Clinicopathological features and prognostic significance of CTNNB1 mutation in low-grade, early-stage endometrial endometrioid carcinoma.
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ABSTRACT:
SUBMITTER: Ruz-Caracuel I
PROVIDER: S-EPMC8724178 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundMost endometrial cancers are of low histological grade and uterine-confined, with a high 5-year survival rate. However, a small subset of women with low-grade and early-stage endometrioid endometrial cancer experience recurrence and death; thus, a more precise risk-stratification is needed.Case presentationA 29-year-old woman presented with abnormal vaginal bleeding and was diagnosed with FIGO grade 1 endometrioid endometrial carcinoma by curettage. Comprehensive cancer staging including pelvic and para-aortic lymphadenectomy was then performed. Postoperative pathological findings suggested an FIGO grade 1 endometrioid endometrial carcinoma infiltrating the superficial muscle layer. The patient did not receive adjuvant therapy. After 4 years of follow-up, the patient returned to our institution with lung metastasis. She underwent thoracoscopic resection of the affected lobes, followed by six cycles of combined chemotherapy of paclitaxel and carboplatin. Next-generation sequencing showed that the primary and lung metastatic tumors shared 4 mutations: PTEN (p.P248Lfs*8), CTNNB1 (p.D32A), BCOR (p.N1425S) and CBL (p.S439N). Immunohistochemistry revealed nuclear location of β-catenin in the primary and lung metastatic tumor samples, indicating abnormal activation of β-catenin.ConclusionCTNNB1p.D32A (c.95A > C) mutation may be related to lung metastasis in this patient with low-grade early-stage endometrioid endometrial carcinoma.
| S-EPMC10273753 | biostudies-literature
Project description:Mutations in multiple oncogenes including KRAS, CTNNB1, PIK3CA and FGFR2 have been identified in endometrial cancer. The aim of this study was to provide insight into the clinicopathological features associated with patterns of mutation in these genes, a necessary step in planning targeted therapies for endometrial cancer. 466 endometrioid endometrial tumors were tested for mutations in FGFR2, KRAS, CTNNB1, and PIK3CA. The relationships between mutation status, tumor microsatellite instability (MSI) and clinicopathological features including overall survival (OS) and disease-free survival (DFS) were evaluated using Kaplan-Meier survival analysis and Cox proportional hazard models. Mutations were identified in FGFR2 (48/466); KRAS (87/464); CTNNB1 (88/454) and PIK3CA (104/464). KRAS and FGFR2 mutations were significantly more common, and CTNNB1 mutations less common, in MSI positive tumors. KRAS and FGFR2 occurred in a near mutually exclusive pattern (p = 0.05) and, surprisingly, mutations in KRAS and CTNNB1 also occurred in a near mutually exclusive pattern (p = 0.0002). Multivariate analysis revealed that mutation in KRAS and FGFR2 showed a trend (p = 0.06) towards longer and shorter DFS, respectively. In the 386 patients with early stage disease (stage I and II), FGFR2 mutation was significantly associated with shorter DFS (HR = 3.24; 95% confidence interval, CI, 1.35-7.77; p = 0.008) and OS (HR = 2.00; 95% CI 1.09-3.65; p = 0.025) and KRAS was associated with longer DFS (HR = 0.23; 95% CI 0.05-0.97; p = 0.045). In conclusion, although KRAS and FGFR2 mutations share similar activation of the MAPK pathway, our data suggest very different roles in tumor biology. This has implications for the implementation of anti-FGFR or anti-MEK biologic therapies.
| S-EPMC3285611 | biostudies-literature
Project description:Ovarian endometrioid carcinomas and endometrial endometrioid carcinomas share many histological and molecular alterations. These similarities are likely due to a common endometrial epithelial precursor cell of origin, with most ovarian endometrioid carcinomas arising from endometriosis. To directly compare the mutation profiles of two morphologically similar tumor types, endometrial endometrioid carcinomas (n=307) and ovarian endometrioid carcinomas (n=33), we performed select exon capture sequencing on a panel of genes: ARID1A, PTEN, PIK3CA, KRAS, CTNNB1, PPP2R1A, TP53. We found that PTEN mutations are more frequent in low-grade endometrial endometrioid carcinomas (67%) compared with low-grade ovarian endometrioid carcinomas (17%) (P<0.0001). By contrast, CTNNB1 mutations are significantly different in low-grade ovarian endometrioid carcinomas (53%) compared with low-grade endometrial endometrioid carcinomas (28%) (P<0.0057). This difference in CTNNB1 mutation frequency may be reflective of the distinct microenvironments; the epithelial cells lining an endometriotic cyst within the ovary are exposed to a highly oxidative environment that promotes tumorigenesis. Understanding the distinct mutation patterns found in the PI3K and Wnt pathways of ovarian and endometrial endometrioid carcinomas may provide future opportunities for stratifying patients for targeted therapeutics.
