Molecular cues on obesity signals, tumor markers and endometrial cancer

AbstractTumor markers are important tools for early diagnosis, prognosis, therapy response and endometrial cancer monitoring. A large number of molecular and pathologic markers have been described in types I and II endometrial cancers, which has served to define the main oncogenic, epidemiological, genetic, clinical and histopathological features. Ongoing attempts to stratify biological markers of endometrial cancer are presented. However, data on changes in tumor marker profiles in obesity-related endometrial cancer are scarce. Obesity is a pandemic in Western countries that has an important impact on endometrial cancers, albeit through not very well-defined mechanisms. Although endometrial cancer is more common in Caucasian women, higher mortality is found in African Americans who also show higher incidence of obesity. Here, we describe how obesity signals (estrogen, leptin, leptin induced-molecules, Notch; cytokines and growth factors) could affect endometrial cancer. Leptin signaling and its crosstalk may be associated to the more aggressive and poor prognosis type II endometrial cancer, which affects more postmenopausal and African-American women. In this regard, studies on expression of novel molecular markers (Notch, interleukin-1 and leptin crosstalk outcome) may provide essential clues for detection, prevention, treatment and prognosis.

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Lynch Syndrome Identification in Endometrial Cancer Patients: Should Universal Screening be Used for all Histologies?

Current Women s Health Reviews ◽

10.2174/1573404817666210302153551 ◽

2021 ◽

Vol 17 ◽

Author(s):

Jessica E. Parker ◽

Caitlin Mauer ◽

Wenxin Zheng ◽

David S. Miller ◽

Jayanthi S. Lea

Keyword(s):

Endometrial Cancer ◽

Genetic Testing ◽

Family History ◽

Lynch Syndrome ◽

Cancer Patients ◽

Universal Screening ◽

Type I ◽

Type Ii ◽

Screening Approach ◽

Endometrial Cancers

Background: There is an increased proportion of non-endometrioid histologies in Lynch syndrome-associated compared to sporadic endometrial cancer, however screening recommendations do not differ between type I and type II cancers. Objective: Our objective was to examine the frequency of Lynch syndrome identified in type I and type II endometrial cancers and their associated characteristics. Methods: We reviewed patients with type I and type II endometrial cancer who were screened for Lynch Syndrome or referred for genetic testing according to an age and family-history based screening protocol. All patients were seen and treated at large academic institution affiliated with a county safety-net hospital. Clinical, pathologic, immunohistochemistry, and germline genetic testing results were obtained as well as choice of genetic screening approach, personal and family history, and compliance with testing. Results: 234 women with type I and 29 patients with type II endometrial cancer were identified. Lynch syndrome was diagnosed in a total of eight (3.4%) type I endometrial cancer patients, all identified after age-based tumor screening. In the type II endometrial cancer group, three (10.3%) patients had Lynch syndrome. One was referred for testing after abnormal immunohistochemistry screening under age 60. The other two were >60 years old and identified after abnormal immunohistochemistry screening performed by physician request. Conclusion: Age based screening may not diagnose Lynch Syndrome in women with type II endometrial cancers. Our findings underscore the need for a universal screening approach in patients with type II endometrial cancers, even in a low resource population.

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Combined genetic mutations and DNA-methylated genes as biomarkers for endometrial cancer detection from cervical scrapings

Clinical Epigenetics ◽

10.1186/s13148-019-0765-3 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Phui-Ly Liew ◽

Rui-Lan Huang ◽

Tzu-I Wu ◽

Chi-Chun Liao ◽

Chien-Wen Chen ◽

...

