer. Data from this project suggest that the underlying molecular mechanism - a tumor-associated immune-inflammation gene signature - could be a shared risk factor among smokers and men of African descent and promotes disease progression (PMID: 26719530). We also investigated the link between regular use of aspirin and prostate cancer. Aspirin use has been shown to protect against several cancers but most effectively against colon cancer. Investigations of mainly European or European-American men observed that aspirin use decreases the risk of prostate cancer development and progression; however, the findings across studies were heterogeneous, and the risk reduction by aspirin was generally modest. In contrast, our study shows that aspirin use significantly reduces the risk of aggressive prostate cancer in African American men (PMID: 28292923). Moreover, regular aspirin use reduced disease recurrence in these men. We did not find the same strong protective effects of aspirin among the European American men. Thus, regular aspirin use before and after a prostate cancer diagnosis may reduce the development of an aggressive disease in African American men who are at high risk of a lethal malignancy. This finding has been corroborated with an analysis of the Southern Community Cohort Study (SCCS), a large prospective study to investigate the causes of cancer health disparities. Here, we found that regular aspirin use at baseline protects against a prostate cancer mortality on follow-up among the African American men in SCCS (PMID:33293340). We think these are significant observations, indicating that regular aspirin use protects against lethal prostate cancer. More recently, we studied if men of African descent harbor a unique systemic immune-oncological signature and measured 82 circulating proteins in almost 3000 Ghanaian, African American, and European American men from the NCI-Maryland and NCI-Ghana studies. Protein signatures for suppression of tumor immunity and chemotaxis were elevated in men of West African ancestry. Importantly, the suppression of tumor immunity protein signa *TRUNCATED*

