Prostate Cancer Studies

前列腺癌研究

• 批准号: 9154201
• 负责人: Michael Cook
• 金额: $ 60.17万
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 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/9154201
• 关键词: 8q24; Africa; African; Age; American; American Cancer Society; Amino Acids; Androgen Metabolism; Androgens; Biochemical; Biological; Biological Assay; Biological Markers; Blood; Burkitt Lymphoma; Cancer Etiology; Cancer Prevention Study II; Case Series; Central obesity; China; Chronic; Cities; Classification; Clinical; Collection; Colorectal; Consent; Data; Databases; Diagnosis; Diet; Dietary Factors; Dietary Practices; Epidemiology; Ethnic group; Fasting; Freezing; Fresh Tissue; Future; Gene Expression; Genes; Genetic; Genetic Markers; Genotype; Ghana; Glycine; Health; Hormonal; Hormonal Carcinogenesis; Hormones; Human; Human Genetics; Inflammation; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Interview; Investigation; Ions; Isoflavones; Journals; Life Style; Link; Low-Density Lipoproteins; Lung; Malaria; Malignant neoplasm of prostate; Manuscripts; Measures; Meta-Analysis; Metabolic; Molecular; Molecular Genetics; Nature; Nested Case-Control Study; Non-Steroidal Anti-Inflammatory Agents; Nutritional; Obesity; Outcome; Ovarian; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Predisposition; Prevalence; Prostate; Prostate Cancer Prevention Trial; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; Prostatic Diseases; Publishing; Questionnaires; Recruitment Activity; Recurrence; Research Personnel; Resources; Risk; Risk Factors; Role; Sampling; Sarcosine; Series; Serum; Stage at Diagnosis; Staining method; Stains; Study Subject; Surveys; TMPRSS2 gene; Techniques; Testosterone; Time; Tissue Microarray; Tissue Sample; Tissues; Urine; Variant; base; cancer risk; cancer type; case control; clinically relevant; cohort; design; follow-up; genetic profiling; genetic risk factor; genetic variant; genome wide association study; indexing; insight; men; multidisciplinary; novel; nutrition; population based; population survey; predictive marker; racial and ethnic; racial difference; resistance gene; soy; tumor

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 recent effort of 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 analyssi 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 will soon begin 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, and the Prostate Cancer Prevention Trial (PCPT), and the American Cancer Society Nutrition Cohort (CPS-II), we are assessing the relationships of obesity, dietary patterns, insulin resistance, and chronic inflammation with subsequent risk of prostate cancer. Together, these cohorts provide over 3,000 prostate cancer cases for the investigation of prostate cancer etiology. They are unique in having collected pre-morbid blood and multiple biologic samples over time, permitting an assessment of how hormone and other biomarker levels change as patients approach diagnosis. 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). Sarcosine (a methylated derivative of the amino acid glycine) measured ion the urine has been shown to be a correlate of sarcosine levels in tissue. Combined with putative evidence that sarcosine may be a predictive marker of future prostate cancer risk, we are assessing such using both the PLCO Trial as well as the ATBC Diet and Health Study (CAS ID: 10603). 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.We are collaborating with investigators from the American Cancer Society (ACS) to investigate the role of insulin resistance and chronic inflammation in prostate cancer in a nested case-control study of 1,209 prostate cancer cases and an equal number of controls selected from the ACSs Cancer Prevention Study (CPS)-II LifeLink Cohort (CAS ID: 10028) (publciations in American Journal of Epidemilogy and JNCI). 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.

