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‣ HE4 (WFDC2) Promotes Tumor Growth in Endometrial Cancer Cell Lines

Li, Jinping; Chen, Haibin; Mariani, Andrea; Chen, Dong; Klatt, Edward; Podratz, Karl; Drapkin, Ronny I.; Broaddus, Russell; Dowdy, Sean; Jiang, Shi-Wen
Fonte: Molecular Diversity Preservation International (MDPI) Publicador: Molecular Diversity Preservation International (MDPI)
Tipo: Artigo de Revista Científica
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HE4, also known as WFDC2, is a useful biomarker for ovarian cancer when either used alone or in combination with CA125. HE4 is also overexpressed in endometrial cancer (EC), but its function in cancer cells is not clear. In this study, we investigate the role of HE4 in EC progression. An HE4-overexpression system was established by cloning the HE4 prototypic mRNA variant (HE4-V0) into a eukaryotic expression vector. Following transfection, stable clones in two EC cell lines were selected. The effects of HE4 overexpression on cell growth and function were measured with the use of cell proliferation assay, matrigel invasion, and soft agar gel colony formation assays. HE4-induced cancer cell proliferation in vivo was examined in a mouse xenograft model. HE4 overexpression significantly enhanced EC cell proliferation, matrigel invasion, and colony formation in soft agar. Moreover, HE4 overexpression promoted tumor growth in the mouse xenograft model. HE4 overexpression enhanced several malignant phenotypes in cell culture and in a mouse model. These results are consistent with our previous observation that high levels of serum HE4 closely correlate with the stage, myometrial invasion and tumor size in patients with EC. This study provides evidence that HE4 overexpression directly impacts tumor progression in endometrial cancer.

‣ HE4 Transcription- and Splice Variants-Specific Expression in Endometrial Cancer and Correlation with Patient Survival

Jiang, Shi-Wen; Chen, Haibin; Dowdy, Sean; Fu, Alex; Attewell, John; Kalogera, Eleftheria; Drapkin, Ronny; Podratz, Karl; Broaddus, Russell; Li, Jinping
Fonte: Molecular Diversity Preservation International (MDPI) Publicador: Molecular Diversity Preservation International (MDPI)
Tipo: Artigo de Revista Científica
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We investigated the HE4 variant-specific expression patterns in various normal tissues as well as in normal and malignant endometrial tissues. The relationships between mRNA variants and age, body weight, or survival are analyzed. ICAT-labeled normal and endometrial cancer (EC) tissues were analyzed with multidimensional liquid chromatography followed by tandem mass spectrometry. Levels of HE4 mRNA variants were measured by real-time PCR. Mean mRNA levels were compared among 16 normal endometrial samples, 14 grade 1 and 14 grade 3 endometrioid EC, 15 papillary serous EC, and 14 normal human tissue samples. The relationship between levels of HE4 variants and EC patient characteristics was analyzed with the use of Pearson correlation test. We found that, although all five HE4 mRNA variants are detectable in normal tissue samples, their expression is highly tissue-specific, with epididymis, trachea, breast and endometrium containing the highest levels. HE4-V0, -V1, and -V3 are the most abundant variants in both normal and malignant tissues. All variants are significantly increased in both endometrioid and papillary serous EC, with higher levels observed in grade 3 endometrioid EC. In the EC group, HE4-V1, -V3, and -V4 levels inversely correlate with EC patient survival...

‣ Proanthocyanidins and other flavonoids in relation to endometrial cancer risk: a case–control study in Italy

