Etiology Of Endometrial Cancer Research Articles

Hypertension and risk of endometrial cancer: a pooled analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2).

The incidence rates of endometrial cancer (EC) are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for EC. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of EC remains unclear. In this study we evaluated hypertension as an independent risk factor for EC and whether this association is modified by other established risk factors. We included 15,631 EC cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between hypertension and EC and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. Hypertension was associated with an increased risk of EC (OR=1.14, 95% CI:1.09-1.19). There was significant heterogeneity by study design (Phet<0.01), with a stronger magnitude of association observed among case-control vs. cohort studies. Stronger associations were also noted for pre-/peri-menopausal women and never users of postmenopausal hormone therapy. Hypertension is associated with EC risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. This study provides evidence that hypertension may be an independent risk factor for EC.

Causal relationship between affect disorders and endometrial cancer: a Mendelian randomisation study

Background The aim was to assess the causal relationship between depression and anxiety disorders and endometrial cancer. Method We performed two-sample Mendelian randomisation analysis using summary statistics from genome-wide association studies to assess associations of major depressive disorder, anxiety and stress-related disorders with endometrial cancer. The genome-wide association studies(GWASs) data were derived from participants of predominantly European ancestry included in the Genome-wide Association Research Collaboration. Inverse variance-weighted, MR-Egger and weighted median MR analyses were performed, together with a range of sensitivity analyses. Results Mendelian randomisation analysis showed no statistically significant genetic responsibility effect of anxiety and stress-related disorders on any pathological type of endometrial cancer. Only the effect of major depressive disorder under the inverse variance weighting method increasing the risk of endometrial endometrial cancer (effect 0.004 p = 0.047) and the effect of major depressive disorder under the MR-Egger method decreasing endometrial cancer of all pathology types (effect −0.691 p = 0.015) were statistically significant. Other Mendelian randomisation analyses did not show a statistically significant effect. Conclusion Major depressive disorder(MDD), anxiety and stress-related disorders(ASRD) are not genetically responsible for endometrial cancer. We consider that emotional disorders may affect endometrial cancer indirectly by affecting body mass index. This study provides us with new insights to better understand the aetiology of endometrial cancer and inform prevention strategies.

Circulating adrenal 11-oxygenated androgens are associated with clinical outcome in endometrial cancer.

Recent evidence support that androgens play an important role in the etiology of endometrial cancer (EC). Adrenal-derived 11-oxygenated androgens are highly potent agonists of the androgen receptor (AR), comparable to testosterone (T) and dihydrotestosterone (DHT) that have not been studied in the context of EC. We studied a cohort of 272 newly diagnosed postmenopausal EC cases undergoing surgical treatment. Circulating concentrations of seven 11-oxygenated androgens including precursors, potent androgens and their metabolites were established in serum samples collected before and 1 month after surgery using a validated liquid chromatography tandem mass spectrometry method (LC-MS/MS). Free (unconjugated) and total (free + sulfate and glucuronide conjugates following enzymatic hydrolysis) were analyzed in relation to clinicopathological features, recurrence and disease-free survival (DFS). Levels of 11-oxygenated androgens were weakly correlated to those of canonical androgens such as testosterone (T) and dihydrotestosterone (DHT), with no evidence of their association with clinicopathological features. Levels of 11-oxygenated androgens declined after surgery but remained higher in overweight and obese compared to normal weight cases. Higher levels of preoperative free 11-ketoandrosterone (11KAST) were associated with an increased risk of recurrence (Hazard ratio (HR) of 2.99 (95%CI=1.09-8.18); P=0.03). Postoperative free 11β-hydroxyandrosterone (11OHAST) levels were adversely associated with recurrence and DFS (HR = 3.23 (1.11-9.40); P=0.03 and 3.27 (1.34-8.00); P=0.009, respectively). 11-oxygenated androgen metabolites emerge as potential prognostic markers of EC.

