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Background: Poorer survival from endometrial cancer in blacks than in whites is well documented. The aims of this study were to determine whether diabetes, hypertension, or other conditions influence survival and whether accounting for these conditions reduces this racial disparity.Methods: Using the SEER-Medicare database, we investigated the influence of diabetes, hypertension, and other comorbid conditions on survival in black and white women age ≥66 with endometrial cancer. We used Cox proportional hazards regression to evaluate the influence of comorbidities on survival for blacks and whites separately and to study survival differences between blacks and whites after adjustment for diabetes, hypertension, and other medical conditions, as well as for demographics, tumor characteristics, and treatment.Results: In both racial subgroups, women with diabetes or other conditions had poorer overall survival, whereas hypertensive black women experienced better survival [HR, 0.74; 95% confidence interval (CI), 0.60–0.92]. For disease-specific survival, diabetes was associated with poorer survival in white women (HR, 1.19; 95% CI, 1.06–1.35) but not in blacks (HR, 0.97; 95% CI, 0.73–1.30); hypertension and other conditions were not significantly related to survival. After adjustment, black women had poorer survival than white women, with HRs of 1.16 (95% CI, 1.05–1.28) for overall and 1.27 (95% CI, 1.08–1.49) for disease-specific survival.Conclusions: Diabetes influences disease-specific survival in white women but not in blacks. The racial disparity in survival is not explained by the presence of other health conditions.Impact: Further research should focus on the unknown factors that lead to poorer survival in black women compared with whites. Cancer Epidemiol Biomarkers Prev; 21(5); 753–60. ©2012 AACR.

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Endometrial cancer is the most common gynecological malignancy in the developed world. Although there is evidence of genetic predisposition to the disease, most of the genetic risk remains unexplained. We present the meta-analysis results of four genome-wide association studies (4907 cases and 11 945 controls total) in women of European ancestry. We describe one new locus reaching genome-wide significance (P < 5 × 10 -8) at 6p22.3 (rs1740828; P = 2.29 × 10 -8, OR = 1.20), providing evidence of an additional region of interest for genetic susceptibility to endometrial cancer.

Childbearing at an older age has been associated with a lower risk of endometrial cancer, but whether the association is independent of the number of births or other factors remains unclear. Individual-level data from 4 cohort and 13 case-control studies in the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 8,671 cases of endometrial cancer and 16,562 controls were included in the analysis. After adjustment for known risk factors, endometrial cancer risk declined with increasing age at last birth (P(trend) < 0.0001). The pooled odds ratio per 5-year increase in age at last birth was 0.87 (95% confidence interval: 0.85, 0.90). Women who last gave birth at 40 years of age or older had a 44% decreased risk compared with women who had their last birth under the age of 25 years (95% confidence interval: 47, 66). The protective association was similar across the different age-at-diagnosis groups and for the 2 major tumor histologic subtypes (type I and type II). No effect modification was observed by body mass index, parity, or exogenous hormone use. In this large pooled analysis, late age at last birth was independently associated with a reduced risk of endometrial cancer, and the reduced risk persisted for many years.

