|
1
|
Zhu P, Ren J, Sun J, Geng J, Wang H, Ma M. The association of endogenous sex hormones with endometrial cancer risk: A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2025; 310:113997. [PMID: 40300286 DOI: 10.1016/j.ejogrb.2025.113997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 04/20/2025] [Accepted: 04/21/2025] [Indexed: 05/01/2025]
Abstract
OBJECTIVES The role of endogenous sex hormones in the risk of endometrial cancer (EC) remains contradictory across the studies. This meta-analysis was carried out to investigate the relation of circulating concentrations of sex hormones and sex hormone-binding globulin (SHBG) to EC risk. METHODS A search of the PubMed, Web of Science, and Scopus databases was conducted to include relevant studies. We used odds ratios (OR) with 95% confidence intervals (CI) to pool effect sizes using a random effects model. RESULTS The analysis included 16 studies with 292,695 participants. SHBG levels showed an inverse relationship with EC (OR: 0.67). In contrast, higher circulating levels of total testosterone (OR: 1.70), free testosterone (OR: 1.75), dehydroepiandrosterone sulfate (OR: 1.39), and androstenedione (OR: 1.58) were positively associated with EC risk. Estrogens also demonstrated significant associations, so that estrone (OR: 1.55), unconjugated estrone (OR: 1.86), estradiol (OR: 1.38), unconjugated estradiol (OR: 2.14), estriol (OR: 1.75), and unconjugated estriol (OR: 1.99) were linked to increased EC risk, while conjugated estrogens showed no significant associations. A non-linear dose-response relationship was found for SHBG, estrone, estradiol, and total testosterone. The results were significantly affected by age, cancer type, geographic region, menopausal status, study type, and the level of adjustments for covariates. For all hormones, the significant associations were found only for postmenopausal women. CONCLUSIONS This study found an inverse association between SHBG and EC, while identified a direct relationship between sex hormones, except for conjugated estrogens, and EC risk only in postmenopausal women.
Collapse
Affiliation(s)
- Pengfei Zhu
- Department of Gynecology, Dezhou Women and Children's Hospital, Dezhou 253000, China
| | - Juanjuan Ren
- Department of Gynecology, Dezhou Women and Children's Hospital, Dezhou 253000, China
| | - Jing Sun
- Department of Gynecology, Dezhou Women and Children's Hospital, Dezhou 253000, China
| | - Jingjing Geng
- Department of Gynecology, Dezhou Women and Children's Hospital, Dezhou 253000, China
| | - Huan Wang
- Department of Gynecology, Dezhou Women and Children's Hospital, Dezhou 253000, China
| | - Mingming Ma
- Department of Gynecology, Dezhou Women and Children's Hospital, Dezhou 253000, China.
| |
Collapse
|
|
2
|
Bosland MC, Gordon T, Solomon JJ, Shore RE, Lippmann M. Seventy-five years of impactful environmental and occupational health research at the Nelson Institute of Environmental Medicine at New York University. Ann N Y Acad Sci 2024; 1540:147-165. [PMID: 39320132 DOI: 10.1111/nyas.15226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/26/2024]
Abstract
Founded in 1947 as the Institute of Industrial Medicine, the Nelson Institute and Department of Environmental Medicine at New York University (NYU) Grossman School of Medicine (NYUGSOM) was supported by a National Institute of Environmental Health Science (NIEHS) Center Grant for over 56 years. Nelson Institute researchers generated 75 years of impactful research in environmental and occupational health, radiation effects, toxicology, and cancer. Environmental health research is continuing at NYUGSOM in its departments of medicine and population health. The objective of this historical commentary is to highlight the major achievements of the Nelson Institute and the department in the context of its history at facilities in Sterling Forest, Tuxedo, NY and Manhattan, NY. Aspects of our discussion include leadership, physical facilities, and research in many areas, including air pollution, health effects of environmental radiation exposures, inhalation toxicology methodology, carcinogenesis by chemicals, metals, and hormones, cancer chemoprevention, human microbiome, ecotoxicology, epidemiology, biostatistics, and community health concerns. The research of the institute and department benefited from unique facilities, strong leadership focused on team-based science, and outstanding investigators, students, and staff. A major lasting contribution has been the training of hundreds of graduate students and postdoctoral fellows, many of whom have been and are training the next generation of environmental and occupational health researchers at various institutions.
Collapse
Affiliation(s)
- Maarten C Bosland
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
- Formerly, Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA
| | - Terry Gordon
- Division of Environmental Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA
| | - Jerome J Solomon
- Retired from Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA
| | - Roy E Shore
- Retired from Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA
| | - Morton Lippmann
- Retired from Nelson Institute and Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA
| |
Collapse
|
|
3
|
Solanki R, Zubbair Malik M, Alankar B, Ahmad FJ, Dohare R, Chauhan R, Kesharwani P, Kaur H. Identification of novel biomarkers and potential molecular targets for uterine cancer using network-based approach. Pathol Res Pract 2024; 260:155431. [PMID: 39029376 DOI: 10.1016/j.prp.2024.155431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 06/20/2024] [Accepted: 06/26/2024] [Indexed: 07/21/2024]
Abstract
A better understanding of incidences at the cellular level in uterine cancer is necessary for its effective treatment and favourable prognosis. Till date, it lacks appropriate molecular target-based treatment because of unknown molecular mechanisms that proceed to cancer and no drug has shown the required results of treatment with less severe side effects. Uterine Cancer is one of the top five cancer diagnoses and among the ten most common death-causing cancer in the United States of America. There is no FDA-approved drug for it yet. Therefore, it became necessary to identify the molecular targets for molecular targeted therapy of this widely prevalent cancer type. For this study, we used a network-based approach to the list of the deregulated (both up and down-regulated) genes taking adjacent p-Value ≤ 0.05 as significance cut off for the mRNA data of uterine cancer. We constructed the protein-protein interaction (PPI) network and analyzed the degree, closeness, and betweenness centrality-like topological properties of the PPI network. Then we traced the top 30 genes listed from each topological property to find the key regulators involved in the endometrial cancer (ECa) network. We then detected the communities and sub-communities from the PPI network using the Cytoscape network analyzer and Louvain modularity optimization method. A set of 26 (TOP2A, CENPE, RAD51, BUB1, BUB1B, KIF2C, KIF23, KIF11, KIF20A, ASPM, AURKA, AURKB, PLK1, CDC20, CDKN2A, EZH2, CCNA2, CCNB1, CDK1, FGF2, PRKCA, PGR, CAMK2A, HPGDS, and CDCA8) genes were found to be key genes of ECa regulatory network altered in disease state and might be playing the regulatory role in complex ECa network. Our study suggests that among these genes, KIF11 and H PGDS appeared to be novel key genes identified in our research. We also identified these key genes interactions with miRNAs.
Collapse
Affiliation(s)
- Rubi Solanki
- School of Interdisciplinary Sciences and Technology, Jamia Hamdard, New Delhi 110062, India
| | - Md Zubbair Malik
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute Dasman 15462, Kuwait
| | - Bhavya Alankar
- Department of Computer Science and Engineering, School of Engineering Sciences and Technology, Jamia Hamdard, New Delhi 110062, India.
| | - Farhan Jalees Ahmad
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Ravins Dohare
- Centre for Interdisciplinary Research in Basic Sciences, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Ritu Chauhan
- Artificial Intelligence and IoT lab, Centre for Computational Biology and Bioinformatics, Amity University, Noida, India
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
| | - Harleen Kaur
- Department of Computer Science and Engineering, School of Engineering Sciences and Technology, Jamia Hamdard, New Delhi 110062, India.
| |
Collapse
|
|
4
|
Bukato K, Kostrzewa T, Gammazza AM, Gorska-Ponikowska M, Sawicki S. Endogenous estrogen metabolites as oxidative stress mediators and endometrial cancer biomarkers. Cell Commun Signal 2024; 22:205. [PMID: 38566107 PMCID: PMC10985914 DOI: 10.1186/s12964-024-01583-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 03/23/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND Endometrial cancer is the most common gynecologic malignancy found in developed countries. Because therapy can be curative at first, early detection and diagnosis are crucial for successful treatment. Early diagnosis allows patients to avoid radical therapies and offers conservative management options. There are currently no proven biomarkers that predict the risk of disease occurrence, enable early identification or support prognostic evaluation. Consequently, there is increasing interest in discovering sensitive and specific biomarkers for the detection of endometrial cancer using noninvasive approaches. CONTENT Hormonal imbalance caused by unopposed estrogen affects the expression of genes involved in cell proliferation and apoptosis, which can lead to uncontrolled cell growth and carcinogenesis. In addition, due to their ability to cause oxidative stress, estradiol metabolites have both carcinogenic and anticarcinogenic properties. Catechol estrogens are converted to reactive quinones, resulting in oxidative DNA damage that can initiate the carcinogenic process. The molecular anticancer mechanisms are still not fully understood, but it has been established that some estradiol metabolites generate reactive oxygen species and reactive nitrogen species, resulting in nitro-oxidative stress that causes cancer cell cycle arrest or cell death. Therefore, identifying biomarkers that reflect this hormonal imbalance and the presence of endometrial cancer in minimally invasive or noninvasive samples such as blood or urine could significantly improve early detection and treatment outcomes.
Collapse
Affiliation(s)
- Katarzyna Bukato
- Department of Obstetrics and Gynecology, Oncological Gynecology and Gynecological Endocrinology, Medical University of Gdansk, Smoluchowskiego 17, Gdańsk, 80-214, Poland
| | - Tomasz Kostrzewa
- Department of Medical Chemistry, Faculty of Medicine, Medical University of Gdansk, Dębinki 1, Gdansk, 80-211, Poland
| | - Antonella Marino Gammazza
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, 90127, Italy
| | - Magdalena Gorska-Ponikowska
- Department of Medical Chemistry, Faculty of Medicine, Medical University of Gdansk, Dębinki 1, Gdansk, 80-211, Poland.
- IEMEST Istituto Euro-Mediterraneo di Scienza e Tecnologia, Palermo, 90127, Italy.
- Department of Biophysics, Institute of Biomaterials and Biomolecular Systems, University of Stuttgart, 70174, Stuttgart, Germany.
| | - Sambor Sawicki
- Department of Obstetrics and Gynecology, Oncological Gynecology and Gynecological Endocrinology, Medical University of Gdansk, Smoluchowskiego 17, Gdańsk, 80-214, Poland.
| |
Collapse
|
|
5
|
Power RF, Doherty DE, Parker I, Gallagher DJ, Lowery MA, Cadoo KA. Modifiable Risk Factors and Risk of Colorectal and Endometrial Cancers in Lynch Syndrome: A Systematic Review and Meta-Analysis. JCO Precis Oncol 2024; 8:e2300196. [PMID: 38207227 DOI: 10.1200/po.23.00196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 09/21/2023] [Accepted: 09/23/2023] [Indexed: 01/13/2024] Open
Abstract
PURPOSE Lynch syndrome is the most common hereditary cause of colorectal and endometrial cancers. Modifiable risk factors, including obesity, physical activity, alcohol intake, and smoking, are well-established in sporadic cancers but are less studied in Lynch syndrome. METHODS Searches were conducted on MEDLINE, Embase, and Web of Science for cohort studies that investigated the association between modifiable risk factors and the risk of colorectal or endometrial cancer in people with Lynch syndrome. Adjusted hazard ratios (HRs) and 95% CIs for colorectal and endometrial cancers were pooled using a random effects model. The protocol was prospectively registered on PROSPERO (CRD 42022378462), and the meta-analysis was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology reporting guidelines. RESULTS A total of 770 citations were reviewed. Eighteen studies were identified for qualitative synthesis, with seven colorectal cancer (CRC) studies eligible for meta-analysis. Obesity (HR, 2.38 [95% CI, 1.52 to 3.73]) was associated with increased CRC risk. There was no increased CRC risk associated with smoking (HR, 1.04 [95% CI, 0.82 to 1.32]) or alcohol intake (HR, 1.32 [95% CI, 0.97 to 1.81]). Type 2 diabetes mellitus (T2DM) and some dietary factors might increase risk of CRC although more studies are needed. In a qualitative synthesis of three endometrial cancer cohort studies, female hormonal risk factors and T2DM may affect the risk of endometrial cancer, but obesity was not associated with an increased risk. CONCLUSION Lifestyle recommendations related to weight and physical activity may also be relevant to cancer prevention for individuals with Lynch syndrome. Further high-quality prospective cohort studies, in particular, including endometrial cancer as an end point, are needed to inform evidence-based cancer prevention strategies in this high-risk population.
Collapse
Affiliation(s)
- Robert F Power
- Mater Misericordiae University Hospital, Dublin, Ireland
- Cancer Genetics Service, Trinity St James's Cancer Institute, Dublin, Ireland
| | | | - Imelda Parker
- Department of Biostatistics, Cancer Trials Ireland, Dublin, Ireland
| | - David J Gallagher
- Cancer Genetics Service, Trinity St James's Cancer Institute, Dublin, Ireland
- School of Medicine, Trinity College Dublin, Dublin, Ireland
- Department of Medical Oncology, Trinity St James's Cancer Institute, Dublin, Ireland
| | - Maeve A Lowery
- School of Medicine, Trinity College Dublin, Dublin, Ireland
- Department of Medical Oncology, Trinity St James's Cancer Institute, Dublin, Ireland
| | - Karen A Cadoo
- Cancer Genetics Service, Trinity St James's Cancer Institute, Dublin, Ireland
- School of Medicine, Trinity College Dublin, Dublin, Ireland
- Department of Medical Oncology, Trinity St James's Cancer Institute, Dublin, Ireland
| |
Collapse
|
|
6
|
Ren H, Zhang Y, Duan H. Recent advances in the management of postmenopausal women with non-atypical endometrial hyperplasia. Climacteric 2023; 26:411-418. [PMID: 37577792 DOI: 10.1080/13697137.2023.2226316] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 04/30/2023] [Accepted: 06/08/2023] [Indexed: 08/15/2023]
Abstract
Non-atypical endometrial hyperplasia is a benign disease without significant somatic genetic changes. Postmenopausal women with non-atypical endometrial hyperplasia have a significant risk of progression to endometrial cancer and persistent endometrial hyperplasia. Most cases of atypical endometrial hyperplasia in postmenopausal women are treated surgically, including hysterectomy. At present, the treatment of postmenopausal women with non-atypical endometrial hyperplasia is still controversial. Correct and timely diagnosis and treatment are of great significance to prevent progression of the lesion. This study mainly provides an updated synthesis of the literature that investigates the etiology, diagnosis and treatment of postmenopausal women with non-atypical endometrial hyperplasia. As of December 2022, a literature search related to postmenopausal non-atypical endometrial hyperplasia was conducted on the PubMed database. For most postmenopausal patients with non-atypical endometrial hyperplasia, regular re-examination should be performed during conservative treatment. For postmenopausal patients with endometrial cancer risk factors, persistent non-atypical endometrial hyperplasia or progesterone contraindications, hysterectomy and bilateral salpingo-oophorectomy should be the first choice.