Epidemiological characteristics of endometrial cancer patients treated at a tertiary health center in National Capital Territory of India

A retrospective study which analyzed the data of female patients attending a tertiary care center in National Capital Territory for the treatment of endometrial cancer. Eighty-six histopathologically confirmed cases of carcinoma endometrium were taken from January 2016 to December 2019. Detailed information was collected regarding patient's case history, sociodemographic data (age of presentation, occupation, religion, residence, and substance addiction), clinical presentation, diagnostic and therapeutic procedures, and known risk factors (age at menarche and menopause, parity, obesity, use of oral contraceptive pills, hormone replacement therapy, and comorbidities such as hypertension and diabetes). After analysis, results were presented as mean ± standard deviation and frequency. Eighty-six percent of the patients (n = 73) were in the age group of 40-70 years; the mean age of the patients at diagnosis of endometrial cancer was 54 years. Eighty-one percent (n = 70) of the patients were from urban areas. Sixty-seven percent of the females (n = 54) were Hindu. All the patients were housewives with nonsedentary lifestyles. Most patients (88%; n = 76) presented with bleeding per vaginum. Fifty-nine percent (n = 51) had stage I disease, followed by 15% (n = 13) with stage II, 14% (n = 12) with stage III, and 12% (n = 10) with stage IV disease. Eighty-two percent (n = 72) of the patients had endometrioid carcinoma. Other less common variants were mixed Mullerian malignant tumor, squamous, adenosquamous, serous, and endometrioid stromal. Forty-four percent (n = 38), 39% (n = 34), and 16% (n = 14) of the patients had grade I, grade II, and grade III tumor, respectively. 53.5% of the cases (n = 46) had >50% myometrial invasion at the time of presentation. Eighty-two percent (n = 71) of the patients were postmenopausal. The mean age at menarche and menopause was 13 years and 47 years, respectively. Fifteen percent (n = 13) of the females were nulliparous. Forty-six percent (n = 40) of the patients were overweight. Most patients (82%) had no history of addiction. Twenty-five percent (n = 22) of the patients had hypertension, and 27% (n = 23) has diabetes as comorbidity. The incidence of endometrium cancer is showing a steady rise in the recent past. Early age of menarche, late age of menopause, nulliparity, obesity, and diabetes mellitus are well-documented risk factors for uterine cancer. Better outcome and control of disease is possible by understanding of endometrial cancer etiology, risk factors, and its preventive measures. Thus, a robust screening program is warranted to detect the disease in early stage and for increased survival.

Endometrial microbiota from endometrial cancer and paired pericancer tissues in postmenopausal women: differences and clinical relevance.

ObjectiveThe incidence of postmenopausal endometrial cancer (EC) is rising, and the uterine microbiota has recently been suggested to be an etiology of EC. However, the differences in microbiota profiles in paired EC and the adjacent non-EC endometrium, and the functional microbiota of clinical relevance remain largely unknown. Therefore, we examined the differences in microbiota profiles between EC and non-EC endometrium and investigated their clinical relevance to EC.MethodsTwenty-eight EC-affected postmenopausal women undergoing hysterectomy were enrolled. Endometrial microbiome from paired EC and adjacent non-EC tissue samples were detected using 16S rRNA sequencing, and the data were analyzed using R language software.ResultsThe α diversity and evenness of the endometrial bacterial community significantly increased in EC tissues than those in pericancer tissues (P < 0.05 for all variables). Lactobacillus and Gardnerella were the main bacterial genera present in both EC and adjacent non–EC-invading endometrium, whereas Prevotella, Atopobium, Anaerococcus, Dialister, Porphyromonas, and Peptoniphilus were more commonly enriched in the EC endometrium (corrected P < 0.05 for all variables). Finally, the abundance of some observed endometrial bacteria was associated with clinical aspects, particularly the vaginal pH, vaginal Lactobacillus abundance, and EC clinical stage.ConclusionsPaired EC and adjacent non-EC endometrium harbor different endometrial microbiota, and the functional bacteria residing in the endometrium are clinically relevant but require further investigation.