| S-EPMC3915240 | biostudies-literature
Project description:To identify prognostic factors in patients with grade 3 (high-grade) endometrial endometrioid carcinoma, we evaluated the spectrum of genomic alterations and examined whether previously reported molecular subtypes of endometrial carcinoma were adapted to clinical outcome prediction. Seventy-five Japanese patients with grade 3 endometrial endometrioid carcinoma, who underwent a potentially curative resection procedure between 1997 and 2018 at the National Cancer Center Hospital, were included. We classified the patients into four risk groups of the disease based on the Proactive Molecular Risk Classifier for Endometrial Cancer. Genomic alterations in PTEN, ARID1A, TP53, and PIK3CA were detected in more than 30% of the patients. Overall survival and recurrence-free survival of patients with genomic alterations in CTNNB1 were poorer than those of patients with wild-type CTNNB1 (p = 0.006 and p = 0.004, respectively). Compared with that of alterations prevalent in Caucasians, the frequency of genomic alterations in POLE and TP53 was higher in our study than in The Cancer Genome Atlas dataset (p = 0.01 and p = 0.01, respectively). The tendency for recurrence-free survival in the POLE exonuclease domain mutation group was better than that in the TP53 mutation and mismatch repair-deficient groups (p = 0.08 and p = 0.07, respectively), consistent with the Proactive Molecular Risk Classifier for Endometrial Cancer risk classifier definition. The CTNNB1 mutation is a potential novel biomarker for the prognosis of patients with grade 3 endometrial endometrioid carcinoma, and prognosis classification using Proactive Molecular Risk Classifier for Endometrial Cancer may help screen Japanese patients with the disease.
| S-EPMC9128156 | biostudies-literature
Project description:OBJECTIVES:Stage I, grade 1 endometrial cancers have low recurrence rates and often do not receive adjuvant therapy. We compared recurrent cases to matched non-recurrent controls to evaluate for molecular markers associated with higher risk of recurrence. METHODS:A case-control study including all cases of recurrent stage I, grade 1 endometrioid endometrial cancer at one institution in a ten-year period. Cases were matched to controls by age, BMI, weight and stage. Molecular testing and immunohistochemistry were performed on archival tumor specimens: microsatellite instability (MSI-H), mismatch repair status, POLE mutational status, and next-generation sequencing. RESULTS:15 stage I, grade 1 endometrial cancer cases with recurrent disease and available tumor specimens were identified. CTNNB1 and MSI-H were present at significantly higher rates in cases than controls (CTNNB1 60% vs. 28%, OR 3.9, 95%CI 1.1-14.7, p?=?0.04 and MSI-H 53% vs. 21%, OR 4.4, 95%CI 1.1-17.0, p?=?0.03). POLE mutations were found in 0% of cases vs. 7% of controls (p?=?0.54). Among specimens demonstrating microsatellite stability (MSS), 100% of cases vs. 26% of controls had CTNNB1 mutations (p?<?0.001). CTNNB1 wild type tumors were MSI-H in 100% of cases vs. 19% of controls (p?<?0.001). CONCLUSIONS:Compared to controls, CTNNB1 mutation is present at significantly higher rates in recurrent stage I, grade 1 endometrial cancers and is found most commonly in MSS tumors. MSI-H is also present at significantly higher rates in recurrent cases. These markers may be useful for prognostic risk stratification and adjuvant therapy decision-making in this otherwise low-risk population.
| S-EPMC7005911 | biostudies-literature
Project description:Introduction: High-risk patients with grade 3 endometrioid endometrial carcinoma (G3EEC) who require adjuvant therapy have not been clearly identified. Therefore, the current study aimed to investigate the prognostic impact of ARID1A, p53, and mismatch repair (MMR) protein expressions, previously reported as prognosticators in some gynecological cancers, in patients with early-stage G3EEC. Methods: A total of 67 patients with pathologically confirmed early-stage G3EEC diagnosed between 1997 and 2020 were identified; none received adjuvant chemotherapy. The recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared with a log-rank test. The protein expressions of ARID1A, p53, and MMR were examined via immunohistochemistry, and the associations between these biomarkers and clinical outcomes were evaluated. Results: Recurrence was observed in 9 (13%) of the 67 patients with early stage G3EEC. The respective 5-years RFS and OS rates were 87.7% and 93.7%, and 68.6% and 85.7%, respectively for stages I and II. Multivariate analysis showed significantly longer RFS among patients with ARID1A loss (hazard ratio = 8.7; 95% CI, 1.09-69.6, p = 0.04). No significant differences were observed in RFS and OS of patients according to p53 and MMR expression status. Conclusion: ARID1A expression status was a prognosticator for patients with early stage G3EEC without adjuvant therapy, whereas p53 and MMR expression status showed no impact on survival outcomes. ARID1A may become a useful biomarker for stratification of adjuvant treatment for early stage G3EEC patients.