Rossi, M; Edefonti, V; Parpinel, M; Lagiou, P; Franchi, M; Ferraroni, M; Decarli, A; Zucchetto, A; Serraino, D; Dal Maso, L; Negri, E; La Vecchia, C
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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Background: Because of their antioxidant and antimutagenic properties, flavonoids may reduce cancer risk. Some flavonoids have antiestrogenic effects that can inhibit the growth and proliferation of endometrial cancer cells. Methods: In order to examine the relation between dietary flavonoids and endometrial cancer, we analysed data from an Italian case–control study including 454 incident, histologically confirmed endometrial cancers and 908 hospital-based controls. Information was collected through a validated food-frequency questionnaire. We applied data on food and beverage composition to estimate the intake of flavanols, flavanones, flavonols, anthocyanidins, flavones, isoflavones, and proanthocyanidins. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from multiple logistic regression models conditioned on age and study centre and adjusted for major confounding factors. Results: Women in the highest quartile category of proanthocyanidins with ⩾3 mers vs the first three quartile categories had an OR for endometrial cancer of 0.66 (95% CI=0.48–0.89). For no other class of flavonoids, a significant overall association was found. There was a suggestion of an inverse association for flavanones and isoflavones among women with body mass index <25 kg m−2...

‣ SALL4 is a new target in endometrial cancer

Li, Ailing; Jiao, Yisheng; Yong, Kol Jia; Wang, Fei; Gao, Chong; Yan, Benedict; Srivastava, Supriya; Lim, Gkeok Stzuan Diana; Tang, Ping; Yang, Henry; Tenen, Daniel G; Chai, Li
Fonte: Harvard University Publicador: Harvard University
Tipo: Artigo de Revista Científica
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Aggressive cancers and embryonic stem (ES) cells share a common gene expression signature. Identifying the key factors/pathway(s) within this ES signature responsible for the aggressiveness of cancers can lead to a potential cure. In this study, we find that SALL4, a gene involved in the maintenance of ES cell self-renewal, is aberrantly expressed in 47.7% of primary human endometrial cancer samples. It is not expressed in normal or hyperplastic endometrial. More importantly, SALL4 expression is positively correlated with worse patient survival and aggressive features such as metastasis in endometrial carcinoma. Further functional studies have shown that loss of SALL4 inhibits endometrial cancer cell growth in vitro and tumorigenicity in vivo, as a result of inhibition of cell proliferation and increased apoptosis. In addition, down-regulation of SALL4 significantly impedes the migration and invasion properties of endometrial cancer cells in vitro and their metastatic potential in vivo. Furthermore, manipulation of SALL4 expression can affect drug sensitivity of endometrial cancer cells to carboplatin. Moreover, we show that SALL4 specifically binds to the c-Myc promoter region in endometrial cancer cells. While down-regulation of SALL4 leads to a decreased expression of c-Myc at both protein and mRNA levels...

‣ Does duration of hysteroscopy increase the risk of disease recurrence in patients with endometrial cancer? A multi-centre trial

Tempfer, C.; Froese, G.; Buerkle, B.; Polterauer, S.; Grimm, C.; Concin, N.; Hofstetter, G.; Weigert, M.; Oehler, M.K.
Fonte: SPANDIDOS PUBL LTD Publicador: SPANDIDOS PUBL LTD
Tipo: Artigo de Revista Científica
Publicado em //2011 Português
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Women with endometrial cancer often undergo hysteroscopy during their diagnostic work-up. Whether or not the duration of hysteroscopy affects the rate of positive peritoneal cells and the duration of recurrence-free survival is unknown. In a retrospective multi-centre study, the records of 552 patients with endometrial cancer were investigated. Duration of hysteroscopy was correlated with clinicopathological parameters and patient survival data. The mean [standard deviation (SD)] duration of hysteroscopy was 18.2 (10.5) min in the study population and 17.9 (10.1) min and 17.9 (10.2) min in patients with positive (n=109) and negative peritoneal cytology (n=443), respectively (p=0.9). There were no statistically significant correlations between duration of hysteroscopy and positive peritoneal cytology (p=0.6; rho=−0.028), FIGO stage (p=0.2; rho=−0.080), lymph node involvement (p=0.2; rho=0.106) and patient age (p=0.5; rho=0.033). Longer duration of hysteroscopy (>15 min) was not associated with positive peritoneal cytology (yes vs. no, p=0.8), advanced tumour stage (FIGO I vs. II, III and IV, p=0.3), lymph node involvement (yes vs. no, p=0.1) and patient age (≤65 vs. >65 years, p=0.4). In a multivariate analysis, FIGO stage [p<0.0001; hazard ratio (HR)=5.1...