Downregulated circular RNA hsa_circ_0005797 inhibits endometrial cancer by modulating microRNA-298/Catenin delta 1 signaling

ABSTRACT Abnormal expression of circular RNA (circRNA) expression has been implicated in endometrial cancer (EC) progression. Thus, investigation of the mechanism of hsa_circ_0005797 during EC etiology may provide new insight into the treatment of EC. In the present study, we found that hsa_circ_0005797 expression was significantly increased in EC biological samples and cell lines, whereas its downregulation inhibited in vitro tumor cells proliferation and invasion phenotypes and suppressed tumor formation in nude mice. In mechanism, we characterized hsa_circ_0005797 as an miR-298 sponge, with CTNND1 identified as a target of miR-298. Our rescue assay data further revealed that hsa_circ_0005797 silencing inhibited EC cells proliferation and invasion via miR-298/CTNND1 signaling. In conclusion, our study confirmed hsa_circ_0005797 is a poor prognostic factor for EC and modulates EC phenotypes by regulating the hsa_circ_000579/miR-298/CTNND1 signaling, which provides potential treatment targets for EC

Immunohistochemical Expression of Fibroblast Activation Protein (FAP) in Endometrial Carcinoma Subtype at The Department of Anatomical Pathology Faculty of Medicine Universitas Sumatera Utara / RSUP H. Adam Malik Medan

Background: Endometrial cancer (EC) is the most commonly diagnosed gynecologic malignancy globally; The etiology of EC is still unknown, but most of the risk factors are related to changes in hormonal patterns that occur in women. In the female reproductive tract, fibroblasts promote epithelial development and differentiation which responsible for extracellular matrix remodeling, survival and death. Fibroblast activation protein (FAP) is a cell surface antigen that expressed on reactive stromal fibroblasts of cancer epithelial cells and appears as an important factor in cancer-associated fibroblasts (CAF), which relevant in tumor development. FAP has effects on cell proliferation, migration, and invasion, which promote tumor growth. To date, only one study of FAP has been found on the endometrium. In addition, there have been no studies on the expression of FAP against endometrial carcinoma subtypes. Objective: This study was conducted to analyze the immunohistochemical expression of FAP in endometrial carcinoma sub subtypes. Methods: The study used 38 samples of paraffin blocks from endometrial carcinoma cases that had been diagnosed at the Laboratory of Anatomical Pathology, RSUP H. Adam Malik and the Department of Anatomical Pathology, Faculty of Medicine, Universitas Sumatera Utara. FAP expression was assessed using immunohistochemical staining of tumor cell cytoplasm and stroma. Expressions were assessed using the Quick Score method and were declared positive if the total score ? 3. Results: Immunohistochemical expression of FAP in endometrial carcinoma was the most positive in the endometrioid carcinoma subtype, namely 27 cases (77.14%). Keywords: endometrial carcinoma, cancer-associated fibroblasts, fibroblast activation protein

Abstract 3490: Investigation of 27-hydroxycholesterol as a biomarker for aggressive endometrial cancer

Abstract Background: Strong risk factors for the most common (endometrioid) type of endometrial cancer (EC) include obesity and exposure to high estrogen levels. While EC has a favorable prognosis overall, one third of women present with advanced stage disease at diagnosis which has high recurrence and mortality rates. Given the estrogen-mediated etiology of EC, the current study focuses on the selective estrogen receptor modulator (SERM) 27-hydroxycholesterol (27HC) pathway. SERMs like 27HC can mimic estrogenic actions, and experimental work indicates 27HC exposure leads to continuous estrogenic stimulation and increases proliferation in the endometrium. Objective: to identify biomarkers for more aggressive disease, particularly markers present in early stages of carcinogenesis, to help guide decisions regarding treatment options. Methods: We conducted immunohistochemical staining on two tissue microarrays (TMAs) representing EC and its precursor endometrial intraepithelial neoplasia (EIN) tissues to measure protein levels of the enzymes that metabolize cholesterol into 27HC (CYP27A1) and 27HC into bile acids (CYP7B1), the receptors that bind 27HC (Estrogen Receptor [ER])-alpha, ER-beta as well as Liver Receptor X [LXR]-alpha and LXR-beta) and progesterone receptor (PR). We will use Fisher's exact test to evaluate 27HC associated biomarkers (categories split at the median) in relation to the presence of myometrial invasion (MI) and final diagnosis (EC or not) in the EIN TMA, and to assess clinico-pathologic factors including disease stage and grade in the EC TMA. Results: We created a new EIN TMA using formalin-fixed paraffin-embedded endometrial curettage or Pipelle endometrial biopsies from 144 EIN cases of diverse racial/ethnic backgrounds (Japanese, Hawaiian, White, Filipino and Asian/Pacific Islander) who were treated between 2007-16 in the Hawaii Pacific Health System. The EIN TMA contains both abnormal EIN tissues and neighboring benign/non-atypical tissues. In total, 50% of the EIN cases had no EC, 30% had cancer with no myometrial invasion (MI) and 20% had cancer with myometrial invasion. We are concurrently evaluating 27HC pathway markers in a TMA representing EC tumors from 96 cases who were treated in the same hospitals between 2001-07. The EC TMA represents diverse racial/ethnic groups including 28% Japanese American, 25% Native Hawaiian and 23% white cases (24% other). The EC TMA contains representative tissues from 91% endometrioid histotype cases and 72% localized and 28% regional/distant stage cases. We will examine associations between 27HC pathway biomarkers and clinico-pathologic characteristics of EC and EIN and will present our findings at the meeting. Conclusions: This study provides new data to determine whether 27HC pathway biomarkers may relate to characteristics of aggressive EC, such as the presence of myometrial invasion and higher stage and grade at diagnosis. Citation Format: Danja Sarink, Lenora W. Loo, Jeffrey Killeen, Brenda Y. Hernandez, Owen T. Chan, Melissa A. Merrit. Investigation of 27-hydroxycholesterol as a biomarker for aggressive endometrial cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3490.

