Hypertension and Risk of Endometrial Cancer: A Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2)

Endometrial cancer is the most common gynecologic cancer and the fourth most common cancer among women in the United States (1). The incidence rates of endometrial cancer are increasing, particularly among younger women (aged <50 years) and women from racial/ethnic minority groups (2–4). The rising incidence rates may by explained, in part, by the rising prevalence of obesity, an established risk factor for endometrial cancer, globally (5–8).

Metabolic syndrome is a cluster of metabolic abnormalities that includes obesity, dyslipidemia, hyperglycemia, and hypertension (9). Several epidemiologic studies have established associations between some components of metabolic syndrome and increased risk of endometrial cancer, independent of obesity (10–16). However, the role of hypertension, independent of the other components of metabolic syndrome, in the etiology of endometrial cancer remains unclear.

Hypertension is a common cardiovascular disease that affects approximately 40% of women in the United States (17). The prevalence of hypertension increases with age: approximately 50% of women aged 40 to 59 years and 74% of women aged 60 years and over are affected (17). Emerging evidence suggests that hypertension may be associated with the development of certain cancers, particularly through inflammatory, hormonal, and metabolic pathways (18). The results from several epidemiologic studies assessing the association between hypertension and endometrial cancer risk have been inconsistent. Some have reported a positive association between hypertension and endometrial cancer risk, although these studies vary on whether they addressed the potential influence of body mass index (BMI) or diabetes on this association (13, 14, 19–22), while others have reported no association, particularly after adjusting for BMI and diabetes (23, 24). Therefore, further research is needed to clarify the role of hypertension in endometrial cancer etiology.

In this study, we examined the association between hypertension and endometrial cancer risk by combining individual-level data for 15,631 endometrial cancer cases and 42,239 controls from 29 studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Our large study population enabled us to evaluate whether the association between hypertension and endometrial cancer is modified by other risk factors for the disease. Understanding this association may enable us to better identify women at higher risk for endometrial cancer and operationalize clinical interventions related to high blood pressure management for cancer prevention.

The E2C2 is an international consortium established in 2006 to identify and evaluate genetic, lifestyle and environmental risk factors for endometrial cancer by pooling resources and data from many studies (25–28). For this study, we pooled data from 29 epidemiologic studies (13 cohort and 16 case–control) from the E2C2 (Table 1). Cohort studies were included as nested case–control studies. Up to four controls were selected per case from females with an intact uterus and without endometrial cancer before the index case diagnosis. For both case–control and cohort studies, within each study, controls were matched with cases by age and other study-specific factors (e.g., race/ethnicity). Informed consent was obtained from all study participants in accordance with each study's Institutional Review Board. We included only individuals who had complete information on hypertension status and the covariates of interest described below (n = 16,694 excluded). The analytic study population included 15,631 cases and 42,239 controls (Supplementary Fig. S1); all controls were matched to at least one case. Written informed consent was obtained from all study participants in accordance with each study's Institutional Review Board and the studies included were conducted in accordance with recognized ethical guidelines (The Declaration of Helsinki).

Data were collected within each study via self-reported questionnaires or in-person interviews, including sociodemographic information, anthropometric measures, reproductive and menstrual information, comorbid conditions, and other known or potential risk factors for endometrial cancer. We used a published data harmonization pipeline to standardize variables across E2C2 study sites (28–32). Incident cases of endometrial cancer were identified by each study site using International Classification of Diseases for Oncology, third edition (ICD-O-3) primary site codes: C54.0-C54.3, C54.8-C54.9, and C55.9 (behavior code 3). Tumor information and characteristics (stage, grade, histology) were collected from medical records, pathology reports, and/or linkages to national cancer registries, where available.

Participating studies provided information on the main exposure of interest, hypertension, which was obtained from the baseline self-reported questionnaires or in-person interviews [reported as “ever diagnosed with hypertension” (yes/no)].

