Prostate Cancer Studies

在非洲加纳，我们对男性进行了一项基于人群的调查，以评估前列腺疾病的人群患病率（CAS ID:01130）。我们还收集了一系列被诊断患有前列腺癌的男性的临床资料。这种人口调查的动态流行病学设计结合了更大的病例系列，使我们能够评估非洲男性前列腺癌的负担，并评估与前列腺癌相关的危险因素，这是一个重要的和未充分研究的人群。在人口调查部分，从1038名健康男性中收集的生物样本将使我们能够建立非洲男性的营养、激素和基因概况。此外，将这1038名健康受试者的访谈数据与生物标志物联系起来，将有助于深入了解非洲男性西化是否与不良代谢特征（肥胖、腹部肥胖、较高水平的胰岛素、低密度脂蛋白和胰岛素样生长因子I）相关，这些代谢特征与前列腺癌风险过高有关。我们通过临床部分招募的额外677例前列腺癌病例使我们能够在这一独特人群中进行前列腺癌的全基因组关联研究（GWAS）（发表在《人类遗传学》上）。此外，我们对8q24区域进行了测序，发现了几个新的变异（发表在《前列腺》杂志上），并在非洲男性中对该区域进行了汇总精细定位研究（发表在《JNCI》杂志上），并在多种癌症类型中对chr5p15.33进行了代入和基于子集的荟萃分析（发表在《人类分子遗传学》杂志上）。我们还为多种族GWAS提供了数据，并确定了23个与前列腺癌相关的新基因（SNP）（发表在Nature Genetics）。我们最近进行了一项综合分析，以确定基因组中前列腺癌易感区域的候选功能snp（发表在《人类分子遗传学》上）。我们现在正在扩大GWAS的工作范围，纳入为本研究招募的其他病例和对照。我们还利用加纳前列腺研究的人口组成部分来评估抗疟疾基因的流行情况，以期揭示非洲伯基特淋巴瘤的遗传风险因素。在加纳前列腺研究中，我们通过对350个人群为基础的对照进行IFNL4变异基因分型，评估IFNL4是否在非洲男性中也很突出。我们也在评估这种变异是否可以使用现有的GWAS数据进行推算。在加纳前列腺研究中，我们正在评估IFNL4是否与前列腺癌诊断时的年龄和/或分期相关。我们目前也在评估这些非洲前列腺癌病例的前列腺癌组织中TMPRSS2-ERG融合的患病率（手稿正在起草中）。我们也开始分析本研究的问卷组成部分，以进一步阐明前列腺癌在这一新人群中的关联。我们在中国开展了一项多学科研究，在低危人群中评估前列腺癌的危险因素，以便更清楚地了解前列腺癌风险存在较大种族差异的原因（CAS ID:01140）。该研究收集了多种生物样本，主要目的是评估风险因素以及西化如何影响前列腺癌的风险。该研究还包括收集前列腺癌肿瘤的组织样本，以便对肿瘤进行精确分类，并对肿瘤生物标志物进行分析，在某些情况下使用新开发的组织微阵列技术。除了特定的饮食因素外，还将确定饮食模式，并将其与对照组进行比较，以评估中国的西式饮食是否与前列腺癌风险过高有关。该研究还评估了西化的生物学相关性，以寻找西化与前列腺癌过度风险之间的潜在生物学联系。基因型和循环激素水平的数据提供了一个独特的机会来研究血清激素和遗传变异之间的相互关系，以深入了解这些遗传标记的功能意义。在另一项针对中国15个城市前列腺癌的研究中，我们正在通过制定膳食异黄酮指数来评估大豆在前列腺癌中的作用。此外，包括前列腺、肺、结直肠和卵巢（PLCO）癌症筛查试验、SEER-Medicare数据库、总Medicare和临床实践研究数据链（CPRD）在内的几项大型队列嵌套病例对照研究，我们正在评估激素相关因素与前列腺癌后续风险和前列腺癌特异性死亡率的关系。目前正在进行一项方法学研究，以评估循环雄激素水平是否反映前列腺内雄激素性，这是前列腺激素致癌的一个关键问题。这项方法学研究收集了来自三个种族/民族的600名研究对象的空腹血液和速冻新鲜组织样本（超过3000份）。这项研究的数据将提供一个独特的机会来研究血清和组织激素以及参与雄激素代谢途径的基因变异之间的相互关系，为确定这些遗传标记的功能意义提供关键数据。组织样本的收集也将为基因表达研究提供一个独特的机会。这份手稿目前正在起草中。在继续研究与前列腺癌有关的激素紊乱这一主题时，我们还利用一个大型健康数据库来评估睾丸激素替代药物是否与前列腺癌风险相关（CAS ID: 10667）。为了在PLCO中进行更准确和详细的随访，以便进行前列腺复发分析和诊断后结果分析，我们目前正在延长随访时间，超过诊断后的第一年，以获取所有临床相关数据（CAS ID: 10515）。正在评估与组织免疫组化染色相关的生化复发。最后，我们使用来自AARP的数据来调查非甾体抗炎药的使用与随后的癌症风险的关系，包括前列腺癌（CAS ID: 10547），其手稿目前正在审查中。

In Ghana, Africa, we have conducted a population-based survey of men to assess the population prevalence of prostatic disease (CAS ID:01130). We have also collected consented into the study a clinical series of men diagnosed with prostate cancer. This dynamic epidemiologic design of a population survey combined with a larger case series, is enabling us to assess the burden of prostate cancer in African men as well as assess risk factors associated with prostate cancer in an important and understudied population. Biological samples collected from the 1,038 healthy men in the population survey component will allow us to establish the nutritional, hormonal, and genetic profiles of African men. In addition, linking interview data from these 1,038 healthy subjects with biomarkers will produce insights into whether westernization in African men is associated with an adverse metabolic profile (obesity; abdominal obesity; higher levels of insulin, low-density lipoprotein, and insulin-like growth factor I), which has been associated with excess prostate cancer risk. The additional 677 prostate cancer cases that we recruited through the clinical component has enabled us to conduct a genome wide association study (GWAS) of prostate cancer in this unique population (published in Human Genetics). In addition, we have sequenced the 8q24 region and identified several novel variants (published in Prostate) as well contributed to a pooled fine-mapping study of this region in African Men (published in JNCI) and an imputation and subset based meta-analysis of chr5p15.33 across multiple cancer types (published in Human Molecular Genetics). We have also contributed data to multi-racial GWAS and have identified 23 novel genetic (SNP) associations with prostate cancer (published in Nature Genetics). We have recently contributed to an integrative analysis to identify candidate functional SNPs at prostate cancer susceptibility regions of the geonome (published in Human Molecular Genetics). We are now extending this GWAS effort to include additional cases and controls that were recruited for this study. We are also using the population component of the Ghana Prostate Study to assess the prevalence