‣ Molecular, pathologic, and clinical features of early-onset endometrial cancer: identifying presumptive Lynch syndrome patients

Walsh, M.D.; Cummings, M.C.; Buchanan, D.D.; Dambacher, W.M.; Arnold, S.; McKeone, D.; Byrnes, R.; Barker, M.A.; Leggett, B.A.; Gattas, M.; Jass, J.R.; Spurdle, A.B.; Young, J.; Obermair, A.
Fonte: American Association for Cancer Research Publicador: American Association for Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2008 Português
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Purpose: A woman with early-onset endometrial cancer (EC) may represent the “sentinel” cancer event in a Lynch syndrome kindred. The aim of this study was to determine the incidence of Lynch syndrome in a series of young-onset EC, and to identify molecular, clinical, and pathologic features that may alert clinicians to the presence of this disorder. Experimental Design: Patients with EC, ages ≤50 years, were identified from the Queensland Centre for Gynaecological Cancer. Tumor sections underwent histopathology review and were immunostained for mismatch repair proteins. Tumor DNA was tested for microsatellite instability and methylation of MLH1. Patients were conservatively classified as presumptive Lynch syndrome if their tumors showed loss of at least one mismatch repair protein and were negative for methylation of MLH1. Personal and family history of cancer was reviewed where available. Results: Presumptive Lynch syndrome was seen in 26 of 146 (18%) tumors. These tumors were more likely to be poorly differentiated, International Federation of Gynecology and Obstetrics stage II and above, have tumor-infiltrating lymphocytes, have higher mitotic rate, and have deeper myometrial invasion (P < 0.05). Lynch syndrome cases were more likely to be associated with a positive family history when analyzed for Amsterdam criteria II...

‣ Report of endometrial cancer in Australian BRCA1 and BRCA2 mutation-positive families

Duffy, D.L.; Antill, Y.C.; Stewart, C.J.; Young, J.P.; Spurdle, A.B.
Fonte: Cambridge University Press (CUP) Publicador: Cambridge University Press (CUP)
Tipo: Artigo de Revista Científica
Publicado em //2011 Português
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There is evidence that tamoxifen treatment of BRCA1 and BRCA2 carriers for prior breast cancer increases risk of endometrioid subtype endometrial cancer (EC), and suggestive evidence that BRCA1 and BRCA2 mutation carriers may be predisposed to EC in the absence of tamoxifen exposure. We assessed the association of EC with BRCA1 or BRCA2 mutation status in Australasian breast-ovarian families. Report of at least one case of EC was significantly greater in BRCA1-positive families (35/218 (16%); p = .03) and non-significantly greater in BRCA2-positive families (23/189 (12%); p = .6), compared to high-risk breast cancer families without a BRCA1/2 mutation (86/796 (11%)). EC was the first/concurrent cancer for 41% of EC cases with multiple cancer diagnoses from BRCA1/2 families, and early onset for most of these diagnoses. Mutation status was imputed for ungeno-typed individuals from 57 BRCA1/2 pedigrees reporting EC using BRCAPRO. Effects of genotype on EC diagnosis age, and interaction with tamoxifen therapy, were assessed using Cox proportional hazards regression analysis. EC risk was non-significantly marginally greater for BRCA1 carriers (hazard ratio = 1.25, 95%CI = 0.65-2.41), and BRCA2 carriers (HR = 1.12, 95%CI = 0.51-2.45), compared to non-carrier family members. Tamoxifen therapy was highly significantly associated with EC (HR = 6.68...