Association of polymorphisms in MALAT1 with the risk of endometrial cancer in Southern Chinese women.

BackgroundEndometrial cancer is the most common gynecologic malignancy worldwide. Polymorphisms in MALAT1 have been demonstrated to play critical roles in cancer. However, the roles of MALAT1 polymorphisms in the etiology of endometrial cancer have not been well documented.MethodsWe genotyped three MALAT1 polymorphisms in 249 endometrial cancer cases and 446 cancer‐free female controls using quantitative polymerase chain reaction with TaqMan probes. To estimate the association between MALAT1 polymorphisms (rs591291 C>T, rs664589 C>G, and rs4102217 G>C) and the risk of endometrial cancer, an unconditional logistic regression model was conducted to calculate the odds ratio (OR) and the 95% confidence interval (CI), adjusting for surgery history, menopause, number of deliveries, BMI, and FIGO stage.ResultsWe found that the MALAT1 rs664589 C>G polymorphism was significantly associated with endometrial cancer risk (heterogeneous: adjusted OR = 0.57, 95% CI = 0.34‐0.93, P = .026; homogenous: adjusted OR = 3.74, 95% CI = 1.12‐12.45, P = .032; and recessive: adjusted OR = 4.06, 95% CI = 1.22‐13.48, P = .022). Stratified analysis further demonstrated that the MALAT1 rs664589 C>G polymorphism significantly increased the risk of endometrial cancer susceptibility in patients with no history of surgery, more deliveries, BMI between 25 and 29.9, and FIGO stages II‐III. Compared with the wild‐type GCG haplotype carriers, individuals with CGG haplotypes had a higher risk of developing endometrial cancer.ConclusionThe MALAT1 rs664589 C>G polymorphism was associated with a significant increase in endometrial cancer risk.

Case-control study of endogenous sex steroid hormones and risk of endometrial cancer.

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. 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. 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). 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.

The investigation of serum levels of ADAMTS 5 and 8 (the A disintegrin and metalloproteinase with thrombospondin motifs) in the etiology of endometrial cancer

The aim of this study was to investigate the serum levels of the A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 5 and 8 in patients diagnosed with endometrial cancer. Our study included 41 patients diagnosed with endometrial cancer. The control group consisted of 41 patients diagnosed with benign endometrial pathology. The serum samples were centrifuged and stored at –80 °C. The serum levels of ADAMTS were significantly higher (p<.001), whereas the levels of ADAMTS 8 were significantly lower in patients diagnosed with cancer (p<.001). In addition to the presence of known factors in the aetiology of endometrial cancer, the effect of inflammatory factors and some new proteins has centred on the causes of tumourigenesis in recent years. In this sense, these proteins, called the ADAMTS, are the source of new studies.Impact StatementWhat is already known on this subject? When the recent studies about endometrial cancer are evaluated, it is seen that the effects of chronic inflammation and cytokines have gained importance in its aetiology. The A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) gene family consist of 19 proteases that play essential role in the formation of the extracellular matrix (ECM) and interact with inflammatory cytokines. These proteases and their substrates provide a wide range of functions in different tissues, including ECM remodelling, angiogenesis, fibrosis and coagulation.What the results of this study add? ADAMTS 5, which causes the degradation of the ECM with Aggrecanase activity, was found to be significantly higher in patients diagnosed with cancer and ADAMTS 8 with anti-angiogenesis activity was significantly lower in patients diagnosed with endometrial cancer.What the implications are of these findings for clinical practice and/or further research? In this study, it is understood that the effect of inflammatory mediators is remarkably important in the aetiology of endometrial cancer, as in many types of organ specific cancer.