of malaria-resistance genes with a view to uncovering the genetic risk factors of Burkitt lymphoma in Africa. We are assessing whether IFNL4 is also prominent in African men by genotyping the IFNL4 variant in 350 population-based controls in the Ghana Prostate Study. We are also assessing whether this variant can be imputed using the existing GWAS data. We are assessing whether IFNL4 is associated with age and/or stage at diagnosis of prostate cancer in the Ghana Prostate Study. We are also currently assessing the prevalence of TMPRSS2-ERG fusions in prostate cancer tissues of these African prostate cancer cases (manuscript being drafted). We have also begun analyses of questionnaire components of this study to further elucidate associations of prostate cancer in this novel population. We have conducted a multidisciplinary study in China to assess risk factors for prostate cancer in a low-risk population in order to understand more clearly the reasons for the large racial differences in prostate cancer risk (CAS ID:01140). That study involved the collection of multiple biologic samples, with a primary aim of assessing risk factors and how westernization influences the risk of prostate cancer. The study also involved the collection of tissue samples from prostate cancer tumors to permit precise tumor classification as well as assays of tumor biomarkers, in some cases using newly developed tissue microarray techniques. In addition to specific dietary factors, dietary patterns will be identified and compared with those of controls to evaluate whether a western-style diet in China is related to excess prostate cancer risk. The study is also assessing biological correlates of westernization to look for potential biological links between westernization and excess prostate cancer risk. Data on genotypes and circulating levels of hormones provide a unique opportunity to investigate the interrelationships between serum hormones and genetic variants to gain insights into the functional significance of these genetic markers. In another study of prostate cancer in 15 cities in China, we are assessing the role of soy in prostate cancer by developing a dietary isoflavone index. In addition, several nested case-control studies in large cohorts, including Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, the SEER-Medicare database, total Medicare, and Clinical Practice Research Datalink (CPRD) we are assessing the relationships of hormone-related factors with subsequent risks of prostate cancer and prostate cancer-specific mortality. A methodologic study is currently underway to evaluate whether circulating levels of androgens reflect intraprostatic androgenicity, a key issue in hormonal carcinogenesis of the prostate (CAS ID:01072). This methodologic study has collected samples of fasting blood and snap-frozen fresh tissue (over 3,000 pieces) from 600 study subjects in three racial/ethnic groups. Data from this study will provide a unique opportunity to investigate the interrelationships among serum and tissue hormones and variants in genes involved in the androgen metabolism pathways to provide critical data for determining the functional significance of these genetic markers. The collection of tissue samples also will provide a unique opportunity for gene expression studies. This manuscript is currently being drafted.In continuing the theme of hormonal perturbations in relation to prostate cancer, we are also using a large health database to assess whether testosterone replacement medications are associated with prostate cancer risk (CAS ID: 10667). For more accurate and detailed follow up in PLCO to enable prostate recurrence analyses and analyses of outcomes post-diagnosis in this resource, we are currently extending the follow-up time beyond the first year post-diagnosis to capture all clinically relevant data (CAS ID: 10515). Biochemical recurrence is being assessed in relation to tissue IHC stains.Lastly, we are using data from AARP to investigate the association of NSAID use and subsequent risk of cancer, including prostate cancer (CAS ID: 10547), the manuscript of which is currently under review.