Hormone-Related Cancers

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、卵巢癌和睾丸癌的重大努力正在进行中。我们也有一个活跃的前列腺癌研究项目，在单独的报告（Z01 CP010180-02）中有涉及。我们对所有这些癌症的研究都与各种环境、遗传和激素的风险预测因素有关。2000-2004年间，在波兰进行了一项大型多学科研究，以评估乳腺癌、卵巢癌和子宫内膜癌的危险因素。该研究收集了多种生物样本，主要目的是评估生物标志物与风险的关联，以及风险的遗传和环境决定因素的相互作用。此外，该研究的特殊组成部分探讨了身体活动、职业因素和家庭化学品暴露的影响。对于体力活动，特别努力改进暴露评估，要求妇女佩戴加速度计，以获得比单独面谈数据更客观的测量。该研究还涉及组织样本的收集，以便进行组织学和分子肿瘤分类（例如利用组织微阵列技术进行免疫组织化学分析）。在这项调查中收集的大量数据使许多分析成为可能。关于乳腺癌，最近的出版物评估了遗传多态性、职业暴露、身体活动水平、围产期暴露以及肿瘤分期和激素受体状态的病因异质性的影响。另一项针对乳腺癌的大型病例对照研究收集了口腔细胞标本。这项工作需要大量的方法学工作，以确定收集、处理和储存样品的最佳方法，以最大限度地提高DNA产量。病例对照研究的重点是评估遗传多态性与风险之间的关系。乳腺癌的风险也是对先前进行骨密度筛查的一组妇女进行随访的主要兴趣。该资源先前涉及血清学样本和详细问卷数据的收集，将能够评估骨密度，遗传因素和内源性激素在预测随后的癌症发生方面的相互关系。乳房x线摄影密度已被认为是随后乳腺癌风险的主要预测因子，但这种关联的生物学基础尚不清楚。通过出售乳腺癌邮票获得的资金目前正用于一项研究，以评估在佛蒙特大学接受乳房活组织检查的一组妇女的乳房x光检查密度与激素和免疫的相关性。与妇科肿瘤学组建立了合作关系，以确定在一些正在进行的试验中收集流行病学数据的方法。一份标准化的调查问卷已经被开发出来并被整合到子宫内膜癌的大型试验中。这项工作应该有助于评估与仔细定义的肿瘤组织学亚群相关的流行病学预测因子和分子标记。调查问卷也开始被整合到其他癌症部位的其他试验中；此外，计划正在制定有针对性的问卷，以解决妇科肿瘤学家感兴趣的具体假设。我们已经对宫颈癌的自然史了解了很多（在另一个项目报告中有描述），现在我们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的自然史，即子宫内膜癌。子宫内膜增生被认为会增加随后发生子宫内膜癌的风险，但缺乏准确预测风险的数据，也不清楚其他因素如何影响这些风险。为了更好地了解诊断为子宫内膜增生的女性患子宫内膜癌的风险，我们在预付费健康计划中进行了巢式病例对照研究。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。本研究的结果有可能改善高危妇女的临床管理，并启发对子宫内膜激素癌变的理解。我们还在开展一项研究的试点阶段，以评估可能对卵巢癌和子宫内膜癌发展很重要的早期标志物。本研究收集了患有多种妇科疾病的患者的卵巢和子宫内膜组织；组织样本将与流行病学数据联系起来，以确定可能与未来恶性肿瘤发生相关的标志物。睾丸癌是美国15-35岁男性中最常见的癌症类型，白人男性的发病率是黑人男性的5倍。为了研究这种肿瘤的病因，我们与美国国防部（DoD）合作，对美国军人进行了一项大型病例对照研究。对诊断前血清样本的分析发现，接触有机氯农药（特别是二氯二苯二氯乙烯和氯丹）与睾丸癌显著相关。血清分析还发现，患有睾丸癌的男性在诊断前的促性腺激素水平异常。另外的研究结果表明，虽然成人身高与风险有关，但青春期的年龄、乳制品的摄入量和母亲在怀孕期间吸烟无关。此外，胰岛素样生长因子途径和激素代谢途径的遗传变异似乎与风险无关。然而，抑制素途径的遗传变异可能与此有关。作为本研究的补充，其他研究正在进行，以确定隐睾的潜在原因，隐睾是公认的睾丸癌的危险因素。这些研究比较了黑人和白人人群中隐睾症的患病率以及这种异常的危险因素。尽管隐睾的患病率在白人人群中明显较高，但这一比例的微小差异与睾丸癌风险的巨大差异并不相符。两组之间的危险因素差异不大，母体激素水平的差异与隐睾无关。该项目还包括关注内源性激素在多种肿瘤部位的病因学作用。在这些研究中，注意力不仅集中在经典接受的激素上，而且还集中在一些新提出的预测因子上，包括脂联素水平。对密苏里州哥伦比亚市梅奥血清库组成部分的参与者进行了长期的后续行动；这将使我们能够扩展先前的发现并解决新出现的病因学假设。随着时间的推移，这种资源在收集多种生物样本方面是独一无二的，允许评估激素水平如何随着患者接近诊断而变化。

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.<BR><BR>A large multi-disciplinary study was conducted in Poland between 2000-2004 to assess risk factors for breast cancer, ovarian cancer and endometrial cancer. The study involved collection of multiple biologic samples, with a primary aim of assessing biomarker associations with risk and the interactive effects of genetic and environmental determinants of risk. In addition, special components of the study addressed effects of physical activity, occupational factors, and household chemical exposures. For physical activity, special efforts were expended to improve exposure assessment, with women being asked to wear accelerometers to obtain more objective measures than interview data alone. The study also involved collection of tissue samples to enable histological and molecular tumor classification (e.g. utilizing tissue microarray techniques for immunohistochemistry analyses). The large amount of data collected in this investigation are enabling a number of analyses. With respect to breast cancer, recent publications have evaluated effects of genetic polymorphisms, occupational exposures, physical activity levels, perinatal exposures, and etiologic heterogeneity by tumor stage and hormone receptor status.<BR><BR>Another large case-control study, focused on breast cancer, has involved collection of buccal cell specimens. This effort required extensive methodologic work to determine the optimal means of collecting, processing and storing samples in order to maximize DNA yield. The focus of the case-control study is to evaluate associations between genetic polymorphisms and risk. Breast cancer risk is also of major interest in a follow-up of a cohort of women previously screened for bone density. This resource, which previously involved collection of serologic samples and detailed questionnaire data, will enable an assessment of the interrelationship of bone density, genetic factors and endogenous hormones in predicting subsequent cancer occurrence.