Collapse
Affiliation(s)
- H Ren
- Department of Minimally Invasive Gynecologic Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Y Zhang
- Department of Minimally Invasive Gynecologic Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - H Duan
- Department of Minimally Invasive Gynecologic Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
7
|
Otsuka K, Nishiyama H, Kuriki D, Kawada N, Ochiya T. Connecting the dots in the associations between diet, obesity, cancer, and microRNAs. Semin Cancer Biol 2023; 93:52-69. [PMID: 37156343 DOI: 10.1016/j.semcancer.2023.05.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/27/2023] [Accepted: 05/01/2023] [Indexed: 05/10/2023]
Abstract
The prevalence of obesity has reached pandemic levels worldwide, leading to a lower quality of life and higher health costs. Obesity is a major risk factor for noncommunicable diseases, including cancer, although obesity is one of the major preventable causes of cancer. Lifestyle factors, such as dietary quality and patterns, are also closely related to the onset and development of obesity and cancer. However, the mechanisms underlying the complex association between diet, obesity, and cancer remain unclear. In the past few decades, microRNAs (miRNAs), a class of small non-coding RNAs, have been demonstrated to play critical roles in biological processes such as cell differentiation, proliferation, and metabolism, highlighting their importance in disease development and suppression and as therapeutic targets. miRNA expression levels can be modulated by diet and are involved in cancer and obesity-related diseases. Circulating miRNAs can also mediate cell-to-cell communications. These multiple aspects of miRNAs present challenges in understanding and integrating their mechanism of action. Here, we introduce a general consideration of the associations between diet, obesity, and cancer and review the current knowledge of the molecular functions of miRNA in each context. A comprehensive understanding of the interplay between diet, obesity, and cancer could be valuable for the development of effective preventive and therapeutic strategies in future.
Collapse
Affiliation(s)
- Kurataka Otsuka
- Tokyo NODAI Research Institure, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo 156-8502, Japan; R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan; Division of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishishinjyuku, Shinjuku-ku, Tokyo 160-0023, Japan; Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Hiroshi Nishiyama
- R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan
| | - Daisuke Kuriki
- R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan
| | - Naoki Kawada
- R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishishinjyuku, Shinjuku-ku, Tokyo 160-0023, Japan
| |
Collapse
|
|
8
|
Li Y, Liu G, Gong R, Xi Y. Gut Microbiome Dysbiosis in Patients with Endometrial Cancer vs. Healthy Controls Based on 16S rRNA Gene Sequencing. Curr Microbiol 2023; 80:239. [PMID: 37294364 DOI: 10.1007/s00284-023-03361-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 06/02/2023] [Indexed: 06/10/2023]
Abstract
Metabolic diseases like obesity, diabetes, and hypertension are considered major risk factors associated with endometrial cancer. Considering that an imbalance in the gut microbiome may lead to metabolic alterations, we hypothesized that alteration in the gut microbioma might be an indirect factor in the development of endometrial cancer. Our aim was to profile the gut microbiota of patients with endometrial cancer compared with healthy controls in this study. Thus, we used 16S rRNA high-throughput gene sequencing on the Illumina NovaSeq platform to profile microbial communities. Fecal samples were collected from 33 endometrial cancer patients (EC group) and 32 healthy controls (N group) between February 2021 and July 2021. The total numbers of operational taxonomic units (OTUs) in the N and EC groups were 28,537 and 18,465, respectively, while the number of OTUs shared by the two groups was 4771. This study was the first to report that the alpha diversity of the gut microbiota was significantly reduced in endometrial cancer patients vs. healthy controls. Also, there was a significant difference in the distribution of microbiome between the two groups: the abundance of Firmicutes, Clostridia, Clostridiales, Ruminococcaceae, Faecalibacterium, and Gemmiger_formicis decreased, while that of Proteobacteria, Gammaproteobacteria, Enterobacteriales, Enterobacteriaceae and Shigella increased significantly in the EC group vs. healthy controls (all p < 0.05). The predominant intestinal microbiota of the endometrial cancer patients was Proteobacteria, Gammaproteobacteria, Enterobacteriales, Enterobacteriaceae, and Shigella. These results imply that adjusting the composition of the gut microbiota and maintaining microbiota homeostasis may be an effective strategy for preventing and treating endometrial cancer.
Collapse
Affiliation(s)
- Yue Li
- Department of Obstetrics and Gynecology, Dalian Municipal Women and Children's Medical Center (Group), No.1, Dunhuang Road, Shahekou District, Dalian, Liaoning, 116033, P.R. China
| | - Geng Liu
- Department of Obstetrics and Gynecology, Dalian Municipal Women and Children's Medical Center (Group), No.1, Dunhuang Road, Shahekou District, Dalian, Liaoning, 116033, P.R. China
| | - Runqi Gong
- Department of Obstetrics and Gynecology, Liaoning Provincial Hospital for women and children, Shenyang, Liaoning, 110004, P.R. China
| | - Yong Xi
- Department of Obstetrics and Gynecology, Dalian Municipal Women and Children's Medical Center (Group), No.1, Dunhuang Road, Shahekou District, Dalian, Liaoning, 116033, P.R. China.
| |
Collapse
|
|
9
|
Yuan S, Wang L, Sun J, Yu L, Zhou X, Yang J, Zhu Y, Gill D, Burgess S, Denny JC, Larsson SC, Theodoratou E, Li X. Genetically predicted sex hormone levels and health outcomes: phenome-wide Mendelian randomization investigation. Int J Epidemiol 2022; 51:1931-1942. [PMID: 35218343 PMCID: PMC9749729 DOI: 10.1093/ije/dyac036] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 02/10/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Sex hormone-binding globulin (SHBG), testosterone and oestradiol have been associated with many diseases in observational studies; however, the causality of associations remains unestablished. METHODS A phenome-wide Mendelian randomization (MR) association study was performed to explore disease outcomes associated with genetically proxied circulating SHBG, testosterone and oestradiol levels by using updated genetic instruments in 339 197 unrelated White British individuals (54% female) in the UK Biobank. Two-sample MR analyses with data from large genetic studies were conducted to replicate identified associations in phenome-wide MR analyses. Multivariable MR analyses were performed to investigate mediation effects of hormone-related biomarkers in observed associations with diseases. RESULTS Phenome-wide MR analyses examined associations of genetically predicted SHBG, testosterone and oestradiol levels with 1211 disease outcomes, and identified 28 and 13 distinct phenotypes associated with genetically predicted SHBG and testosterone, respectively; 22 out of 28 associations for SHBG and 10 out of 13 associations for testosterone were replicated in two-sample MR analyses. Higher genetically predicted SHBG levels were associated with a reduced risk of hypertension, type 2 diabetes, diabetic complications, coronary atherosclerotic outcomes, gout and benign and malignant neoplasm of uterus, but an increased risk of varicose veins and fracture (mainly in females). Higher genetically predicted testosterone levels were associated with a lower risk of type 2 diabetes, coronary atherosclerotic outcomes, gout and coeliac disease mainly in males, but an increased risk of cholelithiasis in females. CONCLUSIONS These findings suggest that sex hormones may causally affect risk of several health outcomes.
Collapse
Affiliation(s)
- Shuai Yuan
- Department of Big Data in Health Science, Center of Clinical Big Data and Analytics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Lijuan Wang
- Department of Big Data in Health Science, Center of Clinical Big Data and Analytics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Sun
- Department of Big Data in Health Science, Center of Clinical Big Data and Analytics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lili Yu
- Department of Big Data in Health Science, Center of Clinical Big Data and Analytics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xuan Zhou
- Department of Big Data in Health Science, Center of Clinical Big Data and Analytics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jie Yang
- Department of Big Data in Health Science, Center of Clinical Big Data and Analytics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yimin Zhu
- Department of Big Data in Health Science, Center of Clinical Big Data and Analytics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dipender Gill
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Stephen Burgess
- MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK
| | - Joshua C Denny
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Susanna C Larsson
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | | | - Xue Li
- Corresponding author. School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. E-mail:
| |
Collapse
|
|
10
|
Dimou N, Omiyale W, Biessy C, Viallon V, Kaaks R, O'Mara TA, Aglago EK, Ardanaz E, Bergmann MM, Bondonno NP, Braaten T, Colorado-Yohar SM, Crous-Bou M, Dahm CC, Fortner RT, Gram IT, Harlid S, Heath AK, Idahl A, Kvaskoff M, Nøst TH, Overvad K, Palli D, Perez-Cornago A, Sacerdote C, Sánchez MJ, Schulze MB, Severi G, Simeon V, Tagliabue G, Tjønneland A, Truong T, Tumino R, Johansson M, Weiderpass E, Murphy N, Gunter MJ, Lacey B, Allen NE, Dossus L. Cigarette Smoking and Endometrial Cancer Risk: Observational and Mendelian Randomization Analyses. Cancer Epidemiol Biomarkers Prev 2022; 31:1839-1848. [PMID: 35900194 PMCID: PMC9437565 DOI: 10.1158/1055-9965.epi-21-1176] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 01/28/2022] [Accepted: 06/16/2022] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Current epidemiologic evidence indicates that smoking is associated with a lower endometrial cancer risk. However, it is unknown if this association is causal or confounded. To further elucidate the role of smoking in endometrial cancer risk, we conducted complementary observational and Mendelian randomization (MR) analyses. METHODS The observational analyses included 286,415 participants enrolled in the European Prospective Investigation into Cancer and Nutrition and 179,271 participants in the UK Biobank, and multivariable Cox proportional hazards models were used. In two-sample MR analyses, genetic variants robustly associated with lifetime amount of smoking (n = 126 variants) and ever having smoked regularly (n = 112 variants) were selected and their association with endometrial cancer risk (12,906 cancer/108,979 controls from the Endometrial Cancer Association Consortium) was examined. RESULTS In the observational analysis, lifetime amount of smoking and ever having smoked regularly were associated with a lower endometrial cancer risk. In the MR analysis accounting for body mass index, a genetic predisposition to a higher lifetime amount of smoking was not associated with endometrial cancer risk (OR per 1-SD increment: 1.15; 95% confidence interval: 0.91-1.44). Genetic predisposition to ever having smoked regularly was not associated with risk of endometrial cancer. CONCLUSIONS Smoking was inversely associated with endometrial cancer in the observational analyses, although unsupported by the MR. Additional studies are required to better understand the possible confounders and mechanisms underlying the observed associations between smoking and endometrial cancer. IMPACT The results from this analysis indicate that smoking is unlikely to be causally linked with endometrial cancer risk.
Collapse
Affiliation(s)
- Niki Dimou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - Wemimo Omiyale
- Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Carine Biessy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - Vivian Viallon
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Tracy A. O'Mara
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Elom K. Aglago
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - Eva Ardanaz
- Navarra Public Health Institute, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Spain
| | | | | | - Tonje Braaten
- Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway
| | - Sandra M. Colorado-Yohar
- CIBER Epidemiología y Salud Pública (CIBERESP), Spain
- Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain
- Research Group on Demography and Health, National Faculty of Public Health, University of Antioquia, Medellín, Colombia
| | - Marta Crous-Bou
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO) - Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Department of Epidemiology, Harvard T.H. Chan School of Public Health. Boston, Massachusetts
| | | | - Renée T. Fortner
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Inger T. Gram
- Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway
| | - Sophia Harlid
- Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Umeå, Sweden
| | - Alicia K. Heath
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Annika Idahl
- Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Umeå, Sweden
| | - Marina Kvaskoff
- Université Paris-Saclay, UVSQ, Inserm CESP U1018, "Exposome and Heredity" Team, Gustave Roussy, Villejuif, France
| | - Therese H. Nøst
- Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - Kim Overvad
- Department of Public Health, Aarhus University, Aarhus, Denmark
| | - Domenico Palli
- Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy
| | - Aurora Perez-Cornago
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Carlotta Sacerdote
- Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital, Turin, Italy
| | - Maria-Jose Sánchez
- Escuela Andaluza de Salud Pública (EASP), Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain
| | - Matthias B. Schulze
- Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
- Institute of Nutritional Science, University of Potsdam, Potsdam, Germany
| | - Gianluca Severi
- Université Paris-Saclay, UVSQ, Inserm CESP U1018, "Exposome and Heredity" Team, Gustave Roussy, Villejuif, France
- Department of Statistics, Computer Science, Applications "G. Parenti", University of Florence, Florence, Italy
| | - Vittorio Simeon
- Dipartimento di Salute Mentale e Fisica e Medicina Preventiva, University of Naples "L. Vanvitelli", Naples, Italy
| | - Giovanna Tagliabue
- Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori Via Venezian 1, Milan, Italy
| | - Anne Tjønneland
- Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Thérèse Truong
- Université Paris-Saclay, UVSQ, Inserm CESP U1018, "Exposome and Heredity" Team, Gustave Roussy, Villejuif, France
| | - Rosario Tumino
- Hyblean Association for Epidemiological Research, AIRE-ONLUS, Ragusa, Italy
| | - Mattias Johansson
- Section of Genetics, International Agency for Research on Cancer, Lyon, France
| | - Elisabete Weiderpass
- Office of the Director, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - Marc J. Gunter
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - Ben Lacey
- Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Naomi E. Allen
- Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Laure Dossus
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| |
Collapse
|
|
11
|
Sobstyl M, Brecht P, Sobstyl A, Mertowska P, Grywalska E. The Role of Microbiota in the Immunopathogenesis of Endometrial Cancer. Int J Mol Sci 2022; 23:ijms23105756. [PMID: 35628566 PMCID: PMC9143279 DOI: 10.3390/ijms23105756] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 05/16/2022] [Accepted: 05/18/2022] [Indexed: 02/01/2023] Open
Abstract
The female reproductive tract hosts a specific microbiome, which plays a crucial role in sustaining equilibrium and good health. In the majority of reproductive women, the microbiota (all bacteria, viruses, fungi, and other single-celled organisms within the human body) of the vaginal and cervical microenvironment are dominated by Lactobacillus species, which benefit the host through symbiotic relationships, in comparison to the uterus, fallopian tubes, and ovaries, which may contain a low-biomass microbiome with a diverse mixture of microorganisms. Although disruption to the balance of the microbiota develops, the altered immune and metabolic signaling may cause an impact on diseases such as cancer. These pathophysiological modifications in the gut–uterus axis may spark gynecological cancers. New information displays that gynecological and gastrointestinal tract dysbiosis (disruption of the microbiota homeostasis) can play an active role in the advancement and metastasis of gynecological neoplasms, such as cervical, endometrial, and ovarian cancers. Understanding the relationship between microbiota and endometrial cancer is critical for prognosis, diagnosis, prevention, and the development of innovative treatments. Identifying a specific microbiome may become an effective method for characterization of the specific microbiota involved in endometrial carcinogenesis. The aim of this study was to summarize the current state of knowledge that describes the correlation of microbiota with endometrial cancer with regard to the formation of immunological pathologies.