| S-EPMC8262237 | biostudies-literature
Project description:Our aim was to investigate whether molecular classification can be used to refine prognosis in grade 3 endometrial endometrioid carcinomas (EECs). Grade 3 EECs were classified into 4 subgroups: p53 abnormal, based on mutant-like immunostaining (p53abn); MMR deficient, based on loss of mismatch repair protein expression (MMRd); presence of POLE exonuclease domain hotspot mutation (POLE); no specific molecular profile (NSMP), in which none of these aberrations were present. Overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method (Log-rank test) and univariable and multivariable Cox proportional hazard models. In total, 381 patients were included. The median age was 66 years (range, 33 to 96?y). Federation Internationale de Gynecologie et d'Obstetrique stages (2009) were as follows: IA, 171 (44.9%); IB, 120 (31.5%); II, 24 (6.3%); III, 50 (13.1%); IV, 11 (2.9%). There were 49 (12.9%) POLE, 79 (20.7%) p53abn, 115 (30.2%) NSMP, and 138 (36.2%) MMRd tumors. Median follow-up of patients was 6.1 years (range, 0.2 to 17.0?y). Compared to patients with NSMP, patients with POLE mutant grade 3 EEC (OS: hazard ratio [HR], 0.36 [95% confidence interval, 0.18-0.70]; P=0.003; RFS: HR, 0.17 [0.05-0.54]; P=0.003) had a significantly better prognosis; patients with p53abn tumors had a significantly worse RFS (HR, 1.73 [1.09-2.74]; P=0.021); patients with MMRd tumors showed a trend toward better RFS. Estimated 5-year OS rates were as follows: POLE 89%, MMRd 75%, NSMP 69%, p53abn 55% (Log rank P=0.001). Five-year RFS rates were as follows: POLE 96%, MMRd 77%, NSMP 64%, p53abn 47% (P=0.000001), respectively. In a multivariable Cox model that included age and Federation Internationale de Gynecologie et d'Obstetrique stage, POLE and MMRd status remained independent prognostic factors for better RFS; p53 status was an independent prognostic factor for worse RFS. Molecular classification of grade 3 EECs reveals that these tumors are a mixture of molecular subtypes of endometrial carcinoma, rather than a homogeneous group. The addition of molecular markers identifies prognostic subgroups, with potential therapeutic implications.
| S-EPMC5893364 | biostudies-literature
Project description:PURPOSE:Endometrioid endometrial carcinoma (EEC) is the major histologic type of endometrial cancer, the most prevalent gynecologic malignancy in the United States. EEC recurrence or metastasis is associated with a poor prognosis. Early-stage EEC is generally curable, but a subset has high risk of recurrence or metastasis. Prognosis estimation for early-stage EEC mainly relies on clinicopathologic characteristics, but is unreliable. We aimed to identify patients with high-risk early-stage EEC who are most likely to benefit from more extensive surgery and adjuvant therapy by building a prognostic model that integrates clinical variables and protein markers. EXPERIMENTAL DESIGN:We used two large, independent early-stage EEC datasets as training (n = 183) and validation cohorts (n = 333), and generated the levels of 186 proteins and phosphoproteins using reverse-phase protein arrays. By applying an initial filtering and the elastic net to the training samples, we developed a prognostic model for overall survival containing two clinical variables and 18 protein markers and optimized the risk group classification. RESULTS:The Kaplan-Meier survival analyses in the validation cohort confirmed an improved discriminating power of our prognostic model for patients with early-stage EEC over key clinical variables (log-rank test, P = 0.565 for disease stage, 0.567 for tumor grade, and 1.3 × 10(-4) for the integrative model). Compared with clinical variables (stage, grade, and patient age), only the risk groups defined by the integrative model were consistently significant in both univariate and multivariate analyses across both cohorts. CONCLUSIONS:Our prognostic model is potentially of high clinical value for stratifying patients with early-stage EEC and improving their treatment strategies.