Information on established risk factors for endometrial cancer were also obtained and evaluated as covariates of interest, including age (continuous), race (Asian, Black, White, Other/Unknown), BMI (continuous and categorical: normal <25, overweight 25–29, obese 30–34, severely obese ≥35 kg/m²), age at menarche (<11, 11–12, 13–14, ≥15 years), parity (0, 1, 2, 3, or ≥4 live births), menopausal status (pre-/perimenopausal, postmenopausal), oral contraceptive use (never, ever), postmenopausal hormone use (never, ever), smoking status (never, former, current), and diabetes status (no, yes; refs. 26, 27, 33–37). For the included cohort studies, participating study sites provided information on covariates closest to the date of diagnosis. If no follow-up was available for a particular study site, covariates reflected cohort baseline. Two studies, the Netherlands Cohort Study on Diet and Cancer and NYU Women's Health Study, did not include information on livebirths only, hence information on livebirths and stillbirths combined was used as a proxy for parity.

To estimate the association between hypertension and endometrial cancer risk, we used individual-level data and performed a pooled complete-case analysis using multivariable unconditional logistic regression to estimate ORs and 95% confidence intervals (CI). All models were adjusted for factors including age (at diagnosis for cases or at index date for controls), race/ethnicity, study site, BMI, age at menarche, parity, menopausal status, oral contraceptive use, postmenopausal hormone therapy use, smoking status, and diabetes status. To examine whether the association between hypertension and endometrial cancer risk is more pronounced among obese or women with diabetes, we stratified by BMI and diabetes status, separately. We also assessed whether the association differed by study design, race/ethnicity, smoking status, or reproductive risk factors including age at menarche, parity, menopausal status, oral contraceptive use, and postmenopausal hormone therapy use. We included interaction terms in models and examined heterogeneity of ORs across subgroups using the Wald test.

To address possible residual confounding by BMI, we reran our models by adjusting for BMI as a continuous variable, however, the effect estimates of these models were not materially different, so we kept our original models adjusting for BMI as a categorical variable. We also conducted a sensitivity analysis excluding BMI as a covariate to test whether BMI is an intermediate factor of the association between hypertension and endometrial cancer.

All reported P values are two-sided and an alpha level of 0.05 was used to define statistical significance. All analyses were conducted using SAS version 9.4.

Deidentified epidemiologic data are available to researchers through a formal protocol submission process. Researchers can request access via the E2C2 website hosted by the NCI (https://epi.grants.cancer.gov/eecc/). Interested parties can follow the information on our E2C2 website to request access to the deidentified data.

Study characteristics of all E2C2 studies included in this analysis are presented in Supplementary Table S1. This study included 15,631 endometrial cancer cases and 42,239 controls (Table 1). The mean age at diagnosis for cases was 63.3 years and the mean index age for controls was 64.2 years. Women with endometrial cancer were more likely to be obese (18.1% vs. 12.2% in controls) or severely obese (18.1% vs. 6.7%), have an early age of menarche (< 11 years; 7.0% vs. 5.6%), be nulliparous (17.5% vs. 13.2%), post-menopausal (74.0% vs. 71.1%), and have diabetes (12.0% vs. 6.8%) compared with controls. Cases were less likely to ever use oral contraceptives (37.5% vs. 42.6%), ever use postmenopausal hormone therapy (34.1% vs. 37.8%), and be former (26.7% vs. 29.0%) or current smokers (9.3% vs. 14.4%) compared with controls.

Nearly 40% of cases had a history of hypertension compared with 31% of controls. After multivariable adjustment, hypertension was associated with an increased risk of endometrial cancer (OR, 1.14; 95% CI, 1.09–1.19; Table 2). While the associations in the cohort (OR, 1.08; 95% CI, 1.02–1.14) and case–control (OR, 1.15; 95% CI, 1.07–1.23) studies were both statistically significant, there was significant heterogeneity by study design (P_het < 0.01). Study-specific effect estimates are shown in Supplementary Fig. S2.