Collapse
Affiliation(s)
- Małgorzata Sobstyl
- Department of Gynecology and Gynecological Endocrinology, Medical University of Lublin, 20-037 Lublin, Poland;
| | - Peet Brecht
- Department of Experimental Immunology, Medical University of Lublin, Chodźki 4a St., 20-093 Lublin, Poland; (P.B.); (A.S.)
| | - Anna Sobstyl
- Department of Experimental Immunology, Medical University of Lublin, Chodźki 4a St., 20-093 Lublin, Poland; (P.B.); (A.S.)
| | - Paulina Mertowska
- Department of Experimental Immunology, Medical University of Lublin, Chodźki 4a St., 20-093 Lublin, Poland; (P.B.); (A.S.)
- Correspondence: (P.M.); (E.G.)
| | - Ewelina Grywalska
- Department of Experimental Immunology, Medical University of Lublin, Chodźki 4a St., 20-093 Lublin, Poland; (P.B.); (A.S.)
- Correspondence: (P.M.); (E.G.)
| |
Collapse
|
|
12
|
Nees LK, Heublein S, Steinmacher S, Juhasz-Böss I, Brucker S, Tempfer CB, Wallwiener M. Endometrial hyperplasia as a risk factor of endometrial cancer. Arch Gynecol Obstet 2022; 306:407-421. [PMID: 35001185 PMCID: PMC9349105 DOI: 10.1007/s00404-021-06380-5] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 12/23/2021] [Indexed: 12/30/2022]
Abstract
Endometrial hyperplasia (EH) is the precursor lesion for endometrioid adenocarcinoma of the endometrium (EC), which represents the most common malignancy of the female reproductive tract in industrialized countries. The most important risk factor for the development of EH is chronic exposure to unopposed estrogen. Histopathologically, EH can be classified into EH without atypia (benign EH) and atypical EH/endometrial intraepithelial neoplasia (EIN). Clinical management ranges from surveillance or progestin therapy through to hysterectomy, depending on the risk of progression to or concomitant EC and the patient´s desire to preserve fertility. Multiple studies support the efficacy of progestins in treating both benign and atypical EH. This review summarizes the evidence base regarding risk factors and management of EH. Additionally, we performed a systematic literature search of the databases PubMed and Cochrane Controlled Trials register for studies analyzing the efficacy of progestin treatment in women with EH.
Collapse
Affiliation(s)
- Lisa K Nees
- Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany
| | - Sabine Heublein
- Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany
| | - Sahra Steinmacher
- Department of Obstetrics and Gynecology, Universität Tübingen, Tübingen, Germany
| | - Ingolf Juhasz-Böss
- Department of Obstetrics and Gynecology, Universität Freiburg, Freiburg, Germany
| | - Sara Brucker
- Department of Obstetrics and Gynecology, Universität Tübingen, Tübingen, Germany
| | - Clemens B Tempfer
- Comprehensive Cancer Center, Ruhr University Bochum (RUCCC), Bochum, Germany
| | - Markus Wallwiener
- Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany.
| |
Collapse
|
|
13
|
Postoperative Radiotherapy for Endometrial Cancer in Elderly (≥80 Years) Patients: Oncologic Outcomes, Toxicity, and Validation of Prognostic Scores. Cancers (Basel) 2021; 13:cancers13246264. [PMID: 34944884 PMCID: PMC8699803 DOI: 10.3390/cancers13246264] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 12/10/2021] [Accepted: 12/12/2021] [Indexed: 01/23/2023] Open
Abstract
Endometrial cancer is a common malignancy in elderly women that are more likely to suffer from limiting medical comorbidities. Given this narrower therapeutic ratio, we aimed to assess the oncologic outcomes and toxicity in the adjuvant setting. Out of a cohort of 975 women, seventy patients aged ≥ 80 years, treated with curative postoperative radiotherapy (RT) for endometrial cancer between 2005 and 2021, were identified. Outcomes were assessed using Kaplan-Meier-analysis and comorbidities using the Charlson Comorbidity Index and G8 geriatric score. The overall survival at 1-, 2- and 5-years was 94.4%, 82.6%, and 67.6%, respectively, with significant correlation to G8 score. At 1- and 5-years, the local control rates were 89.5% and 89.5% and distant control rates were 86.3% and 66.9%, respectively. Severe (≥grade 3) acute toxicity was rare with gastrointestinal (2.9%), genitourinary (1.4%), and vaginal disorders (1.4%). Univariate analysis significantly revealed inferior overall survival with lower RT dose, G8 score, hemoglobin levels and obesity, while higher grading, lymphangiosis, RT dose decrease and the omission of chemotherapy reduced distant control. Despite older age and additional comorbidities, elderly patients tolerated curative treatment well. The vast majority completed treatment as planned with very low rates of acute severe side-effects. RT offers durable local control; however, late distant failure remains an issue.
Collapse
|
|
14
|
Mullee A, Dimou N, Allen N, O'Mara T, Gunter MJ, Murphy N. Testosterone, sex hormone-binding globulin, insulin-like growth factor-1 and endometrial cancer risk: observational and Mendelian randomization analyses. Br J Cancer 2021; 125:1308-1317. [PMID: 34363033 PMCID: PMC8548546 DOI: 10.1038/s41416-021-01518-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 06/04/2021] [Accepted: 07/26/2021] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Dysregulation of endocrine pathways related to steroid and growth hormones may modify endometrial cancer risk; however, prospective data on testosterone, sex hormone-binding globulin (SHBG) and insulin-like growth factor (IGF)-1 are limited. To elucidate the role of these hormones in endometrial cancer risk we conducted complementary observational and Mendelian randomization (MR) analyses. METHODS The observational analyses included 159,702 women (80% postmenopausal) enrolled in the UK Biobank. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. For MR analyses, genetic variants associated with hormone levels were identified and their association with endometrial cancer (12,906 cases/108,979 controls) was examined using two-sample MR. RESULTS In the observational analysis, higher circulating concentrations of total (HR per unit inverse normal scale = 1.38, 95% CI = 1.22-1.57) and free testosterone (HR per unit log scale = 2.07, 95% CI = 1.66-2.58) were associated with higher endometrial cancer risk. An inverse association was found for SHBG (HR per unit inverse normal scale = 0.76, 95% CI = 0.67-0.86). Results for testosterone and SHBG were supported by the MR analyses. No association was found between genetically predicted IGF-1 concentration and endometrial cancer risk. CONCLUSIONS Our results support probable causal associations between circulating concentrations of testosterone and SHBG with endometrial cancer risk.
Collapse
Affiliation(s)
- Amy Mullee
- School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin, Ireland
- School of Agriculture and Food Science, University College Dublin, Dublin, Ireland
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
| | - Niki Dimou
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
| | - Naomi Allen
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Tracy O'Mara
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Marc J Gunter
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
| | - Neil Murphy
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
| |
Collapse
|
|
15
|
Lai YL, Chiang CJ, Chen YL, You SL, Chen YY, Chiang YC, Tai YJ, Hsu HC, Chen CA, Cheng WF. Increased risk of second primary malignancies among endometrial cancer survivors receiving surgery alone: A population-based analysis. Cancer Med 2021; 10:6845-6854. [PMID: 34523816 PMCID: PMC8495277 DOI: 10.1002/cam4.3861] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 02/02/2021] [Indexed: 01/17/2023] Open
Abstract
Background Women with endometrial cancer (EC) have favorable prognoses, leaving them vulnerable to the development of second primary cancers (SPCs). We investigated the SPC risk and survival outcomes among EC patients treated with surgery alone in order to exclude the impact of adjuvant treatment on the results. Methods Data from the Taiwan Cancer Registry from 1995 to 2013 were analyzed. Standardized incidence ratios (SIRs) of SPCs among EC survivors were calculated. Results Among 7725 women enrolled, 478 developed an SPC. The overall SIR for SPCs in EC survivors was 2.84 (95% confidence interval [CI] 2.59–3.10) compared with the general female population. Women diagnosed with EC at age <50 years had a higher SIR for an SPC than those diagnosed at age ≥50 years (SIR = 4.38 vs. 1.28). The most frequent site of an SPC was the small intestine (SIR = 8.39, 95% CI 2.72–19.58), followed by the kidney (SIR = 4.84, 95% CI 1.78–10.54), and oral cavity (SIR = 4.52, 95% CI 2.17–8.31). Women, regardless of age at EC diagnosis, had significantly higher SIRs for subsequent breast, colorectal, lung, and thyroid cancer, and lymphoma. Women with an SPC had shorter overall survival than those without (5‐year: 88.9 vs. 94.2%, 10‐year: 71.3 vs. 89.8%, 15‐year: 62.3 vs. 86.1%, and 20‐year: 47.6 vs. 81.1%, all ps<0.001). Conclusions Even women treated for EC with surgery alone, especially young EC survivors, had an increased risk of SPCs. Genetic counseling/testing is recommended for young EC patients, and all are recommended to receive regular surveillance and screening for breast, colorectal, and lung cancers.
Collapse
Affiliation(s)
- Yen-Ling Lai
- Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan.,Department of Obstetrics and Gynecology, National Taiwan University Hospital, Hsin-Chu City, Taiwan
| | - Chun-Ju Chiang
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.,Taiwan Cancer Registry, Taipei, Taiwan
| | - Yu-Li Chen
- Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan
| | - San-Lin You
- Department of Public Health, College of Medicine and Big Data Research Centre, Fu-Jen Catholic University, New Taipei City, Taiwan
| | | | - Ying-Cheng Chiang
- Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan
| | - Yi-Jou Tai
- Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan
| | - Heng-Cheng Hsu
- Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan.,Department of Obstetrics and Gynecology, National Taiwan University Hospital, Hsin-Chu City, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan
| | - Chi-An Chen
- Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan
| | - Wen-Fang Cheng
- Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.,Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
| |
Collapse
|
|
16
|
Poenaru MO, Pleş L, Sima RM, Ionescu P, Florescu C, Neacşu I, Stănică CD, Neacşu A. Unexpected location of endometrial adenocarcinoma - a case report. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY 2021; 61:941-945. [PMID: 33817738 PMCID: PMC8112785 DOI: 10.47162/rjme.61.3.35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
Endometrial adenocarcinoma (ADK) is one of the most common uterine cancer and the fourth neoplasia mortality cause in women according to the literature data. ADK is encountered in the sixth decade of life, the mean age being 63 years. Only 2–5% of cases are found in women less than 40 years old. We present the case of a 63-year-old woman admitted in our Clinic for hypogastric pain and reduced vaginal sanguinolent discharge. The genital examination and transvaginal ultrasound (US) scan were strongly suggestive for a type 0 myoma tending to be expelled through the cervical canal. Laparotomy and total hysterectomy with bilateral adnexectomy were performed. Histological examination identified a grade G1 well-differentiated endometrioid ADK without uterine wall invasion. The immunohistochemistry study for estrogen receptors expression revealed moderate and strong nuclear immunostaining in more than 70% of the tumoral cells, as well as a mosaic p16 immunoexpression, a cytokeratin 7 (CK7) immunophenotype, no p53 overexpression and low Ki67 index (estimated at 10–15%). Considering the incidental finding, the early stage and limited localization of the ADK at the myoma surface level surgery was considered sufficient as treatment but follow-up was conducted by magnetic resonance imaging (MRI) and general examination every six months. The most interesting aspect of the case was the atypical presence of an active myoma in menopause and the totally unsuspicious US appearance of the endometrium. The endometrial ADK was accidentally discovered in an unusual specimen without any other symptom.
Collapse
Affiliation(s)
- Mircea Octavian Poenaru
- Department of Obstetrics and Gynecology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; Department of Obstetrics and Gynecology, Bucur Maternity, St. John Clinical Hospital, Bucharest, Romania;
| | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Oral contraceptive use by formulation and endometrial cancer risk among women born in 1947-1964: The Nurses' Health Study II, a prospective cohort study. Eur J Epidemiol 2020; 36:827-839. [PMID: 33331993 PMCID: PMC8416825 DOI: 10.1007/s10654-020-00705-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 12/03/2020] [Indexed: 11/22/2022]
Abstract
Oral contraceptives (OCs) have been associated with long-term lower endometrial cancer risk; relatively little is known about associations with more recent OC formulations and associations with longer-term risk. A total of 107,069 women from the Nurses’ Health Study II recalled OC use from age 13 to baseline (1989); biennial questionnaires updated data on OC use until 2009. OCs were classified by estrogen and progestin type, dose, and potency based on reported brand. 864 incident endometrial cancer cases were identified through 2017. Multivariable Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals [95% CI] for the association of OC use with endometrial cancer risk. OC use was associated with lower endometrial cancer risk (ever use, HR 0.77 [95% CI 0.65–0.91]; >10 years of use, 0.43 [0.32–0.58] vs. never OC use). Inverse associations for duration were evident regardless of time since last use. Longer durations (> 5 years) of ethinyl estradiol (0.52 [0.41–0.67]) and second-generation progestins (0.43 [0.30–0.61]), both versus never use, were more strongly associated with lower risk than mestranol (0.66 [0.50–0.88], p-het = 0.01) and first-generation progestins (0.62 [0.49–0.78], p-het = 0.03). Inverse associations were generally observed for cross-classified cumulative average estrogen and progestin dose and potency (< vs. ≥ median; ever use vs. never OC use), with the exception of high estrogen and low progestin dose. OCs were associated with lower endometrial cancer risk, independent of time since last use. Use of ethinyl estradiol and second-generation progestins were more strongly inversely associated with risk compared with older formulations.