<BR><BR>Mammographic density has been recognized as a major predictor of subsequent breast cancer risk, but the biologic basis for this association is unclear. Funds made available through the sale of breast cancer stamps are currently being used for a study to assess hormonal and immunologic correlates of mammographic density among a group of women receiving breast biopsies at the University of Vermont. <BR><BR>A collaboration has been established with the Gynecologic Oncology Group to determine means of collecting epidemiologic data within the context of a number of ongoing trials. A standardized questionnaire has been developed and has been integrated into a large trial of endometrial cancer. This effort should be useful in assessing epidemiologic predictors and molecular markers associated with carefully defined histologic subgroups of tumors. The questionnaire is also beginning to be integrated into other trials of other cancer sites; in addition, plans are underway to develop targeted questionnaires to address specific hypotheses of interest to gynecologic oncologists. <BR><BR>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 that notion that atypical hyperplasia is strongly related to subsequent endometrial cancer risk. Results from this study have the potential to improve clinical management of at-risk women and to enlighten the understanding of hormonal carcinogenesis in the endometrium. We are also in the pilot phases of developing a study to assess early markers which may be important to the development of ovarian cancer and endometrial cancer. This study involves the collection of ovarian and endometrial tissues from patients undergoing a variety of gynecologic conditions; tissue samples will be linked with epidemiologic data to determine markers which may correlate with the future occurrence of malignancies.<BR><BR>Testicular cancer is the most common type of cancer among American men aged 15-35 years and occurs five times more frequently among white men than among black men. To study the etiology of this tumor, we have conducted a large case-control study of U.S. servicemen in collaboration with the U.S. Department of Defense (DoD). Analysis of pre-diagnostic serum samples has found that exposure to organochlorine pesticides (specifically, dichlorodiphenyldichloroethylene (DDE) and chlordane) is significantly associated with testicular cancer. Serum analyses have also found that men who develop testicular cancer have aberrant gonadotropin levels prior to diagnosis. Additional findings indicate that while adult height is associated with risk, age at puberty, consumption of dairy products and maternal smoking in pregnancy are not associated. In addition, genetic variability in the insulin-like growth factor pathway and the hormone metabolizing pathway does not appear to be related to risk. Genetic variability in the inhibin pathway, however, may be associated. As a complement to this research, other studies have being undertaken to identify underlying causes of cryptorchism, a recognized risk factor for testicular cancer. These studies have compared the prevalence of cryptorchism, as well as risk factors for the anomaly, between black and white populations. Though the prevalence of cryptorchism is significantly higher among white populations, the small difference in the rate is not compatible with the large difference in testicular cancer risk. Risk factors between the two groups do not vary greatly and differences in maternal hormone levels are not related to cryptorchism.<BR><BR>This project has also included a focus on the etiologic role of endogenous hormones for a variety of tumor sites. In these studies, attention is focusing not only on classically accepted hormones, but also on some newly suggested predictors, including adiponectin levels. An extended follow-up of participants in the Columbia, Missouri component of the Mayo Serum Bank has been undertaken; this will allow us to expand upon previous findings and to address newly emerging etiologic hypotheses. This resource is unique in having collected multiple biologic samples over time, allowing an assessment of how hormone levels change as patients approach diagnosis.