We present subgroup-specific results from the pooled analysis of the association between hypertension and endometrial cancer risk in Table 3. When stratified by race, we observed a statistically significant association between hypertension and endometrial cancer risk in White women (OR_White, 1.14; 95% CI, 1.09–1.20). In Black, Asian, and Other race women, the magnitude of the effect estimates was comparable w those in White women, but not statistically significant, likely due to smaller cell sizes (OR_Black = 1.09, 95% CI, 0.92–1.29; OR_Asian = 1.12, 95% CI, 0.97–1.30; OR_Other = 1.20, 95% CI, 0.91–1.59; P_het = 0.43).

Hypertension was consistently associated with increased risk of endometrial cancer across most BMI strata, with the strongest association observed among women with BMI > 30 kg/m² (OR_{BMI 30–34 kg/m2} = 1.24, 95% CI, 1.12–1.37; OR_{BMI ≥ 35 kg/m2} = 1.17, 95% CI, 1.04–1.32). Among overweight women, we observed a borderline statistically significant association between hypertension and endometrial cancer risk, when compared with women without hypertension (OR_{BMI 25–29 kg/m2} = 1.07, 95% CI, 0.99–1.15; P_het = 0.08). Hypertension was also associated with increased risk of endometrial cancer among the leanest women (OR_{BMI <25 kg/m2} = 1.16; 95% CI, 1.07–1.26). In the sensitivity analysis excluding BMI as a covariate, the association between hypertension and endometrial cancer was stronger (OR, 1.39; 95% CI, 1.34–1.45) compared with the main model (OR, 1.14; 95% CI, 1.09–1.19).

We additionally performed stratified analyses by age at menarche, parity, oral contraceptive use, menopausal status, postmenopausal hormone therapy use, smoking status, and diabetes status. We observed statistically significant differences across groups for menopausal status (P_het = 0.03) and postmenopausal hormone therapy use (P_het < 0.01). Associations of hypertension and endometrial cancer risk were similar by age at menarche, parity, oral contraceptive use, smoking status, and diabetes status (P_het for all > 0.05). We present results for the association between hypertension and endometrial cancer by histologic subtype removing cases with unknown histology (Supplementary Table S2). Hypertension was associated with an increased risk for both endometrioid (OR, 1.56; 95% CI, 1.39–1.76) and nonendometrioid cancers (OR, 1.51; 95% CI, 1.33–1.71).

In this pooled analysis of individual-level data from almost 58,000 women, including nearly 16,000 cases, we found that hypertension is associated with a 14% increased risk of endometrial cancer, independent of diabetes, BMI, and reproductive factors.

Our results are consistent with several published studies that found that hypertension is a risk factor for endometrial cancer, independent of other known metabolic syndrome risk factors (13, 14, 19–21). A systematic review and meta-analysis of six cohort studies and 19 case–control studies reported that hypertension was associated with a 61% increase in endometrial cancer risk, with a weaker association observed among cohort studies when compared with case–control studies (19), consistent with our study findings. However, our results were not as pronounced as that systematic review, likely because the meta-analysis included effect estimates from studies that did not adjust for all known risk factors for endometrial cancer, particularly BMI. Another possible explanation is publication bias in the meta-analysis. In a case–control study evaluating the association between metabolic syndrome and endometrial cancer risk using SEER-Medicare linked data, hypertension was associated with a 13% increase in endometrial cancer risk, independent of body weight (13). Another case–control study found a 57% increase in endometrial cancer risk in women with hypertension, adjusted for known risk factors and other components of metabolic syndrome (21). A population-based cohort study evaluating hypertension and gynecological cancer risk found an 88% increased risk of endometrial cancer, adjusting for known risk factors and relevant comorbidities, although they did not adjust for BMI (20). Taken together, these data suggest that hypertension may be a modifiable risk factor for endometrial cancer development. However, of note, several previous studies did not observe an increased risk of endometrial cancer by hypertension after adjusting for BMI (23, 24), although one did find that hypertension was associated with an increased risk of endometrial cancer among obese women (24). It is important to note that these studies had small sample sizes.

