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 breast cancer precursor conditions, including mammographic density and terminal duct lobular units. 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 are currently analyzing how these risk 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 regaridng 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 andeither congenital cryptorchidism or hypospadias.BRThis 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 (20) 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 (21). 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. .