Downregulation of PTPN18 can inhibit proliferation and metastasis and promote apoptosis of endometrial cancer.

Endometrial cancer is one of the chief culprits threatening women's lives. Although numerous epidemiological experiments have been carried out into the aetiology of endometrial cancer, the cause of the disease has been unclear up to now. In recent years, PTPN18, a member of the protein tyrosine phosphatases (PTP) family predicted to be tumour suppressors or oncogenes, has been confirmed to participate in the occurrence and progression of many cancers. Few studies, however, have explained the role in the endometrial cancer. So, it caught our attention to explore if PTPN18 participates in and plays a regulatory role in the proliferation, apoptosis, and metastasis of endometrial cancer. In our results, we found that PTPN18 was overexpressed in endometrial cancer tissue compared to paracancerous tissue by immunohistochemistry. Not only that, silencing of PTPN18 in endometrial cancer cell lines (HEC-1-A and HEC-1-B) can significantly impair proliferation detected by CCK8 assay and flow cytometry (FCM) analyses and inhibit the metastasis of endometrial cancer cells shown by the scratch test and the Transwell experiment. PTPN18 knockdown can promote the apoptosis of endometrial cancer. In addition, nude mice tumour formation assay confirmed the results in vivo. Although the exact function of PTPN18 in endometrial cancer is unclear, the targeted therapy drugs enhancing PTPN18 may be considered in the future treatment of endometrial carcinoma.

Increased plasmatic soluble HLA-G levels in endometrial cancer

Human Leukocyte Antigen-G (HLA-G) is known as an immune suppressive molecule; it interacts with several immune cells and inhibits their functions. HLA-G molecule is highly represented in pathological conditions including malignant transformation. To the best of our knowledge this is the first study that focuses on the expression of soluble HLA-G (sHLA-G) in endometrial cancer (EC). We aimed at exploring sHLA-G plasma levels and its prognostic value in EC.We examined total sHLA-G expression as well as the sHLA-G1 and HLA-G5 isoforms expression in plasma samples from 40 patients with EC and 45 healthy controls by a specific sandwich ELISA. Immunoprecipitation and Coomassie blue staining were performed to explore the presence of plasmatic sHLA-G monomers and dimers.sHLA-G plasma level was significantly enhanced in patients with EC compared to healthy controls (p = 0.028). Additionally, HLA-G5 molecules were highly represented than sHLA-G1 molecules in EC, at the borderline of significance (p = 0.061). Interestingly, sHLA-G has been shown to be increased in early stages (Stages I and II) as well as in high grade EC (Grade 3) that is associated with rapid spread of the disease (p = 0.057). sHLA-G positive EC plasma were majorly in monomeric form (75%). Clinically, all the HLA-G dimers were detected in early stages and in high grade of EC.Our data strengthen the implication of HLA-G molecules in EC etiology and especially in progression.

