Hormone-Related Cancers

激素相关癌症

• 批准号: 10007405
• 负责人: Gretchen Gierach
• 金额: $ 842.13万
• 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/10007405
• 关键词: Address; African American; Androgens; Area; Atypical hyperplasia; Biological; Biological Assay; Breast Cancer Risk Factor; Case-Control Studies; Catechols; Caucasians; Characteristics; Clinical; Collaborations; Cryptorchidism; Data; Development; Diagnosis; Disease; Endometrial Carcinoma; Endometrial Hyperplasia; Epidemiology; Estradiol; Estrogen receptor negative; Estrogens; Etiology; Exhibits; Female Genital Neoplasms; Finland; GTP-Binding Protein alpha Subunits, Gs; Genetic; Gestational Diabetes; Ghana; Glucuronides; Gynecologic Oncology Group; Health Maintenance Organizations; Heterogeneity; High Prevalence; Histologic; Hormonal; Hormones; Hydroxylation; Hypospadias; Impairment; Incidence; Individual; Inguinal Hernia; Investigation; Israel; Knowledge; Laboratories; Link; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of esophagus; Malignant neoplasm of male breast; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Malignant neoplasm of testis; Mammographic Density; Mammography; Measures; Medical Records; Menopause; Metabolic; Metabolic Pathway; Methods; Methylation; Mothers; Natural History; Nested Case-Control Study; Parents; Participant; Physical activity; Polishes; Postmenopause; Prepaid Health Plans; Prognostic Factor; Questionnaires; Reporting; Research; Research Personnel; Rest; Risk; Risk Factors; Role; Sampling; Site; Spermatogenesis; Standardization; Sweden; Syndrome; Terminal Ductal Lobular Unit; Testicular Dysgenesis Syndrome; Testicular Germ Cell Tumor; Urine; Woman; Women' s Health; anxious; base; bisphenol A; boys; cancer risk; cohort; congenital anomaly; design; genotoxicity; hormone related cancer; interest; liquid chromatography mass spectrometry; male; malignant breast neoplasm; multidisciplinary; novel; outcome forecast; programs; reproductive; screening; tumor; urinary

This project covers a broad base of studies aimed at assessing the epidemiology of the majority of hormonally-related cancers. Major efforts are underway for breast cancer, endometrial cancer, ovarian cancer, and testicular cancer. We also have an active research program on prostate cancer, covered in a separate report (Z01 CP010180-02). Our efforts for all of these cancers relate to a variety of environmental, genetic and hormonal predictors of risk. It is well recognized that breast cancers that occur among Africans and African-Americans tend to exhibit different clinical characteristics as compared with Caucasians, including a higher prevalence of estrogen receptor negative and triple negative tumors, cancers associated with a generally poor prognosis. To better understand the reasons for the occurrence of these cancers, we are conducting a case-control study in Ghana, where incidence rates of breast cancer have been increasing. The study has been designed to evaluate some novel etiologic hypotheses as well as to relate risk factors to carefully defined subtypes of breast cancers. We have also had a major interest in studying a number of intermediate markers of breast cancer risk, including mammographic breast density and terminal duct lobular unit involution. We have developed and used some novel methods for measuring both of these presumed breast cancer precursors and have related breast cancer risk factors to varied measures. We are also examining how these measures relate to subsequent breast cancers. In collaboration with the Gynecologic Oncology Group, we have administered a standardized questionnaire to women in a large endometrial cancer trial. This has enabled analyses which have demonstrated that there is great etiologic heterogeneity of endometrial cancer across histologic subtypes. We have also assessed how these factors relate to survival after adjusting for other clinical prognostic factors. We have learned much about the natural history of cervical cancer (as described in another project report) and are now anxious