Collapse
|
|
18
|
De Franciscis P, Schiattarella A, Riemma G, Labriola D, Ambrosio D, Vitale SG, Cianci A, Cucinella G, Calagna G, Colacurci N. Hysteroscopic and ultrasonographic evaluation of ulipristal acetate treatment for symptomatic myomas in premenopausal women: a prospective study. MINIM INVASIV THER 2020; 31:435-440. [PMID: 33043778 DOI: 10.1080/13645706.2020.1829648] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE This study aimed to analyze the effects of a six-month therapy with ulipristal acetate (UPA) on myoma size and endometrial thickness in premenopausal women. MATERIAL AND METHODS Seventy-four women undergoing conservative therapy with UPA were enrolled for this study. All women underwent transvaginal ultrasound evaluation to assess the endometrial thickness, and the number and size of myomas at the beginning and after six months. Hysteroscopy and biopsy were performed after six months, if necessary. RESULTS After six months of treatment, sonographic examination showed a statistically significant (p < .05) reduction of the size of the largest myoma (56.3 ± 5.1 vs. 31.7 ± 10.1 mm) and a statistically significant (p < .05) increase in endometrial thickness (5.9 ± 2.1 vs. 9.7 ± 3.4 mm). Twenty-two patients with endometrial thickness >10 mm or nonhomogeneous pattern and ten patients with metrorrhagia underwent hysteroscopy: the most frequent finding was the combination of endometrial hypotrophy, floating surface, and chicken-wire vascular pattern aspect (14 cases, 43.7%). Histologic findings showed no case of complex hyperplasia. CONCLUSION UPA is a safe, effective and assured method to decrease symptoms, reduce the need for surgery in premenopausal women suitable for the treatment.
Collapse
Affiliation(s)
- Pasquale De Franciscis
- Department of Woman, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Antonio Schiattarella
- Department of Woman, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Gaetano Riemma
- Department of Woman, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Domenico Labriola
- Department of Woman, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Domenico Ambrosio
- Department of Woman, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Salvatore Giovanni Vitale
- Obstetrics and Gynecology Unit, Department of General Surgery and Medical Surgical Specialties, University of Catania, Catania, Italy
| | - Antonio Cianci
- Obstetrics and Gynecology Unit, Department of General Surgery and Medical Surgical Specialties, University of Catania, Catania, Italy
| | - Gaspare Cucinella
- Gynecology and Obstetrics Unit, Villa Sofia-Cervello Hospital, University of Palermo, Palermo, Italy
| | - Gloria Calagna
- Gynecology and Obstetrics Unit, Villa Sofia-Cervello Hospital, University of Palermo, Palermo, Italy
| | - Nicola Colacurci
- Department of Woman, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| |
Collapse
|
|
19
|
Workshop on normal reference ranges for estradiol in postmenopausal women, September 2019, Chicago, Illinois. ACTA ACUST UNITED AC 2020; 27:614-624. [PMID: 32379215 DOI: 10.1097/gme.0000000000001556] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The North American Menopause Society (NAMS) organized the Workshop on Normal Ranges for Estradiol in Postmenopausal Women from September 23 to 24, 2019, in Chicago, Illinois. The aim of the workshop was to review existing analytical methodologies for measuring estradiol in postmenopausal women and to assess existing data and study cohorts of postmenopausal women for their suitability to establish normal postmenopausal ranges. The anticipated outcome of the workshop was to develop recommendations for establishing normal ranges generated with a standardized and certified assay that could be adopted by clinical and research communities. The attendees determined that the term reference range was a better descriptor than normal range for estradiol measurements in postmenopausal women. Twenty-eight speakers presented during the workshop.
Collapse
|
|
20
|
Case-control study of endogenous sex steroid hormones and risk of endometrial cancer. Cancer Causes Control 2019; 31:161-171. [PMID: 31865473 DOI: 10.1007/s10552-019-01260-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 12/11/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Epidemiologic evidence regarding the role of endogenous sex hormones in endometrial cancer etiology remains inconsistent. The objective of this study was to investigate if circulating levels of endogenous estrone, estradiol, sex hormone binding globulin (SHBG), testosterone, and androstenedione are associated with endometrial cancer risk. METHODS We conducted a population-based case-control study of 522 incident endometrial cancer cases and 976 population controls, in Alberta, Canada from 2002 to 2006. Study participants completed in-person interviews and provided fasting blood samples. Sex hormone levels were determined by enzyme-linked immunosorbent assays. RESULTS Higher levels of androstenedione were associated with increased endometrial cancer risk (OR 1.44, 95% CI 1.04-2.02). Endometrial cancer risk in pre- and peri-menopausal women was reduced for the highest versus lowest quartiles of estrone (OR 0.44, 95% CI 0.22-0.88) and estradiol (OR 0.30, 95% CI 0.14-0.65), but in post-menopausal women, the endometrial cancer risk was increased for the highest versus lowest quartile of androstenedione (OR 1.82, 95% CI 1.25-2.65). In addition, endometrial cancer risk in normal/underweight women was decreased for the highest versus lowest quartile of serum SHBG (OR 0.39, 95% CI 0.19-0.84). CONCLUSIONS Overall, positive associations were found for androstenedione concentrations, while sub-group analyses revealed = inverse associations with estrogens and SHBG. Results of this study provide empirical evidence for the role of circulating sex hormones in endometrial cancer etiology and highlight the importance of modifiable factors that contribute to changes in sex hormone concentration levels.
Collapse
|
|
21
|
Trabert B, Coburn SB, Falk RT, Manson JE, Brinton LA, Gass ML, Kuller LH, Rohan TE, Pfeiffer RM, Qi L, Stefanick ML, Wentzensen N, Anderson GL, Xu X. Circulating estrogens and postmenopausal ovarian and endometrial cancer risk among current hormone users in the Women's Health Initiative Observational Study. Cancer Causes Control 2019; 30:1201-1211. [PMID: 31542834 PMCID: PMC6785392 DOI: 10.1007/s10552-019-01233-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 09/11/2019] [Indexed: 11/28/2022]
Abstract
PURPOSE Menopausal hormone therapy (MHT) use induces alterations in circulating estrogens/estrogen metabolites, which may contribute to the altered risk of reproductive tract cancers among current users. Thus, the current study assessed associations between circulating estrogens/estrogen metabolites and ovarian and endometrial cancer risk among MHT users. METHODS We conducted a nested case-control study among postmenopausal women using MHT at baseline in the Women's Health Initiative Observational Study (179 ovarian cancers, 396 controls; 230 endometrial cancers, 253 controls). Multivariable logistic regression was utilized to estimate odds ratios and 95% confidence intervals overall and by subtype. RESULTS Estrogen/estrogen metabolite levels were not associated with overall or serous ovarian cancer risk, examined separately. However, unconjugated estradiol was positively associated with non-serous ovarian cancer risk [quintile 5 vs. quintile 1: 3.01 (1.17-7.73); p-trend = 0.03; p-het < 0.01]. Endometrial cancer risk was unrelated to estrogen/estrogen metabolite levels among women who took combined estrogen/progestin therapy (EPT). CONCLUSIONS These findings provide novel evidence that may support a heterogeneous hormonal etiology across ovarian cancer subtypes. Circulating estrogens did not influence endometrial cancer risk among women with EPT-induced high-estrogen levels. Larger studies are needed to delineate the relationship between ovarian/endometrial cancer subtypes and estrogen levels in the context of MHT use.
Collapse
Affiliation(s)
- Britton Trabert
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892-9768, USA.
| | - Sally B Coburn
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892-9768, USA
| | - Roni T Falk
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892-9768, USA
| | - JoAnn E Manson
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Louise A Brinton
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892-9768, USA
| | - Margery L Gass
- Women's Health Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Lewis H Kuller
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Thomas E Rohan
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Ruth M Pfeiffer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892-9768, USA
| | - Lihong Qi
- Public Health Sciences, School of Medicine, UC Davis, Sacramento, CA, USA
| | - Marcia L Stefanick
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Nicolas Wentzensen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892-9768, USA
| | - Garnet L Anderson
- Division of Public Health Sciences, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Xia Xu
- Frederick National Laboratory for Cancer Research, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick, MD, USA
| |
Collapse
|
|
22
|
Abstract
Fluorodeoxyglucose positron emission tomography computed tomography (FDG-PET/CT) provides a comprehensive whole body evaluation in patients with endometrial and vulvar cancer. Here, we discuss the role of FDG-PET/CT in defining the disease extent in patients presenting with these cancers. Detection of lymph node and distant metastases has implications for staging, treatment planning, and patient prognosis. Procedures for image acquisition and interpretation for optimum accuracy and essential elements that should be included in the PET-CT report are described. Common imaging pitfalls are presented and illustrated with examples.
Collapse
Affiliation(s)
- Aoife Kilcoyne
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
| | - David Z Chow
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Susanna I Lee
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| |
Collapse
|
|
23
|
Raglan O, Kalliala I, Markozannes G, Cividini S, Gunter MJ, Nautiyal J, Gabra H, Paraskevaidis E, Martin-Hirsch P, Tsilidis KK, Kyrgiou M. Risk factors for endometrial cancer: An umbrella review of the literature. Int J Cancer 2019; 145:1719-1730. [PMID: 30387875 DOI: 10.1002/ijc.31961] [Citation(s) in RCA: 324] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 10/19/2018] [Indexed: 03/25/2024]
Abstract
Although many risk factors could have causal association with endometrial cancer, they are also prone to residual confounding or other biases which could lead to over- or underestimation. This umbrella review evaluates the strength and validity of evidence pertaining risk factors for endometrial cancer. Systematic reviews or meta-analyses of observational studies evaluating the association between non-genetic risk factors and risk of developing or dying from endometrial cancer were identified from inception to April 2018 using PubMed, the Cochrane database and manual reference screening. Evidence was graded strong, highly suggestive, suggestive or weak based on statistical significance of random-effects summary estimate, largest study included, number of cases, between-study heterogeneity, 95% prediction intervals, small study effects, excess significance bias and sensitivity analysis with credibility ceilings. We identified 171 meta-analyses investigating associations between 53 risk factors and endometrial cancer incidence and mortality. Risk factors were categorised: anthropometric indices, dietary intake, physical activity, medical conditions, hormonal therapy use, biochemical markers, gynaecological history and smoking. Of 127 meta-analyses including cohort studies, three associations were graded with strong evidence. Body mass index and waist-to-hip ratio were associated with increased cancer risk in premenopausal women (RR per 5 kg/m2 1.49; CI 1.39-1.61) and for total endometrial cancer (RR per 0.1unit 1.21; CI 1.13-1.29), respectively. Parity reduced risk of disease (RR 0.66, CI 0.60-0.74). Of many proposed risk factors, only three had strong association without hints of bias. Identification of genuine risk factors associated with endometrial cancer may assist in developing targeted prevention strategies for women at high risk.
Collapse
Affiliation(s)
- Olivia Raglan
- Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, United Kingdom
- Queen Charlotte's and Chelsea - Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Ilkka Kalliala
- Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, United Kingdom
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Georgios Markozannes
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | | | - Marc J Gunter
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC), Lyon, France
| | - Jaya Nautiyal
- Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Hani Gabra
- Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, United Kingdom
- Early Clinical Development, IMED Biotech Unit, Cambridge, United Kingdom
| | | | - Pierre Martin-Hirsch
- Department of Gynaecologic Oncology, Lancashire Teaching Hospitals, Preston, United Kingdom
- Department of Biophysics, University of Lancaster, Lancaster, United Kingdom
| | - Kostas K Tsilidis
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Maria Kyrgiou
- Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, United Kingdom
- Queen Charlotte's and Chelsea - Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| |
Collapse
|
|
24
|
Miyamoto T, Shiozawa T. Two-sided role of estrogen on endometrial carcinogenesis: stimulator or suppressor? Gynecol Endocrinol 2019; 35:370-375. [PMID: 30668178 DOI: 10.1080/09513590.2018.1549219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
Endometrial carcinoma (EC) often expresses estrogen receptors (ER), and the growth of EC is stimulated by estrogen. Therefore, EC is considered to be an estrogen-dependent tumor. However, the role of estrogen in endometrial carcinogenesis is somewhat unclear because the majority of EC occurs at peri- or post menopause when serum estrogen levels are generally decreased. In this article, we describe the double-edged role of estrogen in the genesis of EC, especially in terms of mismatch repair functions in vitro and in vivo, i.e. when serum estradiol (E2) levels are relatively low (approximately less than 90 pg/ml), and E2 enhance the carcinogenesis, whereas high E2 levels may suppress the carcinogenesis. This will deepen mechanistic insight into unopposed estrogen.
Collapse
Affiliation(s)
- Tsutomu Miyamoto
- a Department of Obstetrics and Gynecology , Shinshu University School of Medicine , Matsumoto , Japan
| | - Tanri Shiozawa
- a Department of Obstetrics and Gynecology , Shinshu University School of Medicine , Matsumoto , Japan
| |
Collapse
|
|
25
|
Abstract
In this review, we highlight the benign and premalignant lesions of the endometrium that the pathologist may encounter in daily practice. We begin by detailing our current understanding of excess estrogen in the progression of endometrial neoplasia. We outline the currently accepted terminology to be used when evaluating proliferative endometrial lesions, while highlighting their key features. Attention is then turned to the molecular underpinnings of neoplastic progression and how this can be exploited with immunohistochemical stains when appropriate. Finally, we discuss types of metaplasia and their associations, including so-called papillary proliferations of the endometrium.