‣ Polycystic ovary syndrome increases the risk of endometrial cancer in women aged less than 50 years: an Australian case–control study

Fearnley, E.J.; Marquart, L.; Spurdle, A.B.; Weinstein, P.; Webb, P.M.; Oehler, M.K.; Australian Ovarian Cancer Study Group; Australian National Endometrial Cancer Study Group
Fonte: Springer Netherlands Publicador: Springer Netherlands
Tipo: Artigo de Revista Científica
Publicado em //2010 Português
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Objective: Although polycystic ovary syndrome (PCOS) is commonly cited as a risk factor for endometrial cancer, supporting epidemiological evidence is currently very limited. Our aim was to assess the associations between PCOS, PCOS symptoms, and risk of endometrial cancer in women aged less than 50 years. Methods: Data came from a national population-based case–control study in Australia. Cases with newly diagnosed histologically confirmed endometrial cancer were identified through treatment clinics and cancer registries Australia wide. Controls were randomly selected from the national electoral roll. Women were interviewed about their reproductive and medical history, including self-reported PCOS, and lifestyle. Current analyses were restricted to women aged under 50 (156 cases, 398 controls). We estimated odds ratios (OR) using logistic regression to adjust for confounding factors. Results: Women with PCOS had a fourfold increased risk of endometrial cancer compared to women without PCOS (OR 4.0, 95% CI 1.7–9.3). This association was attenuated when additionally adjusted for body mass index (OR 2.2, 95% CI 0.9–5.7). Risk was slightly greater when restricted to Type I cancers. PCOS symptoms including hirsutism and very irregular periods were significantly associated with endometrial cancer risk. Conclusions: These data extend existing findings...

‣ Quality of life of women with lower limb swelling or lymphedema 3-5years following endometrial cancer

Rowlands, I.J.; Beesley, V.L.; Janda, M.; Hayes, S.C.; Obermair, A.; Quinn, M.A.; Brand, A.; Leung, Y.; McQuire, L.; Webb, P.M.
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em //2014 Português
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Abstract not available; Ingrid J. Rowlands, Vanessa L. Beesley, Monika Janda, Sandra C. Hayes, Andreas Obermair, Michael A. Quinn, Alison Brand, Yee Leung, Lesley McQuire, Penelope M. Webb on behalf of the Australian National Endometrial Cancer Study Group; Martin Oehler is part of the ANECS group.

‣ Predictors of sexual well-being after endometrial cancer: results of a national self-report survey

Rowlands, I.J.; Lee, C.; Beesley, V.L.; Webb, P.M.
Fonte: Springer Verlag Publicador: Springer Verlag
Tipo: Artigo de Revista Científica
Publicado em //2014 Português
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Purpose: We examined whether sociodemographic, physical, reproductive, psychological and clinical factors at the time of diagnosis were related to women’s sexual well-being 3–5 years following treatment for endometrial cancer. Methods: Of the 1,399 women in the Australian National Endometrial Cancer Study, 644 completed a follow-up questionnaire 3–5 years after diagnosis. Of these, 395 women completed the Sexual-Function Vaginal Changes Questionnaire, which was used to assess sexual well-being. Based on two questions assessing worry and satisfaction with their sexuality, women were classified into lower and higher sexual well-being. Multivariable-adjusted logistic regression models were used to examine sexual well-being 3–5 years following cancer treatment and the factors associated with this at diagnosis and at follow-up. Results: Of the 395 women, 46 % (n = 181) were categorized into the “higher” sexual well-being group. Women who were older (odds ratio [OR] = 1.97; 95 % confidence limit [CI], 1.23–3.17), high school educated (OR = 1.75; 95 % CI, 1.12–2.73), who reported good mental health at the time of diagnosis (OR = 2.29; 95 % CI, 1.32–3.95) and whose cancer was treated with surgery alone (OR = 1.93; 95 % CI...

‣ Gynecological conditions and the risk of endometrial cancer

Rowlands, I.J.; Nagle, C.M.; Spurdle, A.B.; Webb, P.M.; Oehler, M.K.; Australian National Endometrial Cancer Study Group; Australian Ovarian Cancer Study Group
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em //2011 Português
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Abstract not available; Ingrid J. Rowlands, Christina M. Nagle, Amanda B. Spurdle, Penelope M. Webb, Australian National Endometrial Cancer Study Group, Australian Ovarian Cancer Study Group; Martin Oehler is a member of the Australian National Endometrial Cancer Study Group and the Australian Ovarian Cancer Study Group

