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.2019.03.100

Cited by 55 publications

(39 citation statements)

References 25 publications

(41 reference statements)

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“…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: Ctnnb1 As a Molecular Markermentioning

confidence: 80%

“…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: Canonical Pathway-β-catenin Dependentmentioning

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: Ctnnb1 As a Molecular Markermentioning

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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Section: Ctnnb1 As a Molecular Markermentioning

confidence: 80%

Section: Canonical Pathway-β-catenin Dependentmentioning

confidence: 99%

Section: Ctnnb1 As a Molecular Markermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Wnt Signaling in Gynecologic Malignancies

McMellen¹,

Woodruff²,

Corr

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

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“…Several retrospective studies have reported that patients with uterine-confined disease whose tumors harbor a somatic CTNNB1 exon 3 mutation have worse clinical outcomes compared with patients whose tumors are CTNNB1 wild-type. [12][13][14] Here, we sought to evaluate the characteristics of patients with recurrent low-grade, non-myoinvasive ('ultra-low risk') endometrioid endometrial cancers. We explored the clinical characteristics of these patients, as well as the molecular profiles of recurrent and non-recurrent ultra-low risk tumors.…”

Section: Original Researchmentioning

confidence: 99%

Clinical patterns and genomic profiling of recurrent ‘ultra-low risk’ endometrial cancer

Stasenko

Feit

Lee

et al. 2020

Int J Gynecol Cancer

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ObjectiveDespite good prognosis for patients with low-risk endometrial cancer, a small subset of women with low-grade/low-stage endometrial cancer experience disease recurrence and death. The aim of this study was to characterize clinical features and mutational profiles of recurrent, low-grade, non-myoinvasive, ‘ultra-low risk’ endometrioid endometrial adenocarcinomas.MethodsWe retrospectively identified patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA endometrioid endometrial cancers who underwent primary surgery at our institution, between January 2009 and February 2017, with follow-up of ≥12 months. ‘Ultra-low risk’ was defined as FIGO tumor grade 1, non-myoinvasive, and lacking lymphovascular space invasion. Tumor-normal profiling using massively parallel sequencing targeting 468 genes was performed. Microsatellite instability was assessed using MSIsensor. DNA mismatch repair (MMR) protein proficiency was determined by immunohistochemistry.ResultsA total of 486 patients with ultra-low risk endometrioid endometrial cancers were identified: 14 (2.9%) of 486 patients developed a recurrence. Median follow-up for non-recurrent endometrioid endometrial cancers: 34 (range 12–116) months; for recurrent endometrioid endometrial cancers: 50.5 (range 20–116) months. Patients with recurrent disease were older, had lower body mass index, and were most commonly non-White (p=0.025, p<0.001, and p<0.001, respectively). Other clinical characteristics did not differ. MMR immunohistochemistry was obtained for 211 (43%) tumors: 158 (75%) MMR-proficient and 53 (25%) MMR-deficient. Primary tumors of 9 recurrent and 27 non-recurrent endometrioid endometrial cancers underwent mutational profiling. Most were microsatellite stable (6/9, 67% recurrent; 25/27, 93% non-recurrent). Recurrent PTEN and PIK3CA mutations were present in both groups. Exon 3 CTNNB1 hotspot mutations were found in 4/9 (44%) recurrent and 8/27 (30%) non-recurrent (p=0.44).ConclusionsPatients diagnosed with ultra-low risk endometrioid endometrial cancers have an overall excellent prognosis. However, in our study, 2.9% of patients with no identifiable clinical or pathologic risk factors developed recurrence. Further work is warranted to elucidate the mechanism for recurrence in this population.

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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 55 publications

References 25 publications

Wnt Signaling in Gynecologic Malignancies

Wnt Signaling in Gynecologic Malignancies

Clinical patterns and genomic profiling of recurrent ‘ultra-low risk’ endometrial cancer

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

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