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population. Some individuals, studies, and centers received individual support. The grant numbers are: Addiction (U01HG004422, NIAAA: U10AA008401, NCI: P01CA089392, NIDA: R01DA013423, R01DA019963); Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (U.S. Public Health Service contracts: N01-CN-45165, N01-RC-45035, N01-RC-37004, NCI contract: HHSN261201000006C); Birth weight (U01HG004415); Blood clotting (R37 HL 039693); Broad Center for Genotyping and Analysis (U01HG04424); Cancer Prevention Study-II (American Cancer Society); Center for Inherited Disease Research (U01HG004438, HHSN268200782096C); Cleft lip/palate (NIDCR: U01DE018993 and R01DE016148, NIH contract: HHSN268200782096C); Dental Caries (NIDCR:U01DE018903 and R01DE014899, NIH CIDR contract: HHSN268200-782096C); Endometrial cancer (R01 CA134958); Fudan Lung Cancer Study (Ministry of Health (201002007); Ministry of Science and Technology (2011BAI09B00); National S&T Major Special Project (2011ZX09102-010-01); China National High-Tech Research and Development Program (2012AA02A517, 2012AA02A518); National Science Foundation of China (30890034); National Basic Research Program (2012CB944600); Scientific and Technological Support Plans from Jiangsu Province (BE2010715)); Gene-Environment Association Studies (Coordinating Center :U01 HG004446, Manuscript preparation: P01-GM099568); Genes and Environment in Lung Cancer, Singapore Study (National Medical Research Council Singapore grant (NMRC/0897/2004, NMRC/1075/2006); Agency for Science, Technology and Research (A*STAR) of Singapore); Genetic Epidemiological Study of Lung Adenocarcinoma (National Research Program on Genomic Medicine in Taiwan (DOH98-TD-G-111-015); National Research Program for Biopharmaceuticals in Taiwan (DOH 100-TD-PB-111-TM013); National Science Council,Taiwan (NSC 100-2319-B-400-001)); Glaucoma (NHGRI: U01HG004728, NEI: R01EY015473, NEI: R01EY015872, Harvard Medical School Distinguished Ophthalmology Scholar Award: Louis Pasquale); Guangdong Study (Foundation of Guangdong Science and Technology Department (2006B60101010, 2007A032000002, 2011A030400010); Guangzhou Science and Information Technology Bureau (2011Y2-00014); Chinese Lung Cancer Research Foundation; National Natural Science Foundation of China (81101549); Natural Science Foundation of Guangdong Province (S2011010000792)); Health Professionals Follow-up Study (UM1 CA167552, R01 HL35464); Hong Kong Study (General Research Fund of Research Grant Council, Hong Kong (781511M)); Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH; Intramural Research Program of the NIH, National Library of Medicine; Intramural Research Program of the National Institute for Occupational Safety and Health; Japanese Female Lung Cancer Collaborative Study (Grants-in-Aid from the Ministry of Health, Labor, and Welfare for Research on Applying Health Technology and for the 3rd-term Comprehensive 10-year Strategy for Cancer Control; National Cancer Center Research and Development Fund; Grant-in-Aid for Scientific Research on Priority Areas and on Innovative Area from the Ministry of Education, Science, Sports, Culture and Technology of Japan; NCI (R01-CA121210)); Lung cancer (Z01CP010200); Lung health (U01HG004738); Ministry of Health (201002007); Ministry of Science and Technology (2011BAI09B00); Melanoma (NCI R29CA70334, R01CA100264, P50CA093459); NLCS (China National High-Tech Research and Development Program Grant (2009AA022705); Priority Academic Program Development of Jiangsu Higher Education Institution; National Key Basic Research Program Grant (2011CB503805)); Nurses’ Health Study (P01 CA87969, R01 CA49449); Nurses’ Health Study II (UM1 CA176726, R01, 67262); OpPancreatic cancer (Mayo Clinic SPORE in Pancreatic Cancer: P50CA102701); Prematurity (U01HG004423); Prostate cancer (U01HG004726, NCI: CA63464, CA54281, CA1326792, RC2 CA148085); Shanghai Women’s Health Cohort Study (National Institutes of Health (R37 CA70867); National Cancer Institute intramural research program; NCI Intramural Research Program contract (N02 CP1101066)); Shenyang Lung Cancer Study (National Nature Science Foundation of China (81102194); Liaoning Provincial Department of Education (LS2010168); China Medical Board (00726)); Singapore Chinese Health Study (NIH grants: NCI R01 CA55069, R35 CA53890, R01 CA80205, and R01 CA144034); South Korea Multi-Center Lung Cancer Study (National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2011-0016106); National R&D Program for Cancer Control, Ministry of Health &Welfare, Republic of Korea (0720550-2); (A010250)); Tianjin Lung Cancer Study (Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT); China (IRT1076), Tianjin Cancer Institute and Hospital, National Foundation for Cancer Research US); Venous thromboembolism (U01HG004735); Wuhan lung cancer study (National Key Basic Research and Development Program (2011CB503800)) and Yunnan Lung Cancer Study (Intramural program of U.S. National Institutes of Health; National Cancer Institute). Additionally, K.C.B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program. The GENEVA consortium thanks the participants and the staff of all GENEVA studies for their important contributions. Support for the GENEVA genome-wide association studies was provided through the NIH Genes, Environment and Health Initiative (GEI).