The relationship between hypertension and endometrial cancer may be related to the influence of hypertension on hormonal, metabolic, and inflammatory pathways. However, the link between hypertension and cancer in general remains unclear (38). There is some evidence that suggests hypertension may play a role in inhibiting apoptosis, leading to the development of cancer (39–41). Hypertension has also been linked to increased levels of cytosolic calcium, which is related to cell proliferation activated by oncogenes and certain hormones that have mitogenic effects, such as angiotensin II, catecholamines, vasopressin, insulin, and growth hormone (41, 42). Further research evaluating these biologic mechanisms are needed to help inform the role of hypertension in endometrial cancer risk.

Strengths of our study include the large sample size and heterogeneous study population; this pooled analysis is one of the largest studies to examine the association between hypertension and endometrial cancer risk, to date. Our study design allowed us to combine individual-level data from 29 studies while consistently defining hypertension and other covariates across study sites. In addition, few studies have comprehensively examined the association between hypertension and endometrial cancer risk. Most published literature on this topic has evaluated hypertension as part of the constellation of components of metabolic syndrome (10). Our study's large sample size also allowed us to evaluate the association between hypertension and endometrial cancer risk within strata of established endometrial cancer risk factors. Our study also has several limitations to be noted. We did not have any information on antihypertensive drug use and the timing of hypertension diagnosis in relation to endometrial cancer diagnosis. Because we are unsure if the women in our study were receiving treatment for hypertension, we may not be observing the full effect of hypertension on endometrial cancer. It is important to note, however, that even with treatment information, not knowing whether individuals are compliant with their prescribed antihypertensive mediation and, therefore, whether individuals’ hypertension diagnoses are managed well or unmanaged is a major issue across studies evaluating hypertension as a risk factor. Obtaining this information would be crucial in further evaluating hypertension as a modifiable risk factor for endometrial cancer risk. In addition, self-reported data was utilized, which may have resulted in residual confounding and misclassification of these variables towards the null, although self-report is an established method in epidemiologic studies. In addition, through the data harmonization process, there may be residual confounding introduced through collapsing of more detailed covariate data. There is potential for recall and selection bias for exposure and covariate data, particularly among the case–control studies, although estimates for risk factors published from the E2C2 have been similar across cohort and case–control study design (26). Cohort study sites provided information on menopausal status closest to the time of diagnosis if available, however some study sites were only able to provide menopausal status at baseline. This may have resulted in misclassification of some of the women. However, endometrial cancer is traditionally a disease affecting older women (74% of cases included were diagnosed postmenopause), thus misclassification is likely to be minimal. Some of the case–control studies included in this pooled analysis are hospital-based. Thus, there is the potential for findings to be influenced by selection bias (i.e., Berkson's bias). However, after stratifying by study design the effect estimates were generally comparable. Finally, 82% of our study population was White and thus, our race/ethnicity stratified analysis is limited by small sample sizes.

In summary, we found that hypertension was associated with endometrial cancer risk, independent of known risk factors. Future risk stratification efforts to identify women at high risk of endometrial cancer should include hypertension as one of many predictive factors. In addition, research to evaluate whether existing intervention strategies to lower blood pressure (i.e., use of antihypertensive mediations, diet, and exercise) may help mitigate the rising burden of endometrial cancer. Further research is warranted evaluating the biological mechanisms underlying the observed association.