‣ Glycemic index, glycemic load and endometrial cancer risk: results from the Australian National Endometrial Cancer study and an updated systematic review and meta-analysis

Nagle, C.M.; Olsen, C.M.; Ibiebele, T.I.; Spurdle, A.B.; Webb, P.M.; Australian National Endometrial Cancer Study Group; Australian Ovarian Cancer Study Group
Fonte: Springer-Verlag Publicador: Springer-Verlag
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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Purpose: The relationship between habitual consumption of foods with a high glycemic index (GI) and/or a diet with a high glycemic load (GL) and risk of endometrial cancer is uncertain, and relatively few studies have investigated these associations. The objectives of this study were to examine the association between GI/GL and risk of endometrial cancer using data from an Australian population-based case–control study and systematically review all the available evidence to quantify the magnitude of the association using meta-analysis. Methods: The case–control study included 1,290 women aged 18–79 years with newly diagnosed, histologically confirmed endometrial cancer and 1,436 population controls. Controls were selected to match the expected Australian state of residence and age distribution (in 5-year bands) of cases. For the systematic review, relevant studies were identified by searching PubMed and Embase databases through to July 2011. Random-effects models were used to calculate the summary risk estimates, overall and dose–response. Results: In our case–control study, we observed a modest positive association between high dietary GI (OR 1.43, 95 % CI 1.11–1.83) and risk of endometrial cancer, but no association with high dietary GL (OR 1.15...

‣ Impact of weight change and weight cycling on risk of different subtypes of endometrial cancer

Nagle, C.M.; Marquart, L.; Bain, C.J.; O’Brien, S.; Lahmann, P.H.; Quinn, M.; Oehler, M.K.; Obermair, A.; Spurdle, A.B.; Webb, P.M.
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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Abstract not available; C.M. Nagle, L. Marquart, C.J. Bain, S. O’Brien, P.H. Lahmann, M. Quinn, M.K. Oehler , A. Obermair, A.B. Spurdle, P.M. Webb, on behalf of the Australian National Endometrial Cancer Study Group

‣ Season of birth and risk of endometrial cancer

Rowlands, I.J.; Weinstein, P.; Nagle, C.M.; Spurdle, A.B.; Webb, P.M.; Oehler, M.K.
Fonte: National Cancer Center, Korea Publicador: National Cancer Center, Korea
Tipo: Artigo de Revista Científica
Publicado em //2011 Português
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OBJECTIVES: Season of birth has been associated with adult morbidity and mortality, but few epidemiological studies have examined whether season of birth contributes to the development of cancer. Using data from the Australian National Endometrial Cancer Study, a population-based case-control study of 1399 cases and 1539 controls, we examined the association between season of birth and risk of endometrial cancer. METHODS: Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association between season of birth and endometrial cancer. Additional analyses were stratified by state of birth. RESULTS: Season of birth was not associated with endometrial cancer overall, but there was an increased risk among women born in summer in Tasmania, the most southerly state (OR = 4.46, 95% CI: 1.24-16.06) and non-significant increases in the other southern states. CONCLUSION: Further data are required to confirm these findings, however the observed associations may be due to the longer days and/or greater hours of sunshine in Australia's southerly states in summer, suppressing melatonin levels in summer-born infants and predisposing them to cancer in adulthood.; Ingrid J Rowlands, Philip Weinstein...