Highlights of This Issue

Metformin is widely used in the management of type 2 diabetes mellitus. Epidemiologic studies have reported strong inverse associations between metformin use and risk of several cancers, including colorectal (CRC). Concern that time-related biases, such as immortal time bias, were influencing reported associations led Bradley and colleagues to re-examine metformin and CRC risk using methods to minimize these biases. Specifically, the authors accounted for time-varying exposure to metformin and other diabetes medications and adjusted for diabetes duration. Despite applying more rigorous methods, the authors observed an inverse association between long-term metformin use and CRC risk that appeared to be restricted to men.Hepatocellular carcinoma (HCC) incidence is rising in regions where established HCC risk factors are not predominant. The rise is likely due to factors such as obesity and unhealthy lifestyle exposures. This study, by Assi and colleagues, presents an analytical framework to explore exposure-specific metabolic signatures and assess their mediating role in the association between various lifestyle behaviors and HCC risk using detailed metabolomic and lifestyle data from a large prospective cohort. Metabolic profiles of obesity, smoking, and alcohol intake mediated HCC carcinogenesis. These findings contribute to further understanding of HCC etiology, thus strengthening public health advice for cancer prevention by modifying unhealthy lifestyle behaviors.Using novel questionnaire, biomarker, and vital records data, this study by Boen and colleagues examines how diverse measures of social support relate to mortality risk among individuals with cancer as well as the mediating role of inflammation as a biological mechanism. Findings revealed that cancer patients reporting less social support satisfaction had higher mortality risk than those reporting greater satisfaction, partly due to the elevated risk of inflammation associated with low satisfaction. The study offers new insights for intervention efforts aimed at promoting meaningful social connections as a means for improving cancer survival.Endometrial cancer incidence has been increasing among black women. Despite established roles of estrogens and progestins in endometrial cancer etiology, few studies have investigated the influence of exogenous hormone use among black women. Similar to prior findings, the Black Women's Health Study found that oral contraceptive use was associated with reduced endometrial cancer risk; estrogen-only menopausal hormone use was associated with increased risk. Also consistent with previous studies, the protective effects of oral contraceptive use were weaker among obese women. The results of this study by Sponholzt and colleagues suggest that the high obesity prevalence among black women may contribute to their increasing endometrial cancer incidence by mitigating the beneficial effects of oral contraceptive use.

Anti-Mullerian hormone and endometrial cancer: a multi-cohort study

Background:The Mullerian ducts are the embryological precursors of the female reproductive tract, including the uterus; anti-Mullerian hormone (AMH) has a key role in the regulation of foetal sexual differentiation. Anti-Mullerian hormone inhibits endometrial tumour growth in experimental models by stimulating apoptosis and cell cycle arrest. To date, there are no prospective epidemiologic data on circulating AMH and endometrial cancer risk.Methods:We investigated this association among women premenopausal at blood collection in a multicohort study including participants from eight studies located in the United States, Europe, and China. We identified 329 endometrial cancer cases and 339 matched controls. Anti-Mullerian hormone concentrations in blood were quantified using an enzyme-linked immunosorbent assay. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) across tertiles and for a doubling of AMH concentrations (ORlog2). Subgroup analyses were performed by ages at blood donation and diagnosis, oral contraceptive use, and tumour characteristics.Results:Anti-Mullerian hormone was not associated with the risk of endometrial cancer overall (ORlog2: 1.07 (0.99–1.17)), or with any of the examined subgroups.Conclusions:Although experimental models implicate AMH in endometrial cancer growth inhibition, our findings do not support a role for circulating AMH in the aetiology of endometrial cancer.

Is There Any Association between Glutathione S-transferases M1 and Glutathione S-transferases T1 Gene Polymorphisms and Endometrial Cancer Risk? A Meta-analysis.

Epidemiological evidence on the association between genetic polymorphisms in glutathione S-transferases M1 (GSTM1) and T1 (GSTT1) genes and risk of endometrial cancer (EC) has been inconsistent. In this meta-analysis, we seek to investigate the relationship between GSTM1 and GSTT1 polymorphisms and the risk of EC. We searched Medline, PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure database, and Chinese Biomedical Literature database to identify eligible studies. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) for the association were determined using a fixed- or random-effect model. Tests for heterogeneity of the results and sensitivity analyses were performed. A total of six case–control studies were included in the final meta-analysis of GSTM1 (1293 cases and 2211 controls) and GSTT1 (1286 cases and 2200 controls) genotypes. Overall, GSTM1 null genotype was not significantly associated with an increased risk of EC (OR = 1.00, 95% CI = 0.76–1.30, P = 0.982). Similarly, for GSTT1 deletion genotype, we observed no association under the investigated model in the overall analysis (OR = 0.91, 95% CI = 0.64–1.30, P = 0.619). Subgroup analysis also showed no significant association between the GSTM1 null genotype and EC risk in hospital-based design (OR = 1.26, 95% CI = 0.93–1.71, P = 0.131) and no relationship between GSTT1 null genotype with EC risk in population-based design (OR = 1.18, 95% CI = 0.79–1.76, P = 0.407). However, GSTM1 null genotype contributed to an increased EC risk in population-based design (OR = 0.76, 95% CI = 0.60–0.97, P = 0.027), while null GSTT1 in hospital-based studies (OR = 0.70, 95% CI = 0.52–0.93, P = 0.015). The present meta-analysis suggested that GSTs genetic polymorphisms may not be involved in the etiology of EC. Large epidemiological studies with the combination of GSTM1 null, GSTT1 null, and design-specific with the development of EC are needed to prove our findings.