X. Shu reports grants from NCI outside the submitted work. L. Costas reports grants from ISCIII (PIE16/00049, PI19/01835, PI23/00790) during the conduct of the study; grants from CIBERESP CB06/02/0073, ESP23PI05 and CIBERONC CB16/12/00231 and CB16/12/00234, Generalitat de Catalunya, and grants to support the activities of research groups 2021SGR01354 and 2021SGR1112; and personal fees and non-financial support from Integrated DNA Technologies and Roche Diagnostics (received supplies) at a 50% discount for a research project on endometrial cancer, and received a speaker's honoraria from Roche. Idibell and Roche signed a contract to collaborate in the development of the bioinformatics pipeline of a research project to early detect endometrial cancer. Idibell has received funding from GSK. L. Costas has received a competitive grant from Novosanis/ European Association for Cancer Research (5.000 €) and received Colli-Pee devices (Novosanis) for a research project free of charge outside the submitted work. J.L. Freudenheim reports grants from NIH during the conduct of the study. S.J. Jordan reports grants from National Health and Medical Research Council of Australia, grants from Cancer Australia, grants from Tour de Cure (charity), and grants from Medical Research Future Fund outside the submitted work. J.R. Palmer reports grants from NIH during the conduct of the study. P.M. Webb reports grants from National Health and Medical Research Council (NHMRC) of Australia and grants from Cancer Council Tasmania during the conduct of the study. A. Zeleniuch-Jacquotte reports grants from NIH/NCI during the conduct of the study. M. Du reports grants from NCI during the conduct of the study. No disclosures were reported by the other authors.

T.S. Habeshian: Conceptualization, data curation, formal analysis, investigation, visualization, methodology, writing–original draft, project administration. N.C. Peeri: Formal analysis, writing–review and editing. I. De Vivo: Funding acquisition, methodology, writing–review and editing. L.J. Schouten: Writing–review and editing. X.-o. Shu: Writing–review and editing. M.L. Cote: Writing–review and editing. K.A. Bertrand: Writing–review and editing. Y. Chen: Writing–review and editing. M.A. Clarke: Writing–review and editing. T.V. Clendenen: Writing–review and editing. L.S. Cook: Writing–review and editing. L. Costas: Writing–review and editing. L. Dal Maso: Writing–review and editing. J.L. Freudenheim: Writing–review and editing. C.M. Friedenreich: Writing–review and editing. G. Gallagher: Writing–review and editing. G.L. Gierach: Writing–review and editing. M.T. Goodman: Writing–review and editing. S.J. Jordan: Writing–review and editing. C. La Vecchia: Writing–review and editing. J.V. Lacey: Writing–review and editing. F. Levi: Writing–review and editing. L.M. Liao: Writing–review and editing. L. Lipworth: Writing–review and editing. L. Lu: Writing–review and editing. X. Matías-Guiu: Writing–review and editing. K.B. Moysich: Writing–review and editing. G.L. Mutter: Writing–review and editing. R. Na: Writing–review and editing. J. Naduparambil: Writing–review and editing. E. Negri: Writing–review and editing. K. O'Connell: Writing–review and editing. T.A. O'Mara: Writing–review and editing. I. Onieva Hernández: Writing–review and editing. J.R. Palmer: Writing–review and editing. F. Parazzini: Writing–review and editing. A.V. Patel: Writing–review and editing. K.L. Penney: Writing–review and editing. A.E. Prizment: Writing–review and editing. F. Ricceri: Writing–review and editing. H.A. Risch: Writing–review and editing. C. Sacerdote: Writing–review and editing. S. Sandin: Writing–review and editing. R.Z. Stolzenberg-Solomon: Writing–review and editing. P.A. van den Brandt: Writing–review and editing. P.M. Webb: Writing–review and editing. N. Wentzensen: Writing–review and editing. A.T. Wijayabahu: Writing–review and editing. L.R. Wilkens: Writing–review and editing. W. Xu: Writing–review and editing. H. Yu: Writing–review and editing. A. Zeleniuch-Jacquotte: Writing–review and editing. W. Zheng: Writing–review and editing. M. Du: Resources, funding acquisition, methodology, writing–review and editing. V.W. Setiawan: Conceptualization, resources, funding acquisition, methodology, project administration, writing–review and editing.