Keyword(s):

Dna Methylation ◽

Endometrial Cancer ◽

Cancer Detection ◽

Type I ◽

Type Ii ◽

Normal Endometrium ◽

Epigenetic Biomarkers ◽

Pap Smear Screening ◽

Endometrial Cancers ◽

Endometrial Carcinomas

Abstract Background Endometrial cancer is a common gynecologic cancer. Noninvasive molecular biomarkers for triage of high-risk patients for invasive procedures are needed. Based on the success of cytological Pap smear screening, cervical scrapings are a good source of DNA for molecular testing. In addition to genetic lesions, DNA methylation is a promising biomarker. We assessed the usefulness of combining genetic and epigenetic biomarkers from cervical scrapings to detect endometrial carcinomas. Methods We performed a retrospective case–control study of 96 consecutive cervical scrapings from patients with abnormal uterine bleeding who underwent surgery for diagnostic evaluation. Thirty and 16 cases were diagnosed with type I and type II endometrial cancers, respectively. The remaining non-cancer cases included normal endometrium (n = 12), benign uterine lesions (n = 20), and endometrial hyperplasia (n = 18). Quantitative methylation-specific PCR and mass spectrometry were used for DNA methylation and genetic mutation analysis. Logistic regression was used to evaluate the clinical performance of these candidate biomarkers. Results We tested the effectiveness of the methylation status of four genes (BHLHE22, CDO1, TBX5, and HAND2) in endometrial cancer detection. The area under the receiver operating characteristic curves ranged from 0.703 to 0.878, and panels of hypermethylated BHLHE22/CDO1/HAND2 (87.0% sensitivity and 86.0% specificity) and BHLHE22/CDO1/TBX5 (89.1% sensitivity and 80.0% specificity) showed significant differences and could distinguish benign from malignant endometrial lesions. The sensitivity and specificity in endometrial cancer detection for BHLHE22/CDO1 were 84.8% and 88.0%, respectively. Both type I and II endometrial carcinomas could be detected using a BHLHE22/CDO1-based methylation profile, suggesting that they may have common epigenomes. Moreover, PTEN and TP53 mutations were found in 63.3% of type I and 93.6% of type II endometrial cancers. Unexpectedly, PTEN and TP53 mutations were commonly found in cervical scrapings of the normal endometrium (25% and 33.3%, respectively) and in cases with benign uterine lesions (10% and 50%, respectively). Finally, combinations of any one mutation of PTEN and TP53 mutations had a sensitivity of 91.3%, but a specificity of only 42.0%. Conclusions Adding PTEN/TP53 mutation testing to BHLHE22/CDO1-based methylation testing did not improve the detection of endometrial cancer.

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Comparing surgical staging methods for type II endometrial cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e17107 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e17107-e17107

Author(s):

Leda Portia A. Gattoc ◽

Hyo K. Park ◽

Laura Carney ◽

Shashank Srivastava ◽

Monica Chiu ◽

...

Keyword(s):

African American ◽

Endometrial Cancer ◽

Perioperative Complications ◽

Multivariable Analysis ◽

Significant Proportion ◽

Type Ii ◽

Invasive Approach ◽

Lymph Node Yield ◽

Endometrial Cancers ◽

Mixed Histology

e17107 Background: Type II endometrial cancers account for 10% of endoemetrial cancers, but their aggresive nature account for a significant proportion of the morbidity and mortality. The goal of this study was to compare outcomes type II endometrial cancer patients who underwent staging via laparotomy vs. minimally invasive approach (MIS). Methods: All patients who underwent surgery for Type II endometrial cancer at two cancer centers in Detroit MI from January 2005 and December 2015 were reviewed. Endometrioid histology and those who never had surgery were excluded. Clinical, demographic characteristics, surgical outcomes and progression free survival were examined using univariate and multivariable analysis, Kaplan-Meier estimates and Cox proportional hazards regression. Results: A total of 249 patients were included, 193 underwent laparotomy, and 58 MIS, including laparoscopic or robotic surgery. The majority had stage I disease (IA, 104 [41.3%] and IB, 20[7.9%]). Stages II, III, and IV were identified in 18 (7.1%), 79 (31.6%), and 31 (12.4%) respectively. Multivariate analysis demonstrated being African American (OR 3.43; 95%CI 1.64-7.15), having mixed histology(OR 2.54; 95% CI 1.02-6.32), and stage III-IV disease (OR 2.20; 95%CI 1.04-4.67) was associated with undergoing laparotomy. Higher perioperative complications, EBL >250 cc and blood transfusion were associated with laparotomy. Higher lymph node yield was associated with MIS approaches vs. laparotomy (26 vs. 14 p =<0.001). Recurrence rate was 38 % for the laparotomy group and 19% for MIS. There was no difference in 3 year-PFS after controlling for age, race, procedure, histology, stage and adjuvant therapy. There was no difference in overall survival between laparotomy and MIS for type II endometrial cancers. Conclusions: Being African American race, having mixed histology and stage were associated with undergoing laparotomy for type II endometrial cancers. MIS approaches offered less morbidity and ability to complete staging. However, patient selection likely played a role in this given earlier stage of these cancers. The route of surgery was not associated with PFS or OS, suggesting that MIS approach should be considered especially for ealry stage disease.