Collapse
Affiliation(s)
- Wesley Daniel Mallinger
- Department of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 517, Little Rock, AR 72205, USA
| | - Charles Matthew Quick
- Department of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 517, Little Rock, AR 72205, USA.
| |
Collapse
|
|
26
|
Blood steroids are associated with prognosis and fat distribution in endometrial cancer. Gynecol Oncol 2018; 152:46-52. [PMID: 30554934 DOI: 10.1016/j.ygyno.2018.10.024] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 10/16/2018] [Accepted: 10/20/2018] [Indexed: 11/24/2022]
Abstract
BACKGROUND Despite being a hormone dependent cancer, there is limited knowledge regarding the relation between level of steroids in blood and prognosis for endometrial cancer (EC) patients. METHODS In this study we investigated plasma levels of 19 steroids using liquid-chromatography tandem mass-spectrometry in 38 postmenopausal EC patients, 19 with long, and 19 with short survival. We explored if estradiol levels were associated with specific abdominal fat distribution patterns and if transcriptional alterations related to estradiol levels could be observed in tumor samples. RESULTS The plasma steroid levels for DHEA, DHEAS, progesterone, 21 OH progesterone and E1S were significantly increased (all p < 0.05) in patients with long survival compared to short. Estradiol levels were significantly positively correlated with visceral fat percentage (p = 0.035), and an increased expression of genes involved in estrogen related signaling was observed in tumors from patients with high estradiol levels in plasma. CONCLUSION Several of the identified plasma steroids represent promising biomarkers in EC patients. The association between increased estradiol levels and a high percentage of visceral fat indicates that visceral fat is a larger contributor to estradiol production compared to subcutaneous fat in this population.
Collapse
|
|
27
|
Canter RJ, Le CT, Beerthuijzen JM, Murphy WJ. Obesity as an immune-modifying factor in cancer immunotherapy. J Leukoc Biol 2018; 104:487-497. [PMID: 29762866 PMCID: PMC6113103 DOI: 10.1002/jlb.5ri1017-401rr] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Revised: 04/17/2018] [Accepted: 04/18/2018] [Indexed: 12/18/2022] Open
Abstract
Immunotherapy has achieved breakthrough status in many advanced stage malignancies and is rapidly becoming the fourth arm of cancer treatment. Although cancer immunotherapy has generated significant excitement because of the potential for complete and sometimes durable responses, there is also the potential for severe and occasionally life-threatening toxicities, including cytokine release syndrome and severe autoimmunity. A large body of work also points to a "metainflammatory" state in obesity associated with impairment of immune responses. Because immune checkpoint blockade (and other cancer immunotherapies) have altered the landscape of immunotherapy in cancer, it is important to understand how immune responses are shaped by obesity and how obesity may modify both immunotherapy responses and potential toxicities.
Collapse
Affiliation(s)
- Robert J. Canter
- University of California, Davis, School of Medicine, Department of Surgery, Division of Surgical Oncology, Sacramento, CA 95817
| | - Catherine T Le
- University of California, Davis, School of Medicine, Departments of Dermatology and Internal Medicine, Sacramento, CA 95817
| | - Johanna M.T. Beerthuijzen
- University of California, Davis, School of Medicine, Departments of Dermatology and Internal Medicine, Sacramento, CA 95817
| | - William J. Murphy
- University of California, Davis, School of Medicine, Departments of Dermatology and Internal Medicine, Sacramento, CA 95817
| |
Collapse
|
|
28
|
Felix AS, Brinton LA. Cancer Progress and Priorities: Uterine Cancer. Cancer Epidemiol Biomarkers Prev 2018; 27:985-994. [PMID: 30181320 PMCID: PMC6504985 DOI: 10.1158/1055-9965.epi-18-0264] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 04/07/2018] [Accepted: 05/15/2018] [Indexed: 12/27/2022] Open
Affiliation(s)
- Ashley S Felix
- Division of Epidemiology, The Ohio State University College of Public Health, Columbus, Ohio.
| | - Louise A Brinton
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| |
Collapse
|
|
29
|
Patel HK, Bihani T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment. Pharmacol Ther 2018; 186:1-24. [DOI: 10.1016/j.pharmthera.2017.12.012] [Citation(s) in RCA: 194] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
|
30
|
Audet-Delage Y, Grégoire J, Caron P, Turcotte V, Plante M, Ayotte P, Simonyan D, Villeneuve L, Guillemette C. Estradiol metabolites as biomarkers of endometrial cancer prognosis after surgery. J Steroid Biochem Mol Biol 2018; 178:45-54. [PMID: 29092787 DOI: 10.1016/j.jsbmb.2017.10.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 10/23/2017] [Accepted: 10/26/2017] [Indexed: 12/18/2022]
Abstract
Endometrial cancer (EC) is the most common gynecologic malignancy prevailing after menopause. Defining steroid profiles may help predict the risk of recurrence after hysterectomy, which remains limited due to the lack of reliable markers. Adrenal precursors, androgens, parent estrogens and catechol estrogen metabolites were measured by mass spectrometry (MS) in preoperative serums and those collected one month after hysterectomy from 246 newly diagnosed postmenopausal EC cases. We also examined the associations between steroid hormones and EC status by including 110 healthy postmenopausal women. Steroid concentrations were analyzed in relation to clinicopathological features, recurrence and overall survival (OS). The mean follow-up time was 65.5 months and 26 patients experienced relapse after surgery for a recurrence incidence of 10.6% (6.4% Type I and 29.5% Type II). Recurrence and OS were related to a more aggressive disease but not linked to body mass index. Preoperative levels of estriol (E3) and estrone-sulfate (E1-S) were inversely associated with recurrence in a multivariate logistic regression analysis (Hazard ratios (HRs) of 0.31, P=0.039 and 3.01, P=0.024; respectively). All circulating steroids declined considerably after surgery almost reaching those of healthy women, except 4-methoxy-E2 (4MeO-E2) for which postoperative levels increased by 35% and were associated to a 68% decreased risk of recurrence (HR=0.32, P=0.015). Women diagnosed with both histological types of EC present significantly higher levels of steroids, in support of their mitogenic effects. The estrogen precursor E1-S, the anticancer metabolite 4MeO-E2, and E3 that exert mixed antagonist and agonist estrogenic activities and immunological effects, are potential independent prognostic factors.
Collapse
Affiliation(s)
- Yannick Audet-Delage
- Centre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, Québec, Canada
| | - Jean Grégoire
- Gynecologic Oncology Service, CHU de Québec, and Department of Obstetrics, Gynecology, and Reproduction, Faculty of Medicine, Laval University, Québec, Canada
| | - Patrick Caron
- Centre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, Québec, Canada
| | - Véronique Turcotte
- Centre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, Québec, Canada
| | - Marie Plante
- Gynecologic Oncology Service, CHU de Québec, and Department of Obstetrics, Gynecology, and Reproduction, Faculty of Medicine, Laval University, Québec, Canada
| | - Pierre Ayotte
- CHU de Québec Research Center, and Department of Social and Preventive Medicine, Faculty of Medicine, Laval University, Québec, Canada
| | - David Simonyan
- Statistical and Clinical Research Platform, CHU de Québec Research Center, Québec, Canada
| | - Lyne Villeneuve
- Centre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, Québec, Canada
| | - Chantal Guillemette
- Centre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, Québec, Canada; Canada Research Chair in Pharmacogenomics, Canada.
| |
Collapse
|
|
31
|
Current perspectives between metabolic syndrome and cancer. Oncotarget 2018; 7:38959-38972. [PMID: 27029038 PMCID: PMC5122443 DOI: 10.18632/oncotarget.8341] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 02/20/2016] [Indexed: 12/21/2022] Open
Abstract
Metabolic syndrome is a cluster of risk factors that lead to cardiovascular morbidity and mortality. Recent studies linked metabolic syndrome and several types of cancer. Although metabolic syndrome may not necessarily cause cancer, it is linked to poorer cancer outcomes including increased risk of recurrence and overall mortality. This review tends to discuss the major biological and physiological alterations involved in the increase of incidence and mortality of cancer patients affected by metabolic syndrome. We focus on metabolic syndrome-associated visceral adiposity, hyperinsulinemia, hyperglycemia, insulin-like growth factor (IGF-I) pathway as well as estrogen signaling and inflammation. Several of these factors are also involved in carcinogenesis and cancer progression. A better understanding of the link between metabolic syndrome and cancer may provide new insight about oncogenesis. Moreover, prevention of metabolic syndrome - related alterations may be an important aspect in the management of cancer patients during simultaneous palliative care.
Collapse
|
|
32
|
Jung S, Allen N, Arslan AA, Baglietto L, Barricarte A, Brinton LA, Egleston BL, Falk RT, Fortner RT, Helzlsouer KJ, Gao Y, Idahl A, Kaaks R, Krogh V, Merritt MA, Lundin E, Onland-Moret NC, Rinaldi S, Schock H, Shu XO, Sluss PM, Staats PN, Sacerdote C, Travis RC, Tjønneland A, Trichopoulou A, Tworoger SS, Visvanathan K, Weiderpass E, Zeleniuch-Jacquotte A, Dorgan JF. Anti-Müllerian hormone and risk of ovarian cancer in nine cohorts. Int J Cancer 2018; 142:262-270. [PMID: 28921520 PMCID: PMC5749630 DOI: 10.1002/ijc.31058] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 08/08/2017] [Accepted: 08/16/2017] [Indexed: 01/08/2023]
Abstract
Animal and experimental data suggest that anti-Müllerian hormone (AMH) serves as a marker of ovarian reserve and inhibits the growth of ovarian tumors. However, few epidemiologic studies have examined the association between AMH and ovarian cancer risk. We conducted a nested case-control study of 302 ovarian cancer cases and 336 matched controls from nine cohorts. Prediagnostic blood samples of premenopausal women were assayed for AMH using a picoAMH enzyme-linked immunosorbent assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable-adjusted conditional logistic regression. AMH concentration was not associated with overall ovarian cancer risk. The multivariable-adjusted OR (95% CI), comparing the highest to the lowest quartile of AMH, was 0.99 (0.59-1.67) (Ptrend : 0.91). The association did not differ by age at blood draw or oral contraceptive use (all Pheterogeneity : ≥0.26). There also was no evidence for heterogeneity of risk for tumors defined by histologic developmental pathway, stage, and grade, and by age at diagnosis and time between blood draw and diagnosis (all Pheterogeneity : ≥0.39). In conclusion, this analysis of mostly late premenopausal women from nine cohorts does not support the hypothesized inverse association between prediagnostic circulating levels of AMH and risk of ovarian cancer.
Collapse
Affiliation(s)
- Seungyoun Jung
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Naomi Allen
- Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, UK
| | - Alan A. Arslan
- Department of Obstetrics and Gynecology, New York University School of Medicine, NY, USA
- Departments of Population Health and Environmental Medicine and Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA
| | - Laura Baglietto
- Cancer Epidemiology Centre, Cancer Council of Victoria, Melbourne, Australia
- Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Australia
| | - Aurelio Barricarte
- Navarra Public Health Institute, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA) Pamplona, Spain
- CIBER Epidemiology and Public Health CIBERESP, Spain
| | - Louise A. Brinton
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, MD, USA
| | | | - Roni T. Falk
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, MD, USA
| | - Renée T. Fortner
- Division of Cancer Epidemiology, German Cancer Research Cancer, Heidelberg, Germany
| | - Kathy J. Helzlsouer
- Division of Cancer Control and Population Sciences, National Cancer Institute, MD, USA
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Yutang Gao
- Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
| | - Annika Idahl
- Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Umeå, Sweden
| | - Rudolph Kaaks
- Division of Cancer Epidemiology, German Cancer Research Cancer, Heidelberg, Germany
| | - Vittorio Krogh
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Melissa A. Merritt
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Eva Lundin
- Department of Medical Biosciences, Pathology, and Public Health and Clinical Medicine: Nutritional Research, Umeå University, Umeå, Sweden
| | | | - Sabina Rinaldi
- International Agency for Research on Cancer, Lyon, France
| | - Helena Schock
- Division of Cancer Epidemiology, German Cancer Research Cancer, Heidelberg, Germany
| | - Xiao-Ou Shu
- Department of Epidemiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Patrick M. Sluss
- Department of Pathology, Harvard Medical School, Boston, MA, USA
| | - Paul N. Staats
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Carlotta Sacerdote
- Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy
| | - Ruth C. Travis
- Cancer Epidemiology Unit, University of Oxford, Oxford United Kingdom
| | | | - Antonia Trichopoulou
- Hellenic Health Foundation, Athens, Greece
- WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Dept. of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Greece
| | - Shelley S. Tworoger
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Channing Division of Network Medicine, Bringham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Elisabete Weiderpass
- Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
- Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland
| | - Anne Zeleniuch-Jacquotte
- Departments of Population Health and Environmental Medicine and Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA
| | - Joanne F. Dorgan
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA
| |
Collapse
|
|
33
|
Tzur T, Kessous R, Weintraub AY. Current strategies in the diagnosis of endometrial cancer. Arch Gynecol Obstet 2017; 296:5-14. [PMID: 28508342 DOI: 10.1007/s00404-017-4391-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 05/04/2017] [Indexed: 02/06/2023]
Abstract
PURPOSE Endometrial cancer is the most common gynecological malignancy in developed countries. There are no uniform recommendations for endometrial cancer screening in the general population. Therefore, it is of paramount importance that the primary physician profoundly understands, and is familiar with the methods for prevention and early detection of endometrial cancer. The aim of this review is to provide the primary physician with a toolbox to reach these goals. METHODS We performed a systemic review to summarize the current strategies to diagnose and prevent endometrial cancer. Many published articles from the last years were identified and included. RESULTS A systematic review that summarizes the important subjects in the diagnosis and prevention of endometrial cancer. CONCLUSION Maintaining a high index of suspicion and obtaining endometrial biopsies from all suspected patients is the key for achieving a timely diagnosis.
