Molecular markers in recurrent stage I, grade 1 endometrioid endometrial cancers

Moroney, Marisa R.; Davies, Kurtis D.; Wilberger, Adam; Sheeder, Jeanelle; Post, Miriam D.; Berning, Amber; Fisher, Christine M.; Lefkowits, Carolyn; Guntupalli, Saketh R.; Behbakht, Kian; Corr, Bradley

doi:10.1016/j.ygyno.2019.03.179

Cited by 10 publications

(23 citation statements)

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“…In particular, in early stage endometrioid ECs, it shows an Fig. 1 Mean age in ProMisE groups of endometrial cancer for each study and as pooled estimate unfavorable prognostic role, while in high-grade ECs it may improve the prognosis [15,30,31].…”

Section: Mmr-d Groupmentioning

confidence: 99%

Clinical features of ProMisE groups identify different phenotypes of patients with endometrial cancer

Raffone

Travaglino

Gabrielli

et al. 2021

Arch Gynecol Obstet

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Background The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) groups has identified four molecular prognostic groups of endometrial cancer (EC): POLE-mutated (POLE-mt), mismatch repair-deficient (MMR-d), p53-abnormal (p53-abn), p53-wild-type (p53-wt). These groups might have different pathogenesis and risk factors, and might occur in different phenotypes of patients. However, these data are still lacking. Objective To provide a clinical characterization of the ProMisE groups of EC. Methods A systematic review and meta-analysis was performed by searching seven electronic databases from their inception to December 2020, for all studies reporting clinical characteristics of EC patients in each ProMisE group. Pooled means of age and BMI and pooled prevalence of FIGO stage I and adjuvant treatment in each ProMisE group were calculated. Results Six studies with 1, 879 women were included in the systematic review. Pooled means (with standard error) and prevalence values were: in the MMR-d group, age = 66.5 ± 0.6; BMI = 30.6 ± 1.2; stage I = 72.6%; adjuvant treatment = 47.3%; in the POLE-mt group, age = 58.6 ± 2.7; BMI = 27.2 ± 0.9; stage I = 93.7%; adjuvant treatment = 53.6%; in the p53-wt group, age = 64.2 ± 1.9; BMI = 32.3 ± 1.4; stage I = 80.5%; adjuvant treatment = 45.3%; in the p53-abn group, age = 71.1 ± 0.5; BMI = 29.1 ± 0.5; stage I = 50.8%; adjuvant treatment = 64.4%. Conclusion The ProMisE groups identify different phenotypes of patients. The POLE-mt group included the youngest women, with the lower BMI and the highest prevalence of stage I. The p53-wt group included patients with the highest BMI. The p53-abn group included the oldest women, with the highest prevalence of adjuvant treatment and the lowest prevalence of stage I. The MMR-d group showed intermediate values among the ProMisE groups for all clinical features.

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Section: Mmr-d Groupmentioning

confidence: 99%

Clinical features of ProMisE groups identify different phenotypes of patients with endometrial cancer

Raffone

Travaglino

Gabrielli

et al. 2021

Arch Gynecol Obstet

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“…Hotspot mutations in Exon 3 of the CTNNB1 gene (encodes for the β-catenin protein) alter the N-terminus of β-catenin and prevent its phosphorylation and degradation by the destruction complex. Concerning gynecologic malignancies, CTNNB1 mutations are detected in uterine endometrial, ovarian endometrioid, and ovarian clear cell carcinomas [ 7 , 47 , 48 ]. Hyperactivation of Wnt/β-catenin signaling through these mechanisms are implicated in tumorigenesis, tumor progression, recurrence, and chemoresistance in several cancers, including gynecologic malignancies [ 7 , 8 , 26 , 49 , 50 ].…”

Section: Wnt Signalingmentioning

confidence: 99%

“…Despite the association with histopathologic and clinical features considered to be low-risk in the current EC risk-stratification system, CTNNB1 -mutant EC has poorer clinical outcomes [ 7 , 14 , 15 , 98 ]. Kurnit et al demonstrated that CTNNB1 mutations were associated with decreased recurrence-free survival in low grade, early-stage EC [ 15 ].…”