AARP: This research was supported [in part] by the Intramural Research Program of the NIH, NCI. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia. Cancer incidence data from California were collected by the California Cancer Registry, California Department of Public Health's Cancer Surveillance and Research Branch, Sacramento, California. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, Lansing, Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System (Miami, Florida) under contract with the Florida Department of Health, Tallahassee, Florida. The views expressed herein are solely those of the authors and do not necessarily reflect those of the FCDC or FDOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Health Sciences Center School of Public Health, New Orleans, Louisiana. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, The Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry, Raleigh, North Carolina. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, PA. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services, Phoenix, Arizona. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas. Cancer incidence data from Nevada were collected by the Nevada Central Cancer Registry, Division of Public and Behavioral Health, State of Nevada Department of Health and Human Services, Carson City, NV. We are indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. We wish to acknowledge Dr. Arthur Schatzkin who was instrumental in conceiving and establishing the NIH-AARP Diet and Health Study. We also thank former and current study leaders at the NCI and AARP, including Louise A. Brinton, Laurence S. Freedman, Albert R. Hollenbeck, Victor Kipnis, Michael F. Leitzmann, Linda M. Liao, Charles E. Matthews, Yikyung Park, Rashmi Sinha, Amy F. Subar and Mary H. Ward. Additionally, we are thankful to Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcomes ascertainment and management and Leslie Carroll and her team at Information Management Services for data support and analysis.

ALBERTA: The study was funded by the Canadian Cancer Society. C Friedenreich received career awards from the Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research (AHFMR) during the conduct of this study. NCI Grants No. 12018, 13010, 17323; ACB Grant No. 22190.

ANECS: The National Health and Medical Research Council (NHMRC) of Australia (APP339435, APP1073898, APP1061341, APP1061779); Cancer Council Tasmania (403031, 457636). The authors acknowledge the members of the ANECS Group.

BCDDP: Intramural Research Programs of the NCI/NIH, Department of Health and Human Services, United States.

BWHS: This work was supported by the NIH (U01CA164974, R03CA169888). The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention's National Program of Cancer Registries (NPCR) and/or the NCI's Surveillance, Epidemiology, and End Results (SEER) Program. Central registries may also be supported by state agencies, universities, and cancer centers. Participating central cancer registries include the following: AL, AR, AZ, CA, CO, CT, DE, DC, FL, GA, HI, IA, IL, IN, KY, LA, MD, MA, MI, MO, MS, NE, NJ, NM, NY, NC, OH, OK, OR, PA, SC, TN, TX, VA, WA, WI. We thank participants and staff of the BWHS for their contributions.

CECS: R01CA098346

CPS-II: The authors express sincere appreciation to all Cancer Prevention Study-II participants, and to each member of the study and biospecimen management group. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention's National Program of Cancer Registries and cancer registries supported by the NCI's SEER Program.

CTS: The California Teachers Study and the research reported in this publication were supported by the NCI of the NIH under award number U01-CA199277; P30-CA033572; P30-CA023100; UM1-CA164917; and R01-CA077398. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or the NIH. “The collection of cancer incidence data used in the California Teachers Study was supported by the California Department of Public Health pursuant to California Health and Safety Code Section 103885; Centers for Disease Control and Prevention's National Program of Cancer Registries, under cooperative agreement 5NU58DP006344; the NCI's SEER Program under contract HHSN261201800032I awarded to the University of California, San Francisco, contract HHSN261201800015I awarded to the University of Southern California, and contract HHSN261201800009I awarded to the Public Health Institute. The opinions, findings, and conclusions expressed herein are those of the author(s) and do not necessarily reflect the official views of the State of California, Department of Public Health, the NCI, the NIH, the Centers for Disease Control and Prevention or their Contractors and Subcontractors, or the Regents of the University of California, or any of its programs. “The authors would like to thank the California Teachers Study Steering Committee that is responsible for the formation and maintenance of the Study within which this research was conducted. A full list of California Teachers Study team members is available at https://www.calteachersstudy.org/team.”