Collapse
Affiliation(s)
- Tamar Tzur
- Department of Obstetrics and Gynecology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
| | - Roi Kessous
- Division of Gynecology Oncology, Segal Cancer Center, Jewish General Hospital, McGill University, Montreal, Canada
| | - Adi Y Weintraub
- Department of Obstetrics and Gynecology, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
| |
Collapse
|
|
34
|
Riggio AI, Blyth K. The enigmatic role of RUNX1 in female-related cancers - current knowledge & future perspectives. FEBS J 2017; 284:2345-2362. [PMID: 28304148 DOI: 10.1111/febs.14059] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 02/15/2017] [Accepted: 03/13/2017] [Indexed: 12/15/2022]
Abstract
Historically associated with the aetiology of human leukaemia, the runt-related transcription factor 1 (RUNX1) gene has in recent years reared its head in an assortment of epithelial cancers. This review discusses the state-of-the-art knowledge of the enigmatic role played by RUNX1 in female-related cancers of the breast, the uterus and the ovary. The weight of evidence accumulated so far is indicative of a very context-dependent role, as either an oncogene or a tumour suppressor. This is corroborated by high-throughput sequencing endeavours which report different genetic alterations affecting the gene, including amplification, deep deletion and mutations. Herein, we attempt to dissect that contextual role by firstly giving an overview of what is currently known about RUNX1 function in these specific tumour types, and secondly by delving into connections between this transcription factor and the physiology of these female tissues. In doing so, RUNX1 emerges not only as a gene involved in female sex development but also as a crucial mediator of female hormone signalling. In view of RUNX1 now being listed as a driver gene, we believe that greater knowledge of the mechanisms underlying its functional dualism in epithelial cancers is worthy of further investigation.
Collapse
Affiliation(s)
| | - Karen Blyth
- Cancer Research UK Beatson Institute, Bearsden, Glasgow, UK
| |
Collapse
|
|
35
|
Jung S, Allen N, Arslan AA, Baglietto L, Brinton LA, Egleston BL, Falk R, Fortner RT, Helzlsouer KJ, Idahl A, Kaaks R, Lundin E, Merritt M, Onland-Moret C, Rinaldi S, Sánchez MJ, Sieri S, Schock H, Shu XO, Sluss PM, Staats PN, Travis RC, Tjønneland A, Trichopoulou A, Tworoger S, Visvanathan K, Krogh V, Weiderpass E, Zeleniuch-Jacquotte A, Zheng W, Dorgan JF. Demographic, lifestyle, and other factors in relation to antimüllerian hormone levels in mostly late premenopausal women. Fertil Steril 2017; 107:1012-1022.e2. [PMID: 28366409 PMCID: PMC5426228 DOI: 10.1016/j.fertnstert.2017.02.105] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 02/09/2017] [Accepted: 02/20/2017] [Indexed: 01/09/2023]
Abstract
OBJECTIVE To identify reproductive, lifestyle, hormonal, and other correlates of circulating antimüllerian hormone (AMH) concentrations in mostly late premenopausal women. DESIGN Cross-sectional study. SETTING Not applicable. PATIENT(S) A total of 671 premenopausal women not known to have cancer. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Concentrations of AMH were measured in a single laboratory using the picoAMH ELISA. Multivariable-adjusted median (and interquartile range) AMH concentrations were calculated using quantile regression for several potential correlates. RESULT(S) Older women had significantly lower AMH concentrations (≥40 [n = 444] vs. <35 years [n = 64], multivariable-adjusted median 0.73 ng/mL vs. 2.52 ng/mL). Concentrations of AMH were also significantly lower among women with earlier age at menarche (<12 [n = 96] vs. ≥14 years [n = 200]: 0.90 ng/mL vs. 1.12 ng/mL) and among current users of oral contraceptives (n = 27) compared with never or former users (n = 468) (0.36 ng/mL vs. 1.15 ng/mL). Race, body mass index, education, height, smoking status, parity, and menstrual cycle phase were not significantly associated with AMH concentrations. There were no significant associations between AMH concentrations and androgen or sex hormone-binding globulin concentrations or with factors related to blood collection (e.g., sample type, time, season, and year of blood collection). CONCLUSION(S) Among premenopausal women, lower AMH concentrations are associated with older age, a younger age at menarche, and currently using oral contraceptives, suggesting these factors are related to a lower number or decreased secretory activity of ovarian follicles.
Collapse
Affiliation(s)
- Seungyoun Jung
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland
| | - Naomi Allen
- Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Alan A Arslan
- Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York; Departments of Population Health and Environmental Medicine and Perlmuttr Cancer Center, New York University School of Medicine, New York, New York
| | - Laura Baglietto
- Cancer Epidemiology Centre, Cancer Council of Victoria, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Australia
| | - Louise A Brinton
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | | | - Roni Falk
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Renée T Fortner
- Division of Cancer Epidemiology, German Cancer Research Cancer, Heidelberg, Germany
| | - Kathy J Helzlsouer
- Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, Maryland; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Annika Idahl
- Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Umeå, Sweden
| | - Rudolph Kaaks
- Division of Cancer Epidemiology, German Cancer Research Cancer, Heidelberg, Germany
| | - Eva Lundin
- Department of Medical Biosciences, Pathology, and Public Health and Clinical Medicine: Nutritional Research, Umeå University, Umeå, Sweden
| | - Melissa Merritt
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Charlotte Onland-Moret
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Sabina Rinaldi
- International Agency for Research on Cancer, Lyon, France
| | - María-José Sánchez
- Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs, GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Sabina Sieri
- Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Helena Schock
- Division of Cancer Epidemiology, German Cancer Research Cancer, Heidelberg, Germany
| | - Xiao-Ou Shu
- Department of Epidemiology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Patrick M Sluss
- Department of Pathology, Harvard Medical School, Boston, Massachusetts
| | - Paul N Staats
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Ruth C Travis
- Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom
| | | | - Antonia Trichopoulou
- Hellenic Health Foundation, Athens, Greece; World Health Organization Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece
| | - Shelley Tworoger
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Baltimore, Maryland; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Vittorio Krogh
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Elisabete Weiderpass
- Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway; Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland
| | - Anne Zeleniuch-Jacquotte
- Departments of Population Health and Environmental Medicine and Perlmuttr Cancer Center, New York University School of Medicine, New York, New York
| | - Wei Zheng
- Department of Epidemiology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Joanne F Dorgan
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland.
| |
Collapse
|
|
36
|
Bulut G, Kosem M, Bulut MD, Erten R, Bayram I. Is Immunohistochemical Sex Hormone Binding Globulin Expression Important in the Differential Diagnosis of Adenocarcinomas? Asian Pac J Cancer Prev 2016; 16:8203-10. [PMID: 26745061 DOI: 10.7314/apjcp.2015.16.18.8203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Adenocarcinomas (AC) are the most frequently encountered carcinomas. It may be quite challenging to detect the primary origin when those carcinomas metastasize and the first finding is a metastatic tumor. This study evaluated the role of sex hormone binding globulin (SHBG) positivity in tumor cells in the subclassification and detection of the original organ of adenocarcinomas. Between 1994 and 2008, 64 sections of normal tissue belonging to ten organs, and 116 cases diagnosed as adenoid cystic carcinoma and mucoepidermoid carcinoma of the salivary gland, lung adenocarcinoma, invasive ductal carcinoma of the breast, adenocarcinoma of stomach, colon, gallbladder, pancreas and prostate, endometrial adenocarcinoma and serous adenocarcinoma and mucinous adenocarcinoma of the ovary, were sent to the laboratory at the Department of Pathology at the Yuzuncu Yil University School of Medicine, where they were stained immunohistochemically, using antibodies against SHBG. The SHBG immunoreactivity in both the tumor cells and normal cells, together with the type, diffuseness and intensity of the staining were then evaluated. In the differential diagnosis of the adenocarcinomas of the organs, including the glandular structures, impressively valuable results are encountered in the tumor cells, whether the SHBG immunopositivity is evaluated alone or together with other IHC markers. Further extensive research with a larger number of cases, including instances of cholangiocarcinoma and cervix uteri AC [which we could not include in the study for technical reasons] should be performed, in order to appropriately evaluate the role of SHBG in the differential diagnosis of AC.
Collapse
Affiliation(s)
- Gulay Bulut
- Department of Pathology, Faculty of Medicine, Yuzuncu Yil University, Van, Turkey E-mail :
| | | | | | | | | |
Collapse
|
|
37
|
Brinton LA, Trabert B, Anderson GL, Falk RT, Felix AS, Fuhrman BJ, Gass ML, Kuller LH, Pfeiffer RM, Rohan TE, Strickler HD, Xu X, Wentzensen N. Serum Estrogens and Estrogen Metabolites and Endometrial Cancer Risk among Postmenopausal Women. Cancer Epidemiol Biomarkers Prev 2016; 25:1081-9. [PMID: 27197275 PMCID: PMC4930692 DOI: 10.1158/1055-9965.epi-16-0225] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 04/05/2016] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Although endometrial cancer is clearly influenced by hormonal factors, few epidemiologic studies have investigated the role of endogenous estrogens or especially estrogen metabolites. METHODS We conducted a nested case-control study within the Women's Health Initiative Observational Study (WHI-OS), a cohort of 93,676 postmenopausal women recruited between 1993 and 1998. Using baseline serum samples from women who were non-current hormone users with intact uteri, we measured 15 estrogens/estrogen metabolites via HPLC/MS-MS among 313 incident endometrial cancer cases (271 type I, 42 type II) and 354 matched controls, deriving adjusted ORs and 95% confidence intervals (CI) for overall and subtype-specific endometrial cancer risk. RESULTS Parent estrogens (estrone and estradiol) were positively related to endometrial cancer risk, with the highest risk observed for unconjugated estradiol (OR 5th vs. 1st quintile = 6.19; 95% CI, 2.95-13.03, Ptrend = 0.0001). Nearly all metabolites were significantly associated with elevated risks, with some attenuation after adjustment for unconjugated estradiol (residual risks of 2- to 3-fold). Body mass index (kg/m(2), BMI) relations were somewhat reduced after adjustment for estrogen levels. The association with unconjugated estradiol was stronger for type I than type II tumors (Phet = 0.01). CONCLUSIONS Parent estrogens as well as individual metabolites appeared to exert generalized uterotropic activity, particularly for type I tumors. The effects of obesity on risk were only partially explained by estrogens. IMPACT These findings enhance our understanding of estrogen mechanisms involved in endometrial carcinogenesis but also highlight the need for studying additional markers that may underlie the effects on risk of certain risk factors, for example, obesity. Cancer Epidemiol Biomarkers Prev; 25(7); 1081-9. ©2016 AACR.
Collapse
Affiliation(s)
- Louise A Brinton
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
| | - Britton Trabert
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Garnet L Anderson
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Roni T Falk
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Ashley S Felix
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. Division of Epidemiology, The Ohio State University College of Public Health, Columbus, Ohio
| | - Barbara J Fuhrman
- Department of Epidemiology, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | | | - Lewis H Kuller
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ruth M Pfeiffer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Thomas E Rohan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
| | - Howard D Strickler
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
| | - Xia Xu
- Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Nicolas Wentzensen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| |
Collapse
|
|
38
|
Clendenen TV, Hertzmark K, Koenig KL, Lundin E, Rinaldi S, Johnson T, Krogh V, Hallmans G, Idahl A, Lukanova A, Zeleniuch-Jacquotte A. Premenopausal Circulating Androgens and Risk of Endometrial Cancer: results of a Prospective Study. HORMONES & CANCER 2016; 7:178-87. [PMID: 26925952 PMCID: PMC4860027 DOI: 10.1007/s12672-016-0258-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 02/19/2016] [Indexed: 12/26/2022]
Abstract
Endometrial cancer risk is increased by estrogens unopposed by progesterone. In premenopausal women, androgen excess is often associated with progesterone insufficiency, suggesting that premenopausal androgen concentrations may be associated with risk. In a case-control study nested within three cohorts, we assessed the relationship between premenopausal androgens and risk of endometrial cancer (161 cases and 303 controls matched on age and date of blood donation). Testosterone, DHEAS, androstenedione, and SHBG were measured in serum or plasma. Free testosterone was calculated from testosterone and SHBG. We observed trends of increasing risk across tertiles of testosterone (ORT3-T1 = 1.59, 95 % CI = 0.96, 2.64, p = 0.08) and free testosterone (ORT3-T1 = 1.76, 95 % CI = 1.01, 3.07, p = 0.047), which were not statistically significant after adjustment for body mass index (BMI). There was no association for DHEAS, androstenedione, or SHBG. There were significant interactions by age at diagnosis (<55 years, n = 51 cases; ≥55 years, n = 110 cases). Among women who were ≥55 years of age (predominantly postmenopausal) at diagnosis, the BMI-adjusted OR was 2.08 (95 % CI = 1.25, 3.44, p = 0.005) for a doubling in testosterone and 1.55 (95 % CI = 1.04, 2.31, p = 0.049) for a doubling in free testosterone. There was no association among women aged <55 years at diagnosis, consistent with the only other prospective study to date. If pre- and post-menopausal concentrations of androgens are correlated, our observation of an association of premenopausal androgens with risk among women aged ≥55 years at diagnosis could be due to the effect on the endometrium of postmenopausal androgen-derived estrogens in the absence of progesterone, which is no longer secreted.
Collapse
Affiliation(s)
- Tess V Clendenen
- Department of Population Health, Division of Epidemiology and Biostatistics, New York University School of Medicine, 650 1st Ave, New York, NY, 10016, USA
| | - Kathryn Hertzmark
- Department of Environmental Medicine, Division of Epidemiology and Biostatistics, New York University School of Medicine, New York, NY, USA
| | - Karen L Koenig
- Department of Population Health, Division of Epidemiology and Biostatistics, New York University School of Medicine, 650 1st Ave, New York, NY, 10016, USA
| | - Eva Lundin
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Sabina Rinaldi
- International Agency for Research on Cancer, Lyon, France
| | - Theron Johnson
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Vittorio Krogh
- Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Göran Hallmans
- Department of Public Health and Clinical Medicine/Nutritional Research and Department of Biobank Research, Umeå University, Umeå, Sweden
| | - Annika Idahl
- Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Umeå, Sweden
| | - Annekatrin Lukanova
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Anne Zeleniuch-Jacquotte
- Department of Population Health, Division of Epidemiology and Biostatistics, New York University School of Medicine, 650 1st Ave, New York, NY, 10016, USA.