Section: Endometrial Cancermentioning

confidence: 99%

“…Kurnit et al demonstrated that CTNNB1 mutations were associated with decreased recurrence-free survival in low grade, early-stage EC [ 15 ]. Our group evaluated low-risk EC in a case-control study comparing recurrent Grade 1 Stage I EC to matched non-recurrent controls and found that CTNNB1 mutations occurred at significantly higher rates in the recurrent EC [ 7 ]. Liu et al have similarly demonstrated that CTNNB1 -mutant low-grade EC exhibits upregulation of the Wnt/β-catenin pathway and poorer overall survival [ 14 ].…”

Section: Endometrial Cancermentioning

confidence: 99%

“…More recently, there is growing research evaluating the role of Wnt signaling in gynecologic malignancies. Specifically, Wnt signaling promotes metastasis and therapy resistance in ovarian cancer, plays a crucial role in tumorigenesis and recurrence in endometrial cancer, and participates in human papillomavirus (HPV) -related tumorigenesis and metastasis in cervical cancer [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. For all of these gynecologic malignancies, Wnt signaling is also being evaluated as a possible therapeutic target [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

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Wnt Signaling in Gynecologic Malignancies

McMellen¹,

Woodruff²,

Corr

et al. 2020

IJMS

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Gynecologic malignancies, including ovarian cancer, endometrial cancer, and cervical cancer, affect hundreds of thousands of women worldwide every year. Wnt signaling, specifically Wnt/β-catenin signaling, has been found to play an essential role in many oncogenic processes in gynecologic malignancies, including tumorigenesis, metastasis, recurrence, and chemotherapy resistance. As such, the Wnt/β-catenin signaling pathway has the potential to be a target for effective treatment, improving patient outcomes. In this review, we discuss the evidence supporting the importance of the Wnt signaling pathways in the development, progression, and treatment of gynecologic malignancies.

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Inhibiting Wnt/beta‐catenin in CTNNB1‐mutated endometrial cancer

Moroney

Woodruff

Qamar

et al. 2021

Molecular Carcinogenesis

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The role of β-catenin/TCF transcriptional activity in endometrial cancer (EC) recurrence is not well understood. We assessed the impact of Wnt/β-catenin inhibition in EC models. In an analysis of the Cancer Genome Atlas, we confirmed that CTNNB1 mutations are enriched in recurrent low-risk EC and showed that aberrant Wnt/β-catenin pathway activation is associated with recurrence. We studied CTNNB1-wildtype (HEC1B, Ishikawa) and CTNNB1-mutant (HEC108, HEC265, HEC1B-S33Y, Ishikawa-S33Y) EC cell lines. Dose response curves were determined for 5 Wnt/β-catenin pathway inhibitors (Wnt-C59, XAV-939, PyrPam, PRI-724, SM04690). XAV939, Wnt-C59 and PyrPam inhibited function upstream of β-catenin transcriptional activity and were ineffective at inhibiting cell viability. In contrast, PRI724 and SM04690 indirectly inhibited β-catenin transcriptional activity and significantly reduced cell viability in CTNNB1-mutant cell lines. Treatment with SM04690 reduced cell viability (Licor Cell stain) in all EC cell lines, but viability was significantly lower in CTNNB1-mutant cell lines (p < 0.01). Mechanistically, SM04690 significantly inhibited proliferation measured via 5′-bromo-2′-deoxyuridine incorporation and reduced T cell factor (TCF) transcriptional activity. HEC1B, HEC1B-S33Y and HEC265 tumor-bearing mice were treated with vehicle or SM04690.Tumors treated with SM04690 had smaller mean volumes than those treated with vehicle (p < 0.001, p = 0.014, p = 0.06). In HEC1B-S33Y and HEC265 tumors, SM04690 treatment significantly reduced Ki67 H-scores compared to vehicle (p = 0.035, p = 0.024). Targeting the Wnt/β-catenin pathway in CTNNB1-mutant EC effectively inhibited proliferation and β-catenin/TCF transcriptional activity and blunted tumor progression in in vivo models. These studies suggest β-catenin transcriptional inhibitors are effective in EC and particularly in CTNNB1-mutant EC, highlighting a potential therapeutic vulnerability for treatment of CTNNB1mutant EC.

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Molecular markers in recurrent stage I, grade 1 endometrioid endometrial cancers

Cited by 10 publications

References 0 publications

Clinical features of ProMisE groups identify different phenotypes of patients with endometrial cancer

Clinical features of ProMisE groups identify different phenotypes of patients with endometrial cancer

Wnt Signaling in Gynecologic Malignancies

Inhibiting Wnt/beta‐catenin in CTNNB1‐mutated endometrial cancer

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