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Race-driven survival differential in women diagnosed with endometrial cancers in the USA

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2020-001560 ◽

2020 ◽

Vol 30 (12) ◽

pp. 1893-1901

Author(s):

Zachary D Horne ◽

Solomiya R Teterichko ◽

Scott M Glaser ◽

Rodney E Wegner ◽

Shaakir Hasan ◽

...

Keyword(s):

African American ◽

African American Women ◽

Type I ◽

Type Ii ◽

American Women ◽

Risk Of Death ◽

Asian Pacific Islander ◽

Caucasian Women ◽

Asian Pacific ◽

Pacific Islander Women

ObjectiveAfrican American women are increasingly being diagnosed with advanced and type II histology endometrial cancers. Outcomes have been observed to be worse in African American women, but whether or not race itself is a factor is unclear. We sought to evaluate the rates of diagnosis and outcomes on a stage-by-stage basis with respect to race using a large national cancer registry database.MethodsThe National Cancer Data Base was searched for patients with surgically staged non-metastatic endometrial cancer between 2004 and 2015. Women were excluded if surgical stage/histology was unknown, there was no follow-up, or no information on subsequent treatment. Pairwise comparison was used to determine temporal trends and Cox hazards tests with Bonferroni correction were used to determine overall survival.ResultsA total of 286 920 women were diagnosed with endometrial cancer and met the criteria for analysis. Median follow-up was 51 months (IQR 25.7–85.3). In multivariable models, in women with stage I disease, African American women had a higher risk of death than Caucasian women (HR 1.262, 95% CI 1.191 to 1.338, p<0.001) and Asian/Pacific Islander women had a lower risk of death than Caucasian women (HR 0.742, 95% CI 0.689 to 0.801, p<0.001). This held for African American women with stage II type I and type II disease (HR 1.26, 95% CI 1.109 to 1.444, p<0.001 and HR 1.235, 95% CI 1.098 to 1.388, p<0.001) but not for Asian/Pacific Islander women. African American women with stage IIIA–B disease also had a higher risk of death for type I and type II disease versus Caucasian women (HR 1.221, 95% CI 1.045 to 1.422, p=0.010 and HR 1.295, 95% CI 1.155 to 1.452, p<0.001). Asian/Pacific Islander women had a lower risk of death than Caucasian women with type I disease (HR 0.783, 95% CI 0.638 to 0.960, p=0.019) and type II disease (HR 0.790, 95% CI 0.624 to 0.999, p=0.05). African American women with stage IIIC1–2 had a higher risk of death with type I disease (HR 1.343, 95% CI 1.207 to 1.494, p<0.001) and type II disease (HR 1.141, 95% CI 1.055 to 1.233, p=0.001) whereas there was no significant difference between Caucasian women and Asian/Pacific Islander women.ConclusionRace appears to play an independent role in survival from endometrial cancer in the USA, with African American women having worse survival on a stage-for-stage basis compared with Caucasian women.

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Type I and II Endometrial Cancers: Have They Different Risk Factors?

Journal of Clinical Oncology ◽

10.1200/jco.2012.48.2596 ◽

2013 ◽

Vol 31 (20) ◽

pp. 2607-2618 ◽

Cited By ~ 323

Author(s):

Veronica Wendy Setiawan ◽

Hannah P. Yang ◽

Malcolm C. Pike ◽

Susan E. McCann ◽

Herbert Yu ◽

...