- New York University Cancer Institute, New York, NY, USA.
| |
Collapse
|
|
39
|
Thompson DJ, O'Mara TA, Glubb DM, Painter JN, Cheng T, Folkerd E, Doody D, Dennis J, Webb PM, Gorman M, Martin L, Hodgson S, Michailidou K, Tyrer JP, Maranian MJ, Hall P, Czene K, Darabi H, Li J, Fasching PA, Hein A, Beckmann MW, Ekici AB, Dörk T, Hillemanns P, Dürst M, Runnebaum I, Zhao H, Depreeuw J, Schrauwen S, Amant F, Goode EL, Fridley BL, Dowdy SC, Winham SJ, Salvesen HB, Trovik J, Njolstad TS, Werner HMJ, Ashton K, Proietto T, Otton G, Carvajal-Carmona L, Tham E, Liu T, Mints M, Scott RJ, McEvoy M, Attia J, Holliday EG, Montgomery GW, Martin NG, Nyholt DR, Henders AK, Hopper JL, Traficante N, Ruebner M, Swerdlow AJ, Burwinkel B, Brenner H, Meindl A, Brauch H, Lindblom A, Lambrechts D, Chang-Claude J, Couch FJ, Giles GG, Kristensen VN, Cox A, Bolla MK, Wang Q, Bojesen SE, Shah M, Luben R, Khaw KT, Pharoah PDP, Dunning AM, Tomlinson I, Dowsett M, Easton DF, Spurdle AB. CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer. Endocr Relat Cancer 2016; 23:77-91. [PMID: 26574572 PMCID: PMC4697192 DOI: 10.1530/erc-15-0386] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Revised: 10/22/2015] [Accepted: 11/16/2015] [Indexed: 12/19/2022]
Abstract
Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.
Collapse
Affiliation(s)
- Deborah J Thompson
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK
| | - Tracy A O'Mara
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
| | - Dylan M Glubb
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
| | - Jodie N Painter
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
| | - Timothy Cheng
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
| | - Elizabeth Folkerd
- Academic Department of Biochemistry, Royal Marsden Hospital, London, SW3 6JJ, UK
| | - Deborah Doody
- Academic Department of Biochemistry, Royal Marsden Hospital, London, SW3 6JJ, UK
| | - Joe Dennis
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK
| | - Penelope M Webb
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
| | | | - Maggie Gorman
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
| | - Lynn Martin
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
| | - Shirley Hodgson
- Department of Clinical Genetics, St George's Hospital Medical School, London, SW17 0RE, UK
| | | | - Kyriaki Michailidou
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK
| | - Jonathan P Tyrer
- Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, CB1 8RN, UK
| | - Mel J Maranian
- Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, CB1 8RN, UK
| | - Per Hall
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SE-171 77, Sweden
| | - Kamila Czene
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SE-171 77, Sweden
| | - Hatef Darabi
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SE-171 77, Sweden
| | - Jingmei Li
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SE-171 77, Sweden
| | - Peter A Fasching
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, 90095, USA
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, 91054, Germany
| | - Alexander Hein
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, 91054, Germany
| | - Matthias W Beckmann
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, 91054, Germany
| | - Arif B Ekici
- Institute of Human Genetics, , University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, 91054, Germany
| | - Thilo Dörk
- Gynaecology Research Unit, Hannover Medical School, Hannover, 30625, Germany
| | - Peter Hillemanns
- Clinics of Gynaecology and Obstetrics, Hannover Medical School, Hannover, 30625, Germany
| | - Matthias Dürst
- Department of Gynaecology, Jena University Hospital – Friedrich Schiller University, Jena, 07743, Germany
| | - Ingo Runnebaum
- Department of Gynaecology, Jena University Hospital – Friedrich Schiller University, Jena, 07743, Germany
| | - Hui Zhao
- Vesalius Research Center, Leuven, 3000, Belgium
- Laboratory for Translational Genetics, Department of Oncology, University Hospitals Leuven, Leuven, 3000, Belgium
| | - Jeroen Depreeuw
- Vesalius Research Center, Leuven, 3000, Belgium
- Laboratory for Translational Genetics, Department of Oncology, University Hospitals Leuven, Leuven, 3000, Belgium
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals, KU Leuven – University of Leuven, Leuven, 3000, Belgium
| | - Stefanie Schrauwen
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals, KU Leuven – University of Leuven, Leuven, 3000, Belgium
| | - Frederic Amant
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals, KU Leuven – University of Leuven, Leuven, 3000, Belgium
| | - Ellen L Goode
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, 55905, USA
| | - Brooke L Fridley
- Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas, 66160, USA
| | - Sean C Dowdy
- Department of Obstetrics and Gynecology Division of Gynecologic Oncology Mayo Clinic, Rochester, Minnesota, 55905, USA
| | - Stacey J Winham
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, 55905, USA
| | - Helga B Salvesen
- Department of Clinical Science, Centre for Cancerbiomarkers, The University of Bergen, Bergen, 5020, Norway
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, 5021, Norway
| | - Jone Trovik
- Department of Clinical Science, Centre for Cancerbiomarkers, The University of Bergen, Bergen, 5020, Norway
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, 5021, Norway
| | - Tormund S Njolstad
- Department of Clinical Science, Centre for Cancerbiomarkers, The University of Bergen, Bergen, 5020, Norway
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, 5021, Norway
| | - Henrica M J Werner
- Department of Clinical Science, Centre for Cancerbiomarkers, The University of Bergen, Bergen, 5020, Norway
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, 5021, Norway
| | - Katie Ashton
- Hunter Medical Research Institute, John Hunter Hospital, Newcastle, New South Wales, 2305, Australia
- Centre for Information Based Medicine, University of Newcastle, Newcastle, New South Wales, 2308, Australia
- School of Biomedical Sciences and Pharmacy, , University of Newcastle Newcastle, Newcastle, New South Wales, 2308, Australia
| | - Tony Proietto
- School of Medicine and Public Health, , University of Newcastle, Newcastle, Newcastle, New South Wales, 2308, Australia
| | - Geoffrey Otton
- School of Medicine and Public Health, , University of Newcastle, Newcastle, Newcastle, New South Wales, 2308, Australia
| | - Luis Carvajal-Carmona
- Grupo de investigación Citogenética, Filogenia y Evolución de Poblaciones, Universidad del Tolima, Ibagué, Tolima, Colombia
- Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, California, 95616, USA
| | - Emma Tham
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, SE-171 77, Sweden
| | - Tao Liu
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, SE-171 77, Sweden
| | - Miriam Mints
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, SE-171 77, Sweden
- Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, SE-171 77, Sweden
| | - for RENDOCAS
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, SE-171 77, Sweden
| | - Rodney J Scott
- Hunter Medical Research Institute, John Hunter Hospital, Newcastle, New South Wales, 2305, Australia
- Centre for Information Based Medicine, University of Newcastle, Newcastle, New South Wales, 2308, Australia
- School of Biomedical Sciences and Pharmacy, , University of Newcastle Newcastle, Newcastle, New South Wales, 2308, Australia
- Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, 2305, Australia
| | - Mark McEvoy
- Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, 2305, Australia
| | - John Attia
- Hunter Medical Research Institute, John Hunter Hospital, Newcastle, New South Wales, 2305, Australia
- Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, 2305, Australia
| | - Elizabeth G Holliday
- Hunter Medical Research Institute, John Hunter Hospital, Newcastle, New South Wales, 2305, Australia
- Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, 2305, Australia
| | - Grant W Montgomery
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
| | - Nicholas G Martin
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
| | - Dale R Nyholt
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, 4006, Australia
| | - Anjali K Henders
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
| | - John L Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne victoria, Melbourne, Victoria, 3010, Australia
| | - Nadia Traficante
- PePeter MacCallum Cancer Center, The University of Melbourne, Melbourne, 3002, Australia
| | - for the AOCS Group
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
| | - Matthias Ruebner
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, 91054, Germany
| | - Anthony J Swerdlow
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, SM2 5NG, UK
- Division of Breast Cancer Research, Institute of Cancer Research, London, SM2 5NG, UK
| | - Barbara Burwinkel
- Department of Gynecology and Obstetrics, Molecular Biology of Breast Cancer, University of Heidelberg, Heidelberg, 69117, Germany
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, 69120, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
| | - Alfons Meindl
- Department of Obstetrics and Gynecology, Division of Tumor Genetics, Technical University of Munich, Munich, 80333, Germany
| | - Hiltrud Brauch
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
- Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, 70376, Germany
- University of Tübingen, Tübingen, 72074, Germany
| | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, SE-171 77, Sweden
| | - Diether Lambrechts
- Vesalius Research Center, Leuven, 3000, Belgium
- Laboratory for Translational Genetics, Department of Oncology, University Hospitals Leuven, Leuven, 3000, Belgium
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, 69120, Germany
| | - Fergus J Couch
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, 55905, USA
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, 55905, USA
| | - Graham G Giles
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne victoria, Melbourne, Victoria, 3010, Australia
- Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, 3004, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, 3004, Australia
| | - Vessela N Kristensen
- Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, 0310, Norway
- Faculty of Medicine, The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, , University of Oslo, Oslo, 0316, Norway
- Department of Clinical Molecular Oncology, Division of Medicine, Akershus University Hospital, Lørenskog, 1478, Norway
| | - Angela Cox
- Department of Oncology, Sheffield Cancer Research, University of Sheffield, Sheffield, S10 2TN, UK
| | - Manjeet K Bolla
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK
| | - Qin Wang
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK
| | - Stig E Bojesen
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 1165, Denmark
- Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, 2730, Denmark
| | - Mitul Shah
- Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, CB1 8RN, UK
| | - Robert Luben
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK
| | - Kay-Tee Khaw
- MRC Centre for Nutritional Epidemiology in Cancer Prevention and Survival (CNC), University of Cambridge, Cambridge, CB1 8RN, UK
| | - Paul D P Pharoah
- Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, CB1 8RN, UK
| | - Alison M Dunning
- Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, CB1 8RN, UK
| | - Ian Tomlinson
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
| | - Mitch Dowsett
- Academic Department of Biochemistry, Royal Marsden Hospital, London, SW3 6JJ, UK
| | - Douglas F Easton
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK
- Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, CB1 8RN, UK
| | - Amanda B Spurdle
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
| |
Collapse
|
|
40
|
Estrogen Metabolism and Risk of Postmenopausal Endometrial and Ovarian Cancer: the B ∼ FIT Cohort. Discov Oncol 2016; 7:49-64. [PMID: 26728471 DOI: 10.1007/s12672-015-0237-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 10/16/2015] [Indexed: 12/29/2022] Open
Abstract
Estrogen metabolites may have different genotoxic and mitogenic properties yet their relationship with endometrial and ovarian cancer risk remains unclear. Within the Breast and Bone Follow-up to the Fracture Intervention Trial (B ∼ FIT, n = 15,595), we conducted a case-cohort study to evaluate 15 pre-diagnostic serum estrogens and estrogen metabolites with risk of incident endometrial and ovarian cancer among postmenopausal women not on hormone therapy. Participants included 66 endometrial and 67 ovarian cancer cases diagnosed during follow-up (∼ 10 years) and subcohorts of 346 and 416 women, respectively, after relevant exclusions. Serum concentrations were measured by liquid chromatography-tandem mass spectrometry. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression. Exposures were categorized in tertiles (T) and analyzed individually, as metabolic pathways (C-2, -4, or -16) and as ratios to parent estrogens (estradiol, estrone). Estradiol was significantly associated with increased endometrial cancer risk (BMI-adjusted HRT3vsT1 = 4.09, 95% CI 1.70, 9.85; p trend = 0.003). 2-Hydroxyestrone and 16α-hydroxyestrone were not associated with endometrial risk after estradiol adjustment (2-OHE1:HRT3vsT1 = 1.97, 95% CI 0.78, 4.94; 16-OHE1:HRT3vsT1 = 1.50, 95% CI 0.65, 3.46; p trend = 0.16 and 0.36, respectively). Ratios of 2- and 4-pathway catechol-to-methylated estrogens remained positively associated with endometrial cancer after BMI or estradiol adjustment (2-pathway catechols-to-methylated: HRT3vsT1 = 4.02, 95% CI 1.60, 10.1; 4-pathway catechols-to-methylated: HRT3vsT1 = 4.59, 95% CI 1.64, 12.9; p trend = 0.002 for both). Estrogens and estrogen metabolites were not associated with ovarian cancer risk; however, larger studies are needed to better evaluate these relationships. Estrogen metabolism may be important in endometrial carcinogenesis, particularly with less extensive methylation of 2- or 4-pathway catechols associated with elevated endometrial cancer risk.
Collapse
|
|
41
|
Abstract
Endometrial cancer is the sixth most common cancer in women worldwide and the most common gynecologic malignancy in the developed world. This chapter explores the current epidemiologic evidence on the association between obesity and endometrial cancer risk and mortality. Using body mass index (BMI) as a measure of obesity, we found that obesity (defined as BMI > 30 and < 35 kg/m2) was associated with a 2.6-fold increase in endometrial cancer risk, while severe obesity (BMI > 35 kg/m2) was associated with a 4.7-fold increase compared to normal-weight women (BMI < 25 kg/m2). Increased central adiposity also increased endometrial cancer risk by 1.5- to twofold. Among both healthy and endometrial cancer patient populations, obesity was associated with a roughly twofold increase in endometrial cancer-specific mortality. This risk reduction was also observed for obesity and all-cause mortality among endometrial cancer patients. In the few studies that assessed risk associated with weight change, an increased endometrial cancer risk with weight gain and weight cycling was observed, whereas some evidence for a protective effect of weight loss was found. Furthermore, early-life obesity was associated with a moderately increased risk of endometrial cancer later in life. There are several mechanisms whereby obesity is hypothesized to increase endometrial cancer risk, including increased endogenous sex steroid hormones, insulin resistance, chronic inflammation and adipokines. Further research should focus on histological subtypes or molecular phenotypes of endometrial tumors and population subgroups that could be at an increased risk of obesity-associated endometrial cancer. Additionally, studies on weight gain, loss or cycling and weight loss interventions can provide mechanistic insight into the obesity-endometrial cancer association. Sufficient evidence exists to recommend avoiding obesity to reduce endometrial cancer risk.
Collapse
Affiliation(s)
- Eileen Shaw
- Department of Cancer Epidemiology and Prevention Research, CancerControl Alberta, Alberta Health Services, Calgary, AB, Canada
| | - Megan Farris
- Department of Cancer Epidemiology and Prevention Research, CancerControl Alberta, Alberta Health Services, Calgary, AB, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Jessica McNeil
- Department of Cancer Epidemiology and Prevention Research, CancerControl Alberta, Alberta Health Services, Calgary, AB, Canada
| | - Christine Friedenreich
- Department of Cancer Epidemiology and Prevention Research, CancerControl Alberta, Alberta Health Services, Calgary, AB, Canada.