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并同意参与这项研究。这种人口调查的动态流行病学设计与更大的病例系列相结合，使我们能够评估非洲男性前列腺癌的负担，并评估重要且未充分研究的人群中与前列腺癌相关的危险因素。在人口调查部分，从 1,038 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、荷尔蒙和遗传特征。此外，将这 1,038 名健康受试者的访谈数据与生物标志物联系起来，将深入了解非洲男性的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）相关。因子 I），它与前列腺癌风险过高有关。我们通过临床部分招募的另外 677 例前列腺癌病例使我们能够针对这一独特人群进行前列腺癌全基因组关联研究 (GWAS)（发表在《人类遗传学》上）。此外，我们对 8q24 区域进行了测序，并鉴定了几种新的变异（发表在《Prostate》上），也有助于最近针对多种癌症类型对 chr5p15.33 进行插补和基于子集的荟萃分析（发表在《Human Molecular Genetics》上）。我们还为多种族 GWAS 提供了数据，并确定了 23 个与前列腺癌新的遗传 (SNP) 关联（发表在 Nature Genetics 上）。我们最近进行了一项综合分析，以确定基因组前列腺癌易感区域的候选功能性 SNP（发表于《人类分子遗传学》）。我们现在正在扩展 GWAS 工作，以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部分来评估抗疟基因的流行率，以期揭示非洲伯基特淋巴瘤的遗传风险因素。我们正在加纳前列腺研究中通过对 350 名基于人群的对照组的 IFNL4 变异进行基因分型来评估 IFNL4 是否在非洲男性中也很突出。我们还在评估是否可以使用现有的 GWAS 数据来估算该变异。我们正在加纳前列腺研究中评估 IFNL4 是否与前列腺癌诊断时的年龄和/或分期相关。我们目前还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）。我们很快将开始分析本研究的问卷组成部分，以进一步阐明这一新人群中前列腺癌的关联。我们在中国进行了一项多学科研究，评估低危人群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巨大种族差异的原因（CAS ID：01140）。该研究收集了多个生物样本，主要目的是评估危险因素以及西方化如何影响前列腺癌的风险。该研究还涉及从前列腺癌肿瘤中收集组织样本，以实现精确的肿瘤分类以及肿瘤生物标志物的测定，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。该研究还评估了西方化的生物学相关性，以寻找西方化与前列腺癌风险过高之间的潜在生物学联系。有关激素基因型和循环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 个城市的前列腺癌研究中，我们通过制定饮食异黄酮指数来评估大豆在前列腺癌中的作用。此外，大型队列中的几项巢式病例对照研究，包括前列腺癌、肺癌、结直肠癌和卵巢癌 (PLCO) 癌症筛查试验、前列腺癌预防试验 (PCPT) 以及美国癌症协会营养队列 (CPS-II) ），我们正在评估肥胖、饮食模式、胰岛素抵抗和慢性炎症与前列腺癌风险的关系。这些队列总共提供了 3,000 多个前列腺癌病例，用于前列腺癌病因学的研究。他们的独特之处在于随着时间的推移收集了病前血液和多个生物样本，从而可以评估随着患者接近诊断而激素和其他生物标志物水平如何变化。目前正在进行一项方法学研究，以评估雄激素的循环水平是否反映前列腺内雄激素性，这是前列腺激素致癌的关键问题 (CAS ID:01072)。这项方法学研究从三个种族/民族的 600 名研究对象中收集了空腹血液和速冻新鲜组织样本（超过 3,000 份）。这项研究的数据将为研究血清和组织激素之间的相互关系以及参与雄激素代谢途径的基因变异提供一个独特的机会，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独特的机会。该手稿目前正在起草中。在继续与前列腺癌相关的激素扰动这一主题的同时，我们还使用大型健康数据库来评估睾酮替代药物是否与前列腺癌风险相关（CAS ID：10667）。尿液中测量的肌氨酸（氨基酸甘氨酸的甲基化衍生物）已被证明与组织中的肌氨酸水平相关。结合肌氨酸可能是未来前列腺癌风险的预测标志物的推定证据，我们正在使用 PLCO 试验以及 ATBC 饮食和健康研究 (CAS ID: 10603) 进行评估。为了在 PLCO 中进行更准确和详细的随访，以便能够在此资源中进行前列腺复发分析和诊断后结果分析，我们目前正在将随访时间延长到诊断后第一年之后，以捕获所有临床相关数据 (CAS ID) ：10515）。正在评估与组织 IHC 染色相关的生化复发情况。我们正在与美国癌症协会 (ACS) 的研究人员合作，通过一项针对 1,209 例前列腺癌病例的巢式病例对照研究，研究胰岛素抵抗和慢性炎症在前列腺癌中的作用以及从 ACS 癌症预防研究 (CPS)-II LifeLink 队列 (CAS ID: 10028)（发表于美国流行病学杂志和国家癌症研究所）。最后，我们正在使用 AARP 的数据来调查 NSAID 使用与后续癌症风险的关联，包括前列腺癌 (CAS ID: 10547)，其手稿目前正在审查中。