Hormone-Related Cancers

激素相关癌症

基本信息

批准号：
10702910
负责人：
Gretchen Gierach
金额：
$ 934.28万
依托单位：
DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
依托单位国家：
美国
项目类别：
财政年份：
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/10702910
关键词：
Address African African American population 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 Prognosis 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&apos s Health anxious base bisphenol A boys cancer risk clinical prognostic cohort congenital anomaly design genotoxicity hormone related cancer interest liquid chromatography mass spectrometry male malignant breast neoplasm multidisciplinary novel programs reproductive system disorder screening tumor urinary

项目摘要

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. .

该项目涵盖了旨在评估大多数荷尔蒙相关癌症的流行病学的广泛研究基础。乳腺癌，子宫内膜癌，卵巢癌和睾丸癌正在进行重大努力。我们还制定了有关前列腺癌的积极研究计划，该计划在单独的报告中涵盖（Z01 CP010180-02）。我们对所有这些癌症的努力都涉及各种风险的环境，遗传和荷尔蒙预测指标。众所周知，与高加索人相比，非洲人和非裔美国人之间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重阴性肿瘤的患病率更高，与普遍预后相关的癌症。为了更好地理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，乳腺癌的发病率正在增加。该研究旨在评估一些新的病因学假设，并将危险因素与精心定义的乳腺癌亚型相关联。我们也对研究乳腺癌风险的许多中间标志物（包括乳房X线照相乳房密度和末端管道叶单位相关性）有重大兴趣。我们已经开发并使用了一些新型方法来测量这两种假定的乳腺癌前体，并具有与各种措施相关的乳腺癌风险因素。我们还在研究这些措施与随后的乳腺癌如何相关。与妇科肿瘤学组合作，我们在一项大型子宫内膜癌症试验中对女性进行了标准化问卷。这已经实现了分析，这些分析表明，整个组织学亚型的子宫内膜癌存在很大的病因异质性。我们还评估了这些因素在调整其他临床预后因素后与生存之间的关系。我们已经了解了很多有关宫颈癌的自然史（如另一份项目报告中所述），现在急于扩大我们在该领域的知识，以解决另一种妇科肿瘤的自然史，即子宫内膜癌。子宫内膜增生被认为会增加随后的子宫内膜癌的风险，但是缺乏准确预测风险的数据，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嵌套的病例对照研究，以更好地了解被诊断为子宫内膜增生的女性子宫内膜癌的风险。这项研究的数据支持了以下观点：非典型增生与随后的子宫内膜癌风险密切相关。我们还正在进行一项研究以评估早期标志物，这可能对卵巢癌和子宫内膜癌的发展很重要。为了进一步了解睾丸癌，我们已经进行了许多有关睾丸发病障碍综合征（TDS）的研究，这是一组与病因相关的男性生殖疾病，其中包括隐齿术，降低，降低，精子生成和睾丸生殖细胞肿瘤（TGCTS）。虽然已广泛认可了密码术，精子发生受损和TGCT之间的关联，但催化性与其他综合征的联系尚不清楚。为了研究这个问题，我们分析了瑞典的链接医疗记录数据，发现Hypospadias与密码术和TGCT都显着相关。我们还发现，另一种先天性异常，腹股沟疝，从而显着相关，从而表明Hypospadias和腹膜疝都应包括在TDS中。鉴于先前在芬兰的一项研究发现，患有妊娠糖尿病的母亲出生的男孩患有隐齿术的风险增加，我们检查了以色列的健康维护组织（HMO）的关联，但是，我们发现妊娠糖尿病与癌症糖尿病与癌症的隐性疾病或催生症之间没有关联。该项目还关注内源激素在各种肿瘤部位的病因作用。我们已经与弗雷德里克（Frederick）的实验室建立了密切合作，该实验室开发了一种液相色谱/质谱法测定法，该测定法，测量15种雌激素代谢。我们已经评估了这些代谢物与三个大型队列中乳腺癌风险的关系。尽管这些研究在单个代谢产物的影响方面存在一些差异，但这三个研究均显示出与雌二醇水平高的风险相关的显着关联。几项研究表明，鉴于这种代谢途径涉及潜在的遗传毒性毒性儿茶素的广泛甲基化，因此，对母雌激素的2或4-羟基化增加可能会降低产后乳腺癌的风险。我们还为几项联盟努力做出了贡献，这些努力进一步阐明了内源激素对乳腺癌风险的影响，以解决对双酚A（BPA）与乳腺癌风险之间可能联系的越来越多的担忧，我们使用了一种测定法，我们最近使用了一种测定法，我们最近帮助开发并验证了其主要的代谢性代谢conjugatebpa-glucuronidy（bpa-bpa-bpa-bpa）。使用在我们的波兰乳腺癌研究（PBC）中收集的尿液样本，我们发现BPA-G浓度在报告更年期激素使用和先前筛查乳房X线照片的女性中较高，但与乳腺癌风险没有关系。我们目前正在与《妇女健康计划》的调查人员合作，以测量与该调查的观察性成分参与者之间发展的卵巢和子宫内膜癌的雌激素。我们还针对雄性乳房，睾丸和食管癌测量了雌激素和雄激素。最后，在波兰研究中，我们测量了控制受试者之间的尿雌激素，以便更充分地了解与已确定的风险因素（包括已经客观确定的身体活动水平）的关系。。