Purpose Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors. Patients and Methods Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors. Results Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m2 increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (Pheterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar. Conclusion The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.

Background: Uterine sarcomas are characterised by early age at diagnosis, poor prognosis, and higher incidence among Black compared with White women, but their aetiology is poorly understood. Therefore, we performed a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We also examined risk factor associations for malignant mixed mullerian tumours (MMMTs) and endometrioid endometrial carcinomas (EECs) for comparison purposes. Methods: We pooled data on 229 uterine sarcomas, 244 MMMTs, 7623 EEC cases, and 28 829 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) for risk factors associated with uterine sarcoma, MMMT, and EEC were estimated with polytomous logistic regression. We also examined associations between epidemiological factors and histological subtypes of uterine sarcoma. Results: Significant risk factors for uterine sarcoma included obesity (body mass index (BMI)≥30 vs BMI

Background: Poorer survival from endometrial cancer in blacks than in whites is well documented. The aims of this study were to determine whether diabetes, hypertension, or other conditions influence survival and whether accounting for these conditions reduces this racial disparity. Methods: Using the SEER-Medicare database, we investigated the influence of diabetes, hypertension, and other comorbid conditions on survival in black and white women age ≥66 with endometrial cancer. We used Cox proportional hazards regression to evaluate the influence of comorbidities on survival for blacks and whites separately and to study survival differences between blacks and whites after adjustment for diabetes, hypertension, and other medical conditions, as well as for demographics, tumor characteristics, and treatment. Results: In both racial subgroups, women with diabetes or other conditions had poorer overall survival, whereas hypertensive black women experienced better survival [HR, 0.74; 95% confidence interval (CI), 0.60–0.92]. For disease-specific survival, diabetes was associated with poorer survival in white women (HR, 1.19; 95% CI, 1.06–1.35) but not in blacks (HR, 0.97; 95% CI, 0.73–1.30); hypertension and other conditions were not significantly related to survival. After adjustment, black women had poorer survival than white women, with HRs of 1.16 (95% CI, 1.05–1.28) for overall and 1.27 (95% CI, 1.08–1.49) for disease-specific survival. Conclusions: Diabetes influences disease-specific survival in white women but not in blacks. The racial disparity in survival is not explained by the presence of other health conditions. Impact: Further research should focus on the unknown factors that lead to poorer survival in black women compared with whites. Cancer Epidemiol Biomarkers Prev; 21(5); 753–60. ©2012 AACR.

Excess body weight is a known risk factor for endometrial cancer but whether it differentially affects histological subtypes of endometrial cancer is unclear. The two proposed main subtypes are the “estrogen-dependent Type I” and “non estrogen-dependent and clinically aggressive Type II”. Little is known about risk factors for Type II tumors mainly because most epidemiologic studies lack sufficient cases to study these rare tumors separately. Here we examined the association between recent adult body mass index (BMI) and endometrial tumor subtypes in a pooled analysis of 25 studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Individual-level data from 10 cohort studies and 15 case-control studies provided a total of 14,409 endometrial cancer cases and 35,950 controls for this analysis. Cohort studies were analyzed using a nested case-control design. The majority of women were white (86%) and postmenopausal (83%). Endometrial cancer cases were classified into two subtypes: Type I (endometrioid adenocarcinomas, adenocarcinoma tubular, papillary adenocarcinomas, mucinous adenocarcinomas, adenocarcinomas with squamous metaplasia, n=13,286) and Type II (serous, squamous cell, small cell, mixed cell, n=1,123). The associations of BMI with the risk of tumor subtypes were evaluated by calculating odds ratios (OR) and 95% confidence intervals (95% CI) using polytomous logistic regression models. Potential confounders included in the analysis were age, race, parity, age at menarche, oral contraceptive (OC) use, menopausal hormone (PMH) use, and smoking status. BMI was positively associated with both Type I and Type II tumors, but the association was stronger for Type I than for Type II tumors (P value for the difference in OR between Type I and Type II was Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1029. doi:1538-7445.AM2012-1029