to expand our knowledge in this area to address the natural history of another gynecologic tumor, namely endometrial cancer. Endometrial hyperplasias are recognized to increase the subsequent risk of endometrial cancer, but data with which to accurately predict risk are lacking, and it is unknown how other factors might influence those risks. We have conducted a nested case-control study within a prepaid health plan to better understand the risk of endometrial cancer in women diagnosed with endometrial hyperplasia. Data from this study have supported the notion that atypical hyperplasia is strongly related to subsequent endometrial cancer risk. We are also conducting a study to assess early markers which may be important to the development of ovarian cancer and endometrial cancer. To further our understanding of testicular cancer, we have conducted a number of studies regarding Testicular Dysgenesis Syndrome (TDS), a group of etiologically related male reproductive disorders which included cryptorchidism, hypospadias, impaired spermatogenesis and testicular germ cell tumors (TGCTs). While the associations among cryptorchism, impaired spermatogenesis and TGCT have been widely acknowledged, the linkage of hypospadias to the rest of the syndrome has been unclear. To examine this question, we analyzed linked medical records data from Sweden and found that hypospadias was significantly associated with both cryptorchidism and TGCT. We also found that another congenital anomaly, inguinal hernia, was significantly associated, thereby suggesting that both hypospadias and inguinal hernia should be included in TDS. Given that a previous study in Finland found that boys born to mothers with gestational diabetes were at an increased risk of cryptorchidism, we examined the association in a health maintenance organization (HMO) in Israel, However, we found no association between gestational diabetes and either congenital cryptorchidism or hypospadias. This project has also included a focus on the etiologic role of endogenous hormones for a variety of tumor sites. We have established a close collaboration with a laboratory in Frederick, which has developed a liquid chromatography/mass spectrometry assay that measures 15 estrogen metabolities. We have assessed the relationship of these metabolites to breast cancer risk in three large cohorts. Although there were some differences across these studies in terms of the effects of individual metabolites, all three showed significant associations of risk with high estradiol levels. Several of the studies suggested that increased 2- or 4-hydroxylation of parent estrogens might lower postmenopausal breast cancer risk, of interest given that this metabolic pathway involves less extensive methylation of potentially genotoxic catechols. We have also contributed our data to several consortial efforts that have further clarified the effects of endogenous hormones on breast cancer risk.To address mounting concerns regarding a possible link between bisphenol A (BPA) and breast cancer risk, we used an assay that we recently helped develop and validate to measure its primary excreted metabolic conjugateBPA-glucuronide (BPA-G). Using urine samples collected in our Polish Breast Cancer Study (PBCS), we found that BPA-G concentrations were higher among women reporting extended use of menopausal hormones and a prior screening mammogram, but there was no relationship with breast cancer risk. We are currently collaborating with investigators of the Womens Health Initiative to measure estrogens in relation to ovarian and endometrial cancers that developed among participants in the observational component of that investigation. We also have measured estrogens and androgens in relation to male breast, testicular and esophageal cancers. Finally, in the Polish study we have measured urinary estrogens among the control subjects in order to more fully understand relationships with identified risk factors, including physical activity levels that have been objectively determined. .