Modelling body mass index and endometrial cancer risk in a pooled‐analysis of three case–control studies

To quantify the relation between body mass index (BMI) and endometrial cancer risk, and to describe the shape of such a relation. Pooled analysis of three hospital-based case-control studies. Italy and Switzerland. A total of 1449 women with endometrial cancer and 3811 controls. Multivariate odds ratios (OR) and 95% confidence intervals (95% CI) were obtained from logistic regression models. The shape of the relation was determined using a class of flexible regression models. The relation of BMI with endometrial cancer. Compared with women with BMI 18.5 to <25 kg/m(2) , the odds ratio was 5.73 (95% CI 4.28-7.68) for women with a BMI ≥35 kg/m(2) . The odds ratios were 1.10 (95% CI 1.09-1.12) and 1.63 (95% CI 1.52-1.75) respectively for an increment of BMI of 1 and 5 units. The relation was stronger in never-users of oral contraceptives (OR 3.35, 95% CI 2.78-4.03, for BMI ≥30 versus <25 kg/m(2) ) than in users (OR 1.22, 95% CI 0.56-2.67), and in women with diabetes (OR 8.10, 95% CI 4.10-16.01, for BMI ≥30 versus <25 kg/m(2) ) than in those without diabetes (OR 2.95, 95% CI 2.44-3.56). The relation was best fitted by a cubic model, although after the exclusion of the 5% upper and lower tails, it was best fitted by a linear model. The results of this study confirm a role of elevated BMI in the aetiology of endometrial cancer and suggest that the risk in obese women increases in a cubic nonlinear fashion. The relation was stronger in never-users of oral contraceptives and in women with diabetes.

Abstract 5044: Role of obesity in Leptin-Notch crosstalk (NILCO) in endometrial cancer from African American and Chinese women

Abstract Introduction: Endometrial cancer is the most common gynecological malignancy of the female reproductive tract. Endometrial cancer is classified into two groups: Type I, which is estrogen dependent, and Type II, which is usually associated with endometrial atrophy and is estrogen independent. Type II is the more aggressive form with a poor prognosis and is often observed more in African American women. Obesity, characterized by high levels of leptin, is a major risk factor for endometrial cancer, which suggests that leptin may play a role in endometrial cancer pathogenesis. Over-expression of Notch, IL-1 and leptin and the signaling crosstalk (NILCO) among these pro-angiogenic factors is associated with metastasis and decreased survival rates in breast cancer patients. However, much is unknown whether this association is found in endometrial cancer. Objective: In this investigation, we aim to determine whether NILCO components are differentially expressed in Type I and Type II endometrial cancer. We hypothesize that there is a positive correlation between endometrial cancer etiology and higher BMI and NILCO expression. We further hypothesize that the correlation is more evident in Type II endometrial cancer. Methods: Expression levels of Notch1, 2, 3 &amp; 4, Jagged-1, DLL4, Survivin, Hey2, IL-1R tI, Leptin, and Ob-R were determined via immunohistochemistry (IHC) in endometrial cancer from overweight/obese African American patients and compared to endometrial cancer tissue array from Chinese women (70 cases of carcinoma and 5 cases of non-malignant duplicated cores per case, US Biomax, Inc). Staining intensity was assigned using semi-quantitative HSCORE [∑pi (i+1), where “i” is the intensity with a value of 1, 2, or 3 (weak, moderate or strong, respectively and “pi” is the percentage of stained cells for each intensity] calculated by two independent observers in 3 different fields (100 cells/each). Western Blot and qPCR analyses of tissue lysates from cancer samples and benign surrounding tissues were also used to examine the expression levels of NILCO components.Student t-test was used to determine statistical differences between samples. Results: IHC results showed that Notch1 and 4, DLL4, Survivin, and Jagged-1 were expressed higher in Type II endometrial cancer patients. IL-1R tI was expressed higher in non-malignant compared to malignant tissue samples. Western blot and qPCR analyses further corroborated these results. Conclusion: The results support our hypothesis that obesity affects the expression of NILCO components, which could be involved in endometrial cancer progression and aggressiveness. [Partially supported by NIH/NCI 1SC1CA138658-05; NIH RR03034,1C06 RR18386, NIH/NCRR 1G12RR026250-03 and MSM/Tuskegee Univ/UAB Cancer Center Partnership grant 5U54CA118638. The National Center for Advancing Translational Sciences of the NIH Award UL1TR000454]. Citation Format: Danielle Daley-Brown, Regina Lee, Gabriela Oprea-Ilies, Emerald Screws, Roland Matthews, Roland Pattillo, Ruben Rene Gonzalez-Perez. Role of obesity in Leptin-Notch crosstalk (NILCO) in endometrial cancer from African American and Chinese women. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5044. doi:10.1158/1538-7445.AM2014-5044