‣ CHEK2, MGMT, SULT1E1 and SULT1A1 polymorphisms and endometrial cancer risk

O'Mara, T.A.; Ferguson, K.; Fahey, P.; Marquart, L.; Yang, H.P.; Lissowska, J.; Chanock, S.; Garcia-Closas, M.; Thompson, D.J.; Healey, C.S.; Dunning, A.M.; Easton, D.F.; Webb, P.M.; Spurdle, A.B.; Young, J.; McQuire, L.; Baron-Hay, S.; Bell, D.; Bonavent
Fonte: Cambridge University Press (CUP) Publicador: Cambridge University Press (CUP)
Tipo: Artigo de Revista Científica
Publicado em //2011 Português
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Several single nucleotide polymorphisms (SNPs) in candidate genes of DNA repair and hormone pathways have been reported to be associated with endometrial cancer risk. We sought to confirm these associations in two endometrial cancer case-control sample sets and used additional data from an existing genome-wide association study to prioritize an additional SNP for further study. Five SNPs from the CHEK2, MGMT, SULT1E1 and SULT1A1 genes, genotyped in a total of 1597 cases and 1507 controls from two case-control studies, the Australian National Endometrial Cancer Study and the Polish Endometrial Cancer Study, were assessed for association with endometrial cancer risk using logistic regression analysis. Imputed data was drawn for CHEK2 rs8135424 for 666 cases from the Study of Epidemiology and Risk factors in Cancer Heredity study and 5190 controls from the Wellcome Trust Case Control Consortium. We observed no association between SNPs in the MGMT, SULT1E1 and SULT1A1 genes and endometrial cancer risk. The A allele of the rs8135424 CHEK2 SNP was associated with decreased risk of endometrial cancer (adjusted per-allele OR 0.83; 95%CI 0.70-0.98; p = .03) however this finding was opposite to that previously published. Imputed data for CHEK2 rs8135424 supported the direction of effect reported in this study (OR 0.85; 95% CI 0.65-1.10). Previously reported endometrial cancer risk associations with SNPs from in genes involved in estrogen metabolism and DNA repair were not replicated in our larger study population. This study highlights the need for replication of candidate gene SNP studies using large sample groups...

‣ A Population-Based Study of Factors Affecting Access to Radiotherapy for Endometrial Cancer in Ontario

HANNA, TIMOTHY
Fonte: Quens University Publicador: Quens University
Tipo: Tese de Doutorado Formato: 2105551 bytes; application/pdf
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Aims: To describe use of post-operative radiation for endometrial cancer in Ontario. To identify system-related and patient-related factors affecting access to this treatment. Materials and Methods: We performed a retrospective population-based cohort study of patients with surgically resected endometrial cancer in the Canadian province of Ontario between 1992-2003. Patients with evidence of incurable cancer at diagnosis or previous cancer diagnosis were excluded. We used multiple logistic regression to assess patient and system factors affecting radiation use. We controlled for disease-related and treatment-related factors: histology, surgical staging, type of hysterectomy and peritoneal biopsy. We applied a mixed model to account for clustering of data by operating hospital. Results: 9,411 women comprised the study cohort. The median age was 63 years. 26.2% received adjuvant radiation. The proportion of patients receiving radiation varied between cancer centre catchment areas from 18.0% to 34.3% (median 26.3%). In multivariate analysis, older patients were more likely to receive radiation up to the age of 80 (p<.0001). Patients who lived further from regional cancer centres were less likely to receive radiation (p=.0210). Patients who had their surgery during longer prevailing wait times at regional cancer centres were less likely to receive radiation (p=.0441). There was a 2.7-fold variation in the odds of radiation use between cancer centre catchments (p<.0001). Management at a comprehensive gynecologic oncology centre was associated with use of radiation for patients who had surgical staging of lymph nodes. Year of diagnosis and neighborhood income quintile did not significantly affect the use of radiation. Conclusions: There is wide variation in use of radiation for endometrial cancer in Ontario. There is evidence that system factors unrelated to patient’s needs affect use of adjuvant radiation for endometrial cancer in Ontario. Age is a key patient-related factor affecting radiation use.; Thesis (Master...

‣ ENDOMETRIAL CANCER AND PRE-MALIGNANT CONDITIONS IN YOUNG WOMEN:SURVEY OF ENDOMETRIAL SAMPLING PRACTICES BY CANADIAN GYNECOLOGISTS