该项目涵盖了广泛的研究基础，旨在评估大多数激素相关癌症的流行病学。 针对乳腺癌、子宫内膜癌、卵巢癌和睾丸癌的主要努力正在进行中。 我们还有一个关于前列腺癌的积极研究计划，在一份单独的报告 (Z01 CP010180-02) 中进行了介绍。 我们针对所有这些癌症所做的努力都与各种环境、遗传和激素风险预测因素有关。众所周知，与白种人相比，非洲人和非裔美国人中发生的乳腺癌往往表现出不同的临床特征，包括雌激素受体阴性和三阴性肿瘤的患病率较高，这些癌症通常预后不良。 为了更好地了解这些癌症发生的原因，我们正在加纳进行一项病例对照研究，该国乳腺癌的发病率一直在上升。 该研究旨在评估一些新的病因学假设，并将危险因素与仔细定义的乳腺癌亚型联系起来。我们还对研究乳腺癌风险的一些中间标志物非常感兴趣，包括乳房 X 光检查乳腺密度和终末导管小叶单位退化。 我们开发并使用了一些新方法来测量这两种假定的乳腺癌前兆，并将乳腺癌危险因素与各种测量方法相关联。 我们还在研究这些措施与随后的乳腺癌有何关系。我们与妇科肿瘤学小组合作，在一项大型子宫内膜癌试验中对女性进行了标准化调查问卷。 这使得分析能够证明子宫内膜癌的不同组织学亚型存在很大的病因异质性。 我们还评估了调整其他临床预后因素后这些因素与生存的关系。我们已经了解了很多关于宫颈癌的自然史（如另一个项目报告中所述），现在迫切希望扩大我们在这一领域的知识，以解决另一种妇科肿瘤（即子宫内膜癌）的自然史。子宫内膜增生被认为会增加随后患子宫内膜癌的风险，但缺乏准确预测风险的数据，并且尚不清楚其他因素如何影响这些风险。我们在预付费健康计划中进行了一项巢式病例对照研究，以更好地了解被诊断患有子宫内膜增生的女性患子宫内膜癌的风险。 这项研究的数据支持了非典型增生与随后的子宫内膜癌风险密切相关的观点。 我们还正在进行一项研究，以评估可能对卵巢癌和子宫内膜癌的发展很重要的早期标志物。为了进一步了解睾丸癌，我们进行了多项关于睾丸发育不全综合征 (TDS) 的研究，这是一组病因相关的男性生殖疾病，包括隐睾、尿道下裂、精子发生受损和睾丸生殖细胞肿瘤 (TGCT)。 虽然隐睾症、精子发生受损和 TGCT 之间的关联已得到广泛认可，但尿道下裂与该综合征其他症状的联系尚不清楚。 为了研究这个问题，我们分析了瑞典的相关医疗记录数据，发现尿道下裂与隐睾和 TGCT 显着相关。 我们还发现另一种先天性异常，腹股沟疝气，显着相关，因此表明尿道下裂和腹股沟疝气都应包含在 TDS 中。 鉴于芬兰之前的一项研究发现，患有妊娠糖尿病的母亲所生的男孩患隐睾的风险增加，我们在以色列的一个健康维护组织 (HMO) 中检查了这种关联。然而，我们发现妊娠糖尿病与先天性隐睾或尿道下裂之间没有关联。该项目还重点关注内源激素对多种肿瘤部位的病因作用。我们与弗雷德里克的一家实验室建立了密切合作，该实验室开发了一种液相色谱/质谱分析方法，可测量 15 种雌激素代谢。 我们在三个大型队列中评估了这些代谢物与乳腺癌风险的关系。 尽管这些研究在个别代谢物的影响方面存在一些差异，但所有三项研究均显示风险与高雌二醇水平存在显着相关性。 几项研究表明，增加母体雌激素的 2- 或 4- 羟基化可能会降低绝经后乳腺癌的风险，这一点很有趣，因为这种代谢途径涉及潜在遗传毒性儿茶酚的不太广泛的甲基化。 我们还向多个联盟的努力贡献了我们的数据，这些努力进一步阐明了内源性激素对乳腺癌风险的影响。为了解决人们对双酚 A (BPA) 与乳腺癌风险之间可能存在联系的日益担忧，我们使用了我们最近帮助开发和验证的一种检测方法来测量其主要分泌的代谢结合物 BPA-葡萄糖醛酸苷 (BPA-G)。 使用我们在波兰乳腺癌研究 (PBCS) 中收集的尿液样本，我们发现在报告长期使用更年期激素和之前进行乳房 X 光检查的女性中，BPA-G 浓度较高，但与乳腺癌风险没有关系。我们目前正在与妇女健康倡议的研究人员合作，测量与该调查观察部分参与者中发生的卵巢癌和子宫内膜癌相关的雌激素。 我们还测量了与男性乳腺癌、睾丸癌和食道癌相关的雌激素和雄激素。 最后，在波兰的研究中，我们测量了对照受试者的尿雌激素，以便更全面地了解与已确定的危险因素的关系，包括客观确定的体力活动水平。 。