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
- Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
| |
Collapse
|
|
42
|
Boisen MM, Andersen CL, Sreekumar S, Stern AM, Oesterreich S. Treating gynecologic malignancies with selective estrogen receptor downregulators (SERDs): promise and challenges. Mol Cell Endocrinol 2015; 418 Pt 3:322-33. [PMID: 26276546 DOI: 10.1016/j.mce.2015.04.035] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Revised: 04/16/2015] [Accepted: 04/16/2015] [Indexed: 02/07/2023]
Abstract
Endometrial and ovarian cancers are estrogen-dependent gynecologic malignancies. Although many are estrogen receptor (ER) positive, treatment with the selective estrogen receptor modulator (SERM) tamoxifen, a tissue selective partial-agonist, has demonstrated only modest clinical benefit. Selective estrogen receptor downregulators (SERDs) are pure ER antagonists showing a benefit for advanced ER positive breast cancer, which has bolstered their potential use for ER positive gynecologic malignancies. We summarize these preclinical and clinical data, suggesting that a subpopulation of patients with endometrial or ovarian cancer exists in which treatment with SERDs results in improved outcome. However, the full potential of SERDs for a gynecologic malignancies will be realized only when the appropriate predictive biomarkers are identified. Additionally, a further understanding ER signaling in the context of ovarian and endometrial tissues that appear to involve c-Src and other kinase pathways is needed to successfully address the emergence of resistance with rationally designed combination therapies.
Collapse
Affiliation(s)
- Michelle M Boisen
- Division of Gynecologic Oncology, Magee-Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
| | - Courtney L Andersen
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine Molecular Pharmacology Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sreeja Sreekumar
- Women's Cancer Research Center, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Andrew M Stern
- University of Pittsburgh Drug Discovery Institute and the Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Steffi Oesterreich
- University of Pittsburgh Cancer Institute, Department of Pharmacology and Chemical Biology, Women's Cancer Research Center, Magee-Womens Research Institute, Pittsburgh, PA, USA
| |
Collapse
|
|
43
|
Abstract
Epidemiological studies have established an association between obesity, insulin resistance, type 2 diabetes and a number of cancer types. Research has focused predominantly on altered endocrine factors, growth factors and signalling pathways, with little known in man about the immune involvement in the relevant pathophysiological processes. Moreover, in an era of exciting new breakthroughs in cancer immunotherapy, there is also a need to study the safety and efficacy of immunotherapeutics in the complex setting of inflammatory-driven obesity-associated cancer. This review addresses key immune cell subsets underpinning obesity-associated inflammation and describes how such immune compartments might be targeted to prevent and treat obesity-associated cancer. We propose that the modulation, metabolism, migration and abundance of pro- and anti-inflammatory cells and tumour-specific T cells might be therapeutically altered to both restore immune balance, alleviating pathological inflammation, and to improve anti-tumour immune responses in obesity-associated cancer.
Collapse
|
|
44
|
Vicennati V, Garelli S, Rinaldi E, Rosetti S, Zavatta G, Pagotto U, Pasquali R. Obesity-related proliferative diseases: the interaction between adipose tissue and estrogens in post-menopausal women. Horm Mol Biol Clin Investig 2015; 21:75-87. [PMID: 25781553 DOI: 10.1515/hmbci-2015-0002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Accepted: 01/21/2015] [Indexed: 01/12/2023]
Abstract
Epidemiological studies have shown that overweight and cancer are closely related, even though obesity alone does not apparently heighten cancer risk by the same amount. Given the low overall risk of all cancers with obesity, it is unlikely that obesity alone causes cancer, but should instead be considered as a tumor promoter. There are three main hypotheses that could explain how obesity might contribute to cancer development and growth: the inflammatory cytokines from adipose tissue hypothesis, the insulin resistance and hyperinsulinemia hypothesis, and the unopposed estrogen cancer hypothesis. The link between obesity and cancer is that adipocytes constitute a major component of the tumor microenvironment for breast and abdominally metastasizing cancers, promoting tumor growth. This review will mainly focus attention on the relationship between adipose tissue, estrogens, and cancer risk.
Collapse
|
|
45
|
Wasniewski T, Woclawek-Potocka I, Boruszewska D, Kowalczyk-Zieba I, Sinderewicz E, Grycmacher K. The significance of the altered expression of lysophosphatidic acid receptors, autotaxin and phospholipase A2 as the potential biomarkers in type 1 endometrial cancer biology. Oncol Rep 2015; 34:2760-7. [PMID: 26327335 DOI: 10.3892/or.2015.4216] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 05/29/2015] [Indexed: 11/06/2022] Open
Abstract
In order to study lysophosphatidic acid (LPA) signaling associated with type 1 endometrial carcinoma (EC), we evaluated the LPA receptors (LPARs), autotaxin (ATX) and phospholipase A2 (PLA2) expression in EC and normal endometrium with correlation to clinicopathological features. We investigated LPAR1, LPAR2, LPAR3, LPAR4, ATX and PLA2 expression at mRNA and protein levels using quantitative real-time PCR and western blot analyses in 37 ECs and 10 normal endometria. All the examined LPARs (except for LPAR3 protein), ATX and PLA2 were overexpressed in cancerous compared to healthy endometrium. The studied ECs showed the highest LPAR2 and LPAR1 expression. Statistically positive correlations were found between depth of myoinvasion and levels of LPAR1, LPAR2 and PLA2 transcripts and proteins. We also found positive correlations between LPAR1, LPAR2, LPAR4 and PLA2 expression with the International Federation of Gynecology and Obstetrics (FIGO) stage. The expression of LPAR1, LPAR2 and PLA2 was positively associated with the age of patients. Positive correlations were found between the expression of LPAR1 mRNA, LPAR2 mRNA and protein and LPAR3 mRNA and body mass index (BMI) of the examined patients. We found no association between the expression levels of the studied factors and diabetes or hypertension among the examined patients. Owing to the highest LPAR2 and LPAR1 expression in EC and positive correlations of these two receptors with the depth of myoinvasion and the FIGO stage, we believe that LPAR2 and LPAR1 show promise as predictors of the EC progression as well as the main receptors responsible for LPA action in the EC tissue.
Collapse
Affiliation(s)
- Tomasz Wasniewski
- Department of Gynecology and Obstetrics, Faculty of Medical Sciences, University of Warmia and Masuria, 10-561 Olsztyn, Poland
| | - Izabela Woclawek-Potocka
- Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10-747 Olsztyn, Poland
| | - Dorota Boruszewska
- Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10-747 Olsztyn, Poland
| | - Ilona Kowalczyk-Zieba
- Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10-747 Olsztyn, Poland
| | - Emilia Sinderewicz
- Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10-747 Olsztyn, Poland
| | - Katarzyna Grycmacher
- Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10-747 Olsztyn, Poland
| |
Collapse
|
|
46
|
Ju W, Kim HJ, Hankinson SE, De Vivo I, Cho E. Prospective study of body fat distribution and the risk of endometrial cancer. Cancer Epidemiol 2015; 39:567-570. [PMID: 26065406 DOI: 10.1016/j.canep.2015.05.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Revised: 04/28/2015] [Accepted: 05/10/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Epidemiologic studies have found that overall obesity is positively related to endometrial cancer (EC) risk. However, data assessing the association between body fat distribution and risk of EC are still limited. METHODS We followed 51,948 women who first reported waist circumference (WC) and hip circumference in 1986 in the Nurses' Health Study. Waist-to-hip ratio (WHR) was calculated. RESULTS During 24 years of follow-up, 449 incident invasive EC cases were diagnosed. In a multivariate analysis without adjusting for body mass index (BMI), the relative risks (RRs) for EC comparing extreme categories were 2.44 (95% confidence interval [CI] 1.72-3.45) for WC and 1.69 (95% CI=1.20-2.40) for WHR. However, after adjustment of BMI, those positive associations were substantially attenuated and no longer significant; RR=1.08 (95% CI=0.69-1.67) for WC and 1.15 (95% CI=0.81-1.64) for WHR, respectively. CONCLUSION In our prospective cohort study, we found no independent association between body fat distribution and the risk of EC after adjustment for BMI.
Collapse
Affiliation(s)
- Woong Ju
- Department of Obstetrics and Gynecology.,Medical Research Institute, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Hyun Ja Kim
- Division of Health and Nutrition Survey, Korea Centers for Disease Control and Prevention, Cheongju-si, Republic of Korea
| | - Susan E Hankinson
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.,Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115.,Division of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, MA
| | - Immaculata De Vivo
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.,Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115
| | - Eunyoung Cho
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.,Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, RI.,Department of Epidemiology, Brown School of Public Health, Providence, RI
| |
Collapse
|
|
47
|
Vanderstraeten A, Tuyaerts S, Amant F. The immune system in the normal endometrium and implications for endometrial cancer development. J Reprod Immunol 2015; 109:7-16. [DOI: 10.1016/j.jri.2014.12.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 12/22/2014] [Indexed: 12/26/2022]
|
|
48
|
Ren P, Zhang Y, Huang Y, Yang Y, Jiang M. Functions of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Gynecologic Disorders. CLINICAL MEDICINE INSIGHTS-ONCOLOGY 2015; 9:43-9. [PMID: 25987855 PMCID: PMC4412418 DOI: 10.4137/cmo.s23527] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 02/25/2015] [Accepted: 02/27/2015] [Indexed: 12/24/2022]
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of a class of nuclear hormone receptors intimately involved in the regulation of expression of myriad genes that regulate energy metabolism, cell differentiation, apoptosis, and inflammation. Although originally discovered as a pivotal regulator of adipocyte differentiation, the roles that PPARγ plays in gynecological disorders are still unknown. There are a number of studies on the functions of PPARγ and its agonists in gynecological disorders. In this mini-review, we provide a brief summary of the advances in recent years.
Collapse
Affiliation(s)
- Ping Ren
- Laboratory of Nuclear Receptors and Cancer Research, Basic Medical Research Center, Nantong University School of Medicine, Nantong, Jiangsu, China ; Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Yuquan Zhang
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Yan Huang
- Laboratory of Nuclear Receptors and Cancer Research, Basic Medical Research Center, Nantong University School of Medicine, Nantong, Jiangsu, China ; Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Yingli Yang
- Laboratory of Nuclear Receptors and Cancer Research, Basic Medical Research Center, Nantong University School of Medicine, Nantong, Jiangsu, China ; Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Ming Jiang
- Laboratory of Nuclear Receptors and Cancer Research, Basic Medical Research Center, Nantong University School of Medicine, Nantong, Jiangsu, China
| |
Collapse
|
|
49
|
Ju W, Keum N, Lee DH, Kim YH, Kim SC, Ding EL, Cho E. Red meat intake and the risk of endometrial cancer: Meta-analysis of observational studies. World J Meta-Anal 2015; 3:125-132. [DOI: 10.13105/wjma.v3.i2.125] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 08/20/2014] [Accepted: 02/12/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To evaluate whether red meat intake is related to the risk of endometrial cancer (EC) using meta-analysis.
METHODS: We searched PubMed, EMBASE, and the Cochrane Library up to June 2013, using common keywords related to red meat and EC. Case-control studies and cohort studies comparing the risk of endometrial cancer among categories by the amount of intake were included. Eleven case-control studies and five cohort studies met our criteria. We performed a conventional and a dose-response meta-analysis of case-control studies using the DerSimonian-Laird method for random-effects. For cohort studies we performed a conventional meta-analysis. Publication bias was evaluated using Egger’s test.
RESULTS: In the meta-analysis of 11 case-control studies including 5419 cases and 12654 controls, higher red meat consumption was associated with an increased risk of EC [summary relative risk (SRR) = 1.43, 95%CI: 1.15-1.79; I2 = 73.3% comparing extreme intake categories). In a dose-response analysis, for red meat intake of 100 g/d, SRR was 1.84 (95%CI: 1.64-2.05). In contrast, in the meta-analysis of five prospective studies including a total of 2549 cases among 247746 participants, no significant association between red meat intake and EC risk (SRR = 0.97, 95%CI: 0.85-1.11; I2 = 4.9% comparing extreme intake categories) was observed.
CONCLUSION: Our meta-analysis found a significant linear association between red meat intake and EC risk based on case-control studies but this was not confirmed in prospective studies.
Collapse
|
|
50
|
Zhou Y, Shen J, Xia L, Wang Y. Estrogen mediated expression of nucleophosmin 1 in human endometrial carcinoma clinical stages through estrogen receptor-α signaling. Cancer Cell Int 2014; 14:540. [PMID: 25663821 PMCID: PMC4319226 DOI: 10.1186/s12935-014-0145-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Accepted: 12/10/2014] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Endometrial carcinoma is one of the most common gynecologic malignancies. Estrogen plays a critical role in its pathogenesis, but the underlying mechanism is not clear. Nucleophosmin 1 (NPM1), a multifunctional protein involved in many cellular activities, has been implicated in the tumorigenesis processes. However, the role of NPM1 in endometrial carcinogenesis remains to be elucidated. The present study was aimed to elucidate the role of NPM1 in different clinical stages of human endometrial carcinoma and the underlying mechanism of NPM1 action. METHODS The distribution and expression of NPM1 in normal endometrium, FIGO stages I to IV endometrial carcinoma tissues was analyzed using immunohistochemistry, RT-qPCR and Western blotting. The association between NPM1 expression and estrogen and estrogen receptor signaling was investigated in primary-cultured FIGO stage I endometrial adenocarcinoma cells. RESULTS A strong positive correlation between NPM1 level and the clinical stage and histological grade of endometrial carcinomas was observed. Expression of NPM1 was up-regulated by estrogen in primary-cultured human endometrial adenocarcinoma cells. Furthermore, estrogen increased NPM1 level via estrogen receptor-α (ERα) signaling, nor estrogen receptor-β signaling. CONCLUSIONS Expression of NPM1 was gradually increased with the increase of clinical stages of endometrial carcinomas. Overexpression of NPM1 may play a role in the effects of estrogen on the malignant progression of endometrioid adenocarcinoma via ERα signaling. These findings may extend our understanding of the oncogenesis of steroid hormone-related cancers and have significance for the diagnosis and treatment of this carcinoma.
Collapse
Affiliation(s)
- Yunxiao Zhou
- Department of Gynecology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 China
| | - Jie Shen
- Department of Gynecology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 China
| | - Liqun Xia
- Department of Gynecology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 China
| | - Yanli Wang
- Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 China
| |
Collapse
|