Maryland Prostate Cancer Case-Control Study

我们的研究分两个阶段进行。第一阶段于2005年4月开始，是一项评价征聘程序的试验性研究。这一阶段是成功的，2006年4月开始了全面的研究，对方案进行了轻微的修改。完整的研究于2015年完成[976例（489例非洲裔美国人和487例欧洲裔美国人）和1034例基于人群的对照（486例非洲裔美国人和548例欧洲裔美国人）]。我们收集了135例前列腺切除术患者的血液和尿液以及石蜡包埋和新鲜冷冻组织标本。病例来自巴尔的摩的两家医院，退伍军人事务医疗中心和马里兰大学医疗中心。病例经病理证实为前列腺癌。他们在招募前的最后两年内被诊断出患有前列腺癌，并且在疾病的各个阶段都表现出前列腺癌。晚期138例（T3 79例，T4 59例）。根据患者的TNM分期、Gleason评分、Gleason模式和诊断时的PSA水平，根据2.2021版前列腺癌指南，将病例分配到国家综合癌症网络风险组。根据他们的疾病发展为致命前列腺癌的可能性，他们被分为低、中、高和非常高的风险。最后，我们从病例的国家死亡指数记录中获得了总体生存和疾病特异性生存的最新信息。最近的最新数据显示，死于各种原因的人数达到247人，其中66人被报告为前列腺癌特有的死亡。该队列的中位生存随访时间现在为8.4年。我们将继续为病例和对照收集这一信息。最近，我们从对照组中确定了888名男性的PSA值。其中16例在入组时PSA为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例欧洲裔美国人），当他们在疾病诊断后一年内被纳入研究时，从诊断到纳入研究的平均间隔为4.8个月（非裔美国人4.4个月，欧洲裔美国人5.2个月）。以人群为基础的对照是通过马里兰州机动车辆管理局的数据库确定的，并根据年龄和种族与病例进行频率匹配。这项研究包括对所有研究对象进行调查和收集血液和尿液。肿瘤标本取自前列腺切除术后可用的癌症患者。我们的调查评估了烟草使用、药物使用、职业史、饮食、医疗和性史、家族癌症史和社会经济地位。目前这项研究的活动包括从病理和医疗记录中收集额外的数据，以获得所有病例的临床病理和疾病复发信息。我们继续对研究参与者进行特征描述，并与Kittles实验室（City of Hope）合作进行血统分型。使用105个祖先信息标记对参与者的西非、欧洲和美洲原住民血统进行评估。基因分型数据显示，自认为是非洲裔美国人的参与者在病例中平均有75.5%的西非血统，在对照组中有72.1%，而自认为是欧洲裔美国人的参与者在病例中平均有85.8%的欧洲血统，在对照组中有89.9%的欧洲血统。对于一部分（83%）的病例和对照，我们使用Infinium HumanOmni5-Quad BeadChip阵列获得了额外的西非血统估计（706例病例和744例对照的基因分型数据提交给dbGaP）。使用这两种方法估计的西非祖先非常相似（r=0.98）。2021年，我们完成了一项将邻里贫困指标与研究参与者联系起来的多年努力。邻里剥夺指数是根据梅塞尔等人的指导方针生成的。我们的指数包含以下变量：贫困家庭百分比、有受抚养子女的女性户主家庭百分比、依靠公共援助的家庭百分比、年收入低于3万美元的家庭百分比、无车家庭百分比、男性和女性失业百分比。我们的研究旨在确定非洲裔美国人和欧洲裔美国人在危险因素暴露和肿瘤生物学方面的差异。分子工作将用于检查肿瘤生物学中的种族/民族差异。我们的研究还旨在确定促进侵袭性疾病发展的环境和遗传因素（例如，感染和免疫反应，吸烟暴露，祖先相关因素，低外显率易感性位点），特别是导致非洲裔美国人和欧洲裔美国人之间的生存差异。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，因为我们之前观察到非裔美国患者的肿瘤包含一个突出的免疫炎症基因特征。此外，我们一直在研究吸烟在转移性前列腺癌发展中的作用，通过对人类肿瘤的分析，使用细胞系和转移性前列腺癌的小鼠模型。该项目的数据表明，潜在的分子机制-肿瘤相关的免疫炎症基因标记-可能是吸烟者和非洲裔男性之间共同的风险因素，并促进疾病进展（PMID: 26719530）。我们还调查了经常服用阿司匹林和前列腺癌之间的联系。服用阿司匹林已被证明可以预防几种癌症，但对结肠癌最有效。主要针对欧洲或欧美男性的调查发现，服用阿司匹林可降低前列腺癌发生和发展的风险；然而，不同研究的结果是不同的，阿司匹林降低风险的效果一般是温和的。相比之下，我们的研究表明阿司匹林的使用显著降低了非裔美国男性患侵袭性前列腺癌的风险（PMID: 28292923）。此外，定期服用阿司匹林减少了这些男性的疾病复发。我们没有发现阿司匹林对欧美男性有同样强的保护作用。因此，在前列腺癌诊断前后定期服用阿司匹林可能会减少非裔美国男性罹患致命恶性肿瘤的风险。这一发现得到了南方社区队列研究（SCCS）分析的证实。SCCS是一项大型前瞻性研究，旨在调查癌症健康差异的原因。在本研究中，我们发现在基线时定期使用阿司匹林可以预防非裔美国男性SCCS患者的前列腺癌死亡率（PMID:33293340）。我们认为这些都是重要的观察结果，表明定期服用阿司匹林可以预防致命的前列腺癌。最近，我们研究了非洲裔男性是否拥有独特的系统性免疫肿瘤学特征，并测量了来自nci -马里兰州和nci -加纳研究的近3000名加纳人、非裔美国人和欧裔美国人的82种循环蛋白。抑制肿瘤免疫和趋化性的蛋白质特征在西非血统的男性中升高。重要的是抑制肿瘤免疫蛋白信号*TRUNCATED*

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*