Keyword(s):

Risk Factors ◽

Endometrial Cancer ◽

Pooled Analysis ◽

Age At Menarche ◽

Type I ◽

Type Ii ◽

Case Control Studies ◽

Mixed Cell ◽

Cancer Risk Factors ◽

Endometrial Cancers

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

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BREAST CANCER PATIENTS AT INCREASED RISK OF DEVELOPING TYPE II ENDOMETRIAL CANCER; RELATIVE AND ABSOLUTE RISK ESTIMATION AND IMPLICATIONS FOR GENETIC COUNSELLING

10.26226/morressier.5fa3ee5d55b1fd4cc4dd93a8 ◽

2020 ◽

Author(s):

Alexandros Laios

Keyword(s):

Breast Cancer ◽

Endometrial Cancer ◽

Cancer Patients ◽

Genetic Counselling ◽

Risk Estimation ◽

Absolute Risk ◽

Type Ii ◽

Breast Cancer Patients ◽

Increased Risk

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Coexpression of Survivin+/VEGF+ Indicates Poor Prognosis of Endometrial Cancer

10.29011/2638-003x.100041 ◽

2020 ◽

Keyword(s):

Endometrial Cancer ◽

Poor Prognosis

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Interleukin-1 receptor antagonist binds to the type II interleukin-1 receptor on B cells and neutrophils.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)54924-3 ◽

1991 ◽

Vol 266 (30) ◽

pp. 20311-20315 ◽

Cited By ~ 3

Author(s):

D.J. Dripps ◽

E. Verderber ◽

R.K. Ng ◽

R.C. Thompson ◽

S.P. Eisenberg

Keyword(s):

B Cells ◽

Receptor Antagonist ◽

Interleukin 1 ◽

Type Ii ◽

Interleukin 1 Receptor Antagonist

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Molecular Classification to Prognosticate Response in Medically Managed Endometrial Cancers and Endometrial Intraepithelial Neoplasia

Cancers ◽

10.3390/cancers13112847 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2847

Author(s):

Allison M. Puechl ◽

Daniel Spinosa ◽

Andrew Berchuck ◽

Angeles Alvarez Secord ◽

Kerry E. Drury ◽

...

Keyword(s):

Endometrial Cancer ◽

Single Gene ◽

Intraepithelial Neoplasia ◽

Molecular Classification ◽

Definitive Treatment ◽

Time To Progression ◽

Endometrial Intraepithelial Neoplasia ◽

Definitive Therapy ◽

Patients At Risk ◽

Endometrial Cancers

Background: The aim of this study was to evaluate whether molecular classification prognosticates treatment response in women with endometrial cancers and endometrial intraepithelial neoplasia (EIN) treated with levonorgestrel intrauterine system (LNG-IUS). Methods: Patients treated with LNG-IUS for endometrial cancer or EIN from 2013 to 2018 were evaluated. Using immunohistochemistry and single gene sequencing of POLE, patients were classified into four groups as per the Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE): POLE-mutated, mismatch repair-deficient (MMRd), p53 wild type (p53wt), and p53-abnormal (p53abn). Groups were assessed relative to the primary outcome of progression or receipt of definitive treatment. Results: Fifty-eight subjects with endometrioid endometrial cancer or EIN treated with LNG-IUS were included. Of these, 22 subjects (37.9%) had endometrial cancer and 36 subjects (62.1%) had EIN. Per the ProMisE algorithm, 44 patients (75.9%) were classified as p53wt, 6 (10.3%) as MMRd, 4 (6.9%) as p53abn, and 4 (6.9%) as POLE-mutated. Of the 58 patients, 11 (19.0%) progressed or opted for definitive therapy. Median time to progression or definitive therapy was 7.5 months, with p53abn tumors having the shortest time to progression or definitive therapy. Conclusions: Molecular classification of endometrial cancer and EIN prior to management with LNG-IUS is feasible and may predict patients at risk of progression.

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