Evidence of androgen action in endometrial and ovarian cancers

Endometrial cancer (EC) and ovarian cancer are common gynaecological malignancies. The impact of androgen action in these cancers is poorly understood; however, there is emerging evidence to suggest that targeting androgen signalling may be of therapeutic benefit. Epidemiological evidence suggests that there is an increased risk of EC associated with exposure to elevated levels of androgens, and genetic variants in genes related to both androgen biosynthesis and action are associated with an increased risk of both EC and ovarian cancer. Androgen receptors (ARs) may be a potential therapeutic target in EC due to reported anti-proliferative activities of androgens. By contrast, androgens may promote growth of some ovarian cancers and anti-androgen therapy has been proposed. Introduction of new therapies targeting ARs expressed in EC or ovarian cancer will require a much greater understanding of the impacts of cell context-specific AR-dependent signalling and how ARs can crosstalk with other steroid receptors during progression of disease. This review considers the evidence that androgens may be important in the aetiology of EC and ovarian cancer with discussion of evidence for androgen action in normal and malignant endometrial and ovarian tissue.

Associations of long-chain ω-3 fatty acids and fish intake with endometrial cancer risk in the VITamins And Lifestyle cohort

Inflammation plays an important role in endometrial cancer etiology. Long-chain ω-3 (n-3) polyunsaturated fatty acids (PUFAs), derived from marine sources, are thought to be antiinflammatory; however, several studies of fish consumption suggest an increase in risk. This study examined whether intakes of long-chain ω-3 PUFAs, including eicosapentaenoic acid (EPA; 20:5ω-3) and docosahexaenoic acid (DHA; 22:6ω-3), from diet and supplements and intake of fish are associated with endometrial cancer risk. Between 2000 and 2002, 22,494 women aged 50-76 y, living in western Washington State, were recruited to the VITamins And Lifestyle cohort study. Incident endometrial cancers (n = 263) were identified through the Surveillance, Epidemiology, and End Results cancer registry after 9 y of follow-up. Multivariable-adjusted HRs and 95% CIs for the association of intakes of individual long-chain ω-3 PUFAs and fish with endometrial cancer risk were estimated by using Cox proportional hazards. Women in the highest compared with the lowest quintile of dietary EPA + DHA intake had a 79% increased risk of endometrial cancer (95% CI: 16%, 175%; P-trend = 0.026). Results were similar for EPA and DHA measured individually and for fish intake. When data were stratified by body mass index (in kg/m²; <25 or ≥ 25), increases in risk of long-chain ω-3 PUFAs were restricted to overweight and obese women, and statistically significant reductions in risk were observed for normal-weight women. The overall increased risk reported here confirms the findings of several prior observational studies of fish intake, which observed similar increases in risk. Randomized trials are needed to confirm these findings.