Background: Endometrial cancer shows the largest disparity in outcomes between black and white cases of any cancer in the US. Black women have higher prevalence of diabetes and hypertension, conditions that might be associated with poorer survival. Our objectives were to determine whether the presence of diabetes or hypertension was related to disease-specific survival and to investigate whether accounting for these conditions influenced the survival difference for the two racial groups. Methods: Using Surveillance, Epidemiology and End Results cancer registry data linked with Medicare claims, we identified women with diabetes (as defined by Hebert et al, Univ of Minn Rural Health Research Center Working Paper 22, March 1998) and hypertension (defined as 2 claims at least 30 days apart for ICD9 codes 401-404) and investigated the influence of these conditions on survival in black and white women age >=66 diagnosed with endometrial cancer between 2000 and 2005. We used Cox proportional hazards models, adjusted for demographics, tumor characteristics, and treatment, to evaluate whether presence of diabetes or hypertension influenced disease-specific survival and whether adjustment for these factors influenced the difference in outcome between blacks and whites. Results: 22% of whites and 41% of blacks with endometrial cancer met the criteria for diabetes and 52% and 73%, respectively, met the criteria for hypertension. Having diabetes was associated with poorer endometrial cancer specific survival in whites (HR=1.19, 95% CI 1.06-1.35) but not in blacks (HR=0.97, 95% CI 0.73-1.30), after adjustment for variables related to demographics, tumor characteristics, and treatment. Presence of hypertension did not significantly influence survival in either group. As expected, both overall survival and endometrial cancer specific survival were poorer in black women compared to whites, with adjusted hazard ratios for blacks of 1.19 (95% CI 1.08-1.31) for overall survival and 1.30 (95% CI 1.11-1.52) for disease-specific survival. Very little influence was found for diabetes or hypertension for either overall or disease specific survival: after adjustment for these variables the hazard ratios were 1.16 (95% CI 1.05-1.28) for overall survival and 1.27 (95% CI 1.08-1.49) for disease-specific survival. Conclusions: Diabetes influences disease-specific survival only in white women, while hypertension is not associated with disease-specific survival. The racial disparity in survival after a diagnosis of endometrial cancer is not explained by the presence of diabetes or hypertension. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1927. doi:10.1158/1538-7445.AM2011-1927

Endometrial cancer (EC), a neoplasm of the uterine epithelial lining, is the most common gynecological malignancy in developed countries and the fourth most common cancer among US women. Women with a family history of EC have an increased risk for the disease, suggesting that inherited genetic factors play a role. We conducted a two-stage genome-wide association study of Type I EC. Stage 1 included 5,472 women (2,695 cases and 2,777 controls) of European ancestry from seven studies. We selected independent single-nucleotide polymorphisms (SNPs) that displayed the most significant associations with EC in Stage 1 for replication among 17,948 women (4,382 cases and 13,566 controls) in a multiethnic population (African America, Asian, Latina, Hawaiian and European ancestry), from nine studies. Although no novel variants reached genome-wide significance, we replicated previously identified associations with genetic markers near the HNF1B locus. Our findings suggest that larger studies with specific tumor classification are necessary to identify novel genetic polymorphisms associated with EC susceptibility. Electronic supplementary material The online version of this article (doi:10.1007/s00439-013-1369-1) contains supplementary material, which is available to authorized users.