TURIN: This work was supported by the Italian Association for Cancer Research (AIRC).

EDGE: The authors acknowledge the critical role of Sara Olson who made the study possible as founder of the Epidemiology of Endometrial Cancer Consortium as well as Estrogen, Diet, Genetics, and Endometrial Cancer studies. The E2C2 Data Coordinating Center at Memorial Sloan Kettering Cancer Center and multiple authors are supported by the NCI grant U01 CA250476. The Data Coordinating Center is additionally supported by NCI P30 CA008748. EDGE was additionally supported by NCI R01 CA083918.

HAW: This investigation was supported in part by USPHS Grants P01-CA-33619, R01-CA-58598, R01-CA-55700, and P20-CA-57113 and by contracts N01-CN-05223 and N01-CN-55424 from the NCI, NIH, Department of Health and Human Services. NCI/NIH (R35 CA39779, R01 CA47749, R01 CA75977, N01 HD 2 3166, K05 CA92002, R01 CA105212, R01 CA87538).

IWHS: The authors are thankful to the IWHS participants. We would also like to thank Ching-Ping Hong for consultation and assistance in data preparation. R01 CA39742.

Italian Multicentre Study: Grant number: 1468. Italian Association for Cancer Research (AIRC; Associazione Italiana per la Ricerca sul Cancro) Foundation.

MEC: NCI U01CA164973.

MILA-1: Grant number: 1468. AIRC Foundation.

MILA-2: Grant number: 1468. AIRC Foundation.

NCI: ZIA CP010126. Intramural Research Programs of the NCI, NIH, Department of Health and Human Services, United States.

NHS: 2R01 CA082838 and P01 CA87969. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention's National Program of Cancer Registries (NPCR) and/or the NCI's SEER Program. Central registries may also be supported by state agencies, universities, and cancer centers. Participating central cancer registries include the following: AL, AK, AZ, AR, CA, CO, CT, DE, FL, GA, HI, ID, IN, IA, KY, LA, MA, ME, MD, MI, MT, NE, NV, NH, NJ, NM, NY, NC, ND, OH, OK, OR, PA, PR, RI, Seattle SEER Registry, SC, TN, TX, UT, VA, WV, and WY.

NLCS: The Netherlands Cohort Study (NLCS) was supported by grants from the Dutch Cancer Society and the World Cancer Research Fund. The authors would like to thank the participants of the NLCS, the Netherlands Cancer Registry and the Netherlands Pathology Registry. Furthermore, NLCS staff members are acknowledged for their valuable assistance and advice.

NYUWHS: NCI (R01 CA081212, U01 CA182934, and P30 CA016087) and U.S. National Institute of Environmental Health Sciences (P30 ES000260).

PEDS: P30CA016056

PLCO: Intramural Research Programs of the NCI, NIH, Department of Health and Human Services, United States.

SCCS: U01CA202979 (SCCS)

Screenwide: Carlos III Health Institute through projects PI19/01835, PI23/00790, and FI20/00031, cofinanced by the European Regional Development Fund ERDF, a way to build Europe; as well as through CIBERESP CB06/02/0073 and CIBERONC CB16/12/00231. It also counts with the support of the Secretariat for Universities and Research of the Department of Business and Knowledge of the Generalitat de Catalunya, grants to support the activities of research group 2021SGR01354. We thank CERCA Programme / Generalitat de Catalunya for institutional support.

SECS: R01 CA092585

SWISS: Swiss National Science Foundation grant 32.9495.88 and the Swiss National Cancer Research Foundation grant OCS 1633–02–2005.

US Endometrial Case-Control Study: Intramural Research Programs of the NCI, NIH, Department of Health and Human Services, United States.

WLHS: Research Council (521–2011–2955 Swedish).

WNYDS: P30CA016056