我们的研究分为两个阶段。第一阶段始于2005年4月，构成了一项试点研究，以评估招聘程序。这一阶段是成功的，整个研究是在2006年4月开始对该方案进行了微小变化的。整个研究于2015年完成[976例（489例非裔美国人和487个欧洲裔美国人）和1034个基于人口的对照组（486名非裔美国人和548欧洲裔美国人）]。我们从所有个体和石蜡包裹和新鲜的组织标本中收集血液和尿液，形成135个前列腺切除术。病例来自两家巴尔的摩医院，退伍军人事务医学中心和马里兰大学医学中心。病例有病理确认的前列腺癌。他们在招募前的最后两年内进行了疾病诊断，并在该疾病的各个阶段出现了前列腺癌。一百三十八例患有晚期疾病（n = 79，T3和n = 59带有T4疾病）。 还根据患者的TNM阶段，格里森评分，格里森（Gleason）的模式和PSA水平，根据《前列腺癌》（Prostate Cancer）（2.2021版）将病例分配给国家综合癌症网络风险组。基于其疾病的可能性发展为致命的前列腺癌的可能性，它们被归类为低，中间，高且非常高的风险。最后，我们从国家死亡指数记录中获得了有关总体和疾病特定生存的当前信息。最近的最新消息使所有原因的死亡人数为247人死亡，其中66个被报告为前列腺癌特异性死亡率。该队列的中位生存随访时间现在为8。4年。我们将继续为案例和控件收集此信息。最近，我们能够确定来自对照组的888名男性募集时的PSA值。他们中有16人在招募时有PSA 4（2％）。此外，我们将823例患者定义为事件病例（422例非裔美国人，401欧洲人），当时他们在疾病诊断后的一年内被招募到研究中，在诊断和入学率之间的平均间隔为4.8个月（非裔美国人为4.4个月，欧洲美洲男性为5.2个月）。基于人群的控制是通过马里兰州机动车数据库确定的，并按年龄和竞赛匹配。该研究涉及对所有研究对象的血液和尿液进行调查和收集。如果前列腺切除术后可用，则从癌症患者那里获得肿瘤标本。我们的调查评估了烟草使用，用药，职业史，饮食，医学和性史，家族癌症史和社会经济状况。这项研究中的当前活动包括收集病理学和病历的其他数据，以使所有病例都有临床病理学以及有关疾病复发的信息。我们继续描述研究参与者，并与小猫实验室（希望之城）合作进行了祖先类型。使用105个祖先信息标记，对参与者的西非，欧洲和美国原住民血统进行了评估。基因分型数据表明，自我认同的非洲裔美国参与者的平均西非血统为75.5％，在对照组中，欧洲的欧洲欧洲人的欧洲祖先在对照组中的平均水平为75.5％，在对照组中，欧洲美国参与者的平均范围从85.8％到89.9％。对于案例和对照组的子集（83％），我们使用Infinium humanomni5-Quad Beadchip阵列获得了其他西非血统估计（706例基因分型数据，并将744例对照提交给DBGAP）。使用两种方法的西非血统估计高度相似（r = 0.98）。在2021年，我们完成了多年的努力，将贫困的邻里衡量标准与我们的研究参与者联系起来。根据梅塞尔（Messer）在Al的指南中生成了一个社区剥夺指数。我们的指数包含以下变量：贫困百分比（百分比）家庭，女性头为抚养子女，百分比公共援助家庭的百分比家庭，百分比赚取30,000美元/年的家庭，没有汽车的百分比家庭以及男性和女性的百分比失业。我们的研究旨在确定非洲裔美国和欧美男人之间危险因素暴露和肿瘤生物学的差异。分子工作将用于检查肿瘤生物学的种族/种族差异。 我们的研究还旨在鉴定环境和遗传因素（例如，感染和免疫反应，吸烟，与祖先相关的因素，较低的渗透率易感性基因座），这些因素促进了侵略性疾病的发展，并特别有助于非裔美国人和欧洲男性之间的生存差异。一个主要的研究重点是肿瘤和全身性炎症在疾病进展中的作用，因为我们先前的观察到非裔美国人患者的肿瘤包含明显的免疫炎症基因特征。此外，通过分析人类肿瘤和使用细胞系和转移性前列腺癌的小鼠模型，我们一直在研究吸烟在转移性前列腺癌发展中的作用。该项目的数据表明，潜在的分子机制（一种与肿瘤相关的免疫 - 炎症基因信号）可能是非洲血统和促进疾病进展的吸烟者和男性的共同危险因素（PMID：26719530）。我们还研究了定期使用阿司匹林和前列腺癌之间的联系。已证明使用阿司匹林可以预防几种癌症，但最有效地免受结肠癌的影响。对主要是欧洲或欧美男性的调查观察到，阿司匹林使用降低了前列腺癌发展和进展的风险。但是，整个研究的发现是异质的，阿司匹林的风险降低通常是适度的。相比之下，我们的研究表明，阿司匹林使用大大降低了非洲裔美国男性侵略性前列腺癌的风险（PMID：28292923）。此外，普通阿司匹林在这些男性中使用疾病复发减少。 我们在欧美男人中没有发现阿司匹林的强大保护作用。 因此，前列腺癌诊断前后的定期使用阿司匹林可能会减少具有致命恶性肿瘤风险的非洲裔美国男性的侵略性疾病的发展。通过对南方社区队列研究（SCC）的分析，这一发现得到了证实，这是一项大量的前瞻性研究，以调查癌症健康差异的原因。在这里，我们发现基线的定期使用阿司匹林可预防SCC中非洲裔美国男性随访的前列腺癌死亡率（PMID：33293340）。我们认为这些是重要的观察结果，表明定期使用阿司匹林可以预防致命的前列腺癌。最近，我们研究了非洲血统的男性是否具有独特的系统性免疫综合签名，并在NCI-Maryland和NCI-Ghana研究的近3000名加纳，非裔美国人和欧美男人中测量了82个循环蛋白质。西非血统的男性，抑制肿瘤免疫和趋化性的蛋白质特征升高。重要的是，抑制肿瘤免疫蛋白信号 *截短 *