PALERME, Stephanie
Fonte: Quens University Publicador: Quens University
Tipo: Tese de Doutorado
Português
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Objective: To identify the physician-, patient- and health-system-related factors that influence gynecologists’ decision to recommend endometrial sampling in young women (less than 40 years) with abnormal uterine bleeding Study methods: A mail-based survey study was conducted using the Salant-Dillman method with 4 points of contact over 9 weeks. All Canadian obstetrician/gynecologists were initially surveyed (N=1746), receiving either French or English questionnaires. Eligible respondents were gynecologists practicing in Canada who treat these young women (N=834). Order response bias was taken into consideration by mailing two versions of the survey. Categorical data were analyzed using Pearson’s Chi-square statistics. A logistic regression with mixed effect model was performed to determine the odds of sampling the endometrium, using physician as random factor. Results: Overall response rate was 56.5%. The majority of respondents were generalists (83.6%). 70.3% of respondents have had young patients with malignant or pre-malignant endometrial conditions. Physicians ≤ 39 years have had less experience with these patients (59.6%, p=0.002) as have physicians practicing in communities without ob/gyn residents (35.2%, p=0.006). Sampling method was predominantly by office pipelle (79.7%)...

‣ Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer

O'Mara, Tracy A.; Glubb, Dylan M.; Painter, Jodie N.; Cheng, Timothy; Dennis, Joe; Australian National Endometrial Cancer Study Group (ANECS); Attia, John; Holliday, Elizabeth G.; McEvoy, Mark; Scott, Rodney J.; Ashton, Katie; Proietto, Tony; Otton, Geoff
Fonte: Society for Endocrinology Publicador: Society for Endocrinology
Tipo: Article; published version
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This is the final version of the article. It first appeared from the Society for Endocrinology via http://dx.doi.org/10.1530/ERC-15-0319; Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86?10?5), which was stronger for cancers of endometrioid subtype (P=3.76?10?6). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer...

‣ CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer.

Thompson, Deborah J.; O?Mara, Tracy A.; Glubb, Dylan M.; Painter, Jodie N.; Cheng, Timothy; Folkerd, Elizabeth; Doody, Deborah; Dennis, Joe; Webb, Penelope M.; Australian National Endometrial Cancer Study Group (ANECS); Gorman, Maggie; Martin, Lynn; Hodgs
Fonte: Bioscientifica Publicador: Bioscientifica
Tipo: Article; published version
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This is the author accepted manuscript. The final version is available from Bioscientifica via http://dx.doi.org/10.1530/ERC-15-0386; Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol concentrations. We analysed 2,937 SNPs in 6,608 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=4.8x10-11). SNP rs727479 was also among those most strongly associated with circulating estradiol concentrations in 2,767 post-menopausal controls (P=7.4x10- 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 estradiol concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by estradiol. 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.; Fine-mapping analysis was supported by NHMRC project grant [ID#1031333] to ABS...

‣ Evidence of a causal association between insulinemia and endometrial cancer: A Mendelian randomization analysis

Nead, Kevin T.; Sharp, Stephen J.; Thompson, Deborah J.; Painter, Jodie N.; Savage, David B.; Semple, Robert K.; Barker, Adam; Australian National Endometrial Cancer Study Group (ANECS); Perry, John R. B.; Attia, John; Dunning, Alison M.; Easton, Douglas
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Article; pulished version
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This is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/jnci/djv178; Background: Insulinemia and type 2 diabetes (T2D) have been associated with endometrial cancer risk in numerous observational studies. However, the causality of these associations is uncertain. Here we use a Mendelian randomization (MR) approach to assess whether insulinemia and T2D are causally associated with endometrial cancer. Methods: We used single nucleotide polymorphisms (SNPs) associated with T2D (49 variants), fasting glucose (36 variants), fasting insulin (18 variants), early insulin secretion (17 variants) and body mass index (32 variants) as instrumental variables in MR analyses. We calculated MR estimates for each risk factor with endometrial cancer using an inverse-variance weighted method with SNP-endometrial cancer associations from 1,287 cases and 8,273 controls. Results: Genetically-predicted higher fasting insulin levels were associated with greater risk of endometrial cancer (odds ratio (OR) per standard deviation = 2.34, 95% confidence internal [CI] = 1.06-5.14, p = 0.03). Consistently, genetically-predicted higher 30 minute post-challenge insulin levels were also associated with endometrial cancer risk (OR = 1.40...