| S-EPMC4715969 | biostudies-literature
Project description:Study designRetrospective cohort study.IntroductionDebates remain regarding the role of lymphadenectomy in patients with apparent stage IA endometrial cancer, especially subtypes with a favorable prognosis. This study aimed to explore the prognostic value of staging surgeries in apparent stage IA endometrial endometrioid cancer patients in a retrospective cohort study.MethodsCases from June 1, 2010 to June 1, 2017 were reviewed in patients with pathologically confirmed endometrial endometrioid carcinoma limited to <1/2 of the myometrium, without extrauterine metastasis on preoperative evaluation and during surgical inspection. Survival outcomes were compared between patients with and without lymphadenectomy and between patients with and without metastasis to lymph nodes.ResultsIn total, 1,312 eligible patients were included, among which 836 underwent staging surgeries and 476 underwent simple hysterectomy. Twenty-eight patients were found with metastasis to retroperitoneal lymph nodes. After a median follow-up of 57.4 months, lost to follow-up, recurrence, death, and cancer-specific death occurred in 28, 39, 24, and 16 patients, respectively. In a univariate analysis, lymphadenectomy of the pelvis with or without para-aortic lymph nodes had no significant impact on disease-free survival, overall survival or cancer-specific overall survival (p values >0.05). However, after adjusting for important baseline risk factors [menopausal status, tumor differentiation, maximum diameter and location, lymph-vascular space invasion (LVSI) status, and postoperative adjuvant therapy), lymphadenectomy resulted in significantly improved survival outcomes (p values <0.05). Menopause (odds ratio [OR] 4.7, 95% confidence interval [CI] 1.3-16.4, p=0.015), tumor diameter larger than 2 cm (OR 4.6, 95% CI 1.3-16.0, p=0.016), grade 3 tumors (OR 3.0, 95% CI 1.0-8.5, p=0.042), positive LVSI (OR 8.7, 95% CI 3.7-20.4, p<0.001) and lower uterine segment involvement (OR 3.1, 95% CI 1.4-7.2, p=0.007) had more extrauterine metastases.ConclusionIn cases of apparent stage IA endometrioid endometrial carcinoma, staging surgeries should be considered in patients with larger, higher grade tumors, positive LVSI, or lower uterine segment involvement.
| S-EPMC7921700 | biostudies-literature
Project description:Endometrial carcinoma (EC) is the most common gynecological malignancy and fibroblast growth factor receptor 2 (FGFR2) is a frequently dysregulated receptor tyrosine kinase. FGFR2b and FGFR2c are the two main splice isoforms of FGFR2 and are normally localized in epithelial and mesenchymal cells, respectively. Previously, we demonstrated that FGFR2c mRNA expression was associated with aggressive tumor characteristics, shorter progression-free survival (PFS), and disease-specific survival (DSS) in endometrioid ECs (EECs). The objectives of this study were to investigate the spatial expression of FGFR2b in normal and hyperplasia with and without atypia of human endometrium and to assess the prognostic significance of FGFR2b expression in EC. FGFR2b and FGFR2c mRNA expression was evaluated in normal (proliferative [n = 10], secretory [n = 15], and atrophic [n = 10] endometrium), hyperplasia with and without atypia (n = 19) as well as two patient cohorts of EC samples (discovery [n = 78] and Vancouver [n = 460]) using isoform-specific BaseScope RNA in situ hybridization assays. Tumors were categorized based on FGFR2 isoform expression (one, both, or neither) and categories were correlated with clinicopathologic markers, molecular subtypes, and clinical outcomes. The FGFR2b splice isoform was exclusively expressed in the epithelial compartment of normal endometrium and hyperplasia without atypia. We observed FGFR2c expression at the basalis layer of glands in 33% (3/9) of hyperplasia with atypia. In patients with EEC, FGFR2b+/FGFR2c- expression was found in 48% of the discovery cohort and 35% of the validation Vancouver cohort. In univariate analyses, tumors with FGFR2b+/FGFR2c- expression had longer PFS (hazard ratio [HR] 0.265; 95% CI 0.145-0.423; log-rank p < 0.019) and DSS (HR 0.31; 95% CI 0.149-0.622; log-rank p < 0.001) compared to tumors with FGFR2b-/FGFR2c+ expression in the large EEC Vancouver cohort. In multivariable Cox regression analyses, tumors with FGFR2b+/FGFR2c- expression were significantly associated with longer DSS (HR 0.37; 95% CI 0.153-0.872; log-rank p < 0.023) compared to FGFR2b-/FGFR2c+ tumors. In conclusion, FGFR2b+/FGFR2c- expression is associated with favorable clinicopathologic markers and clinical outcomes suggesting that FGFR2b could play a role in tailoring the management of EEC patients in the clinic if these findings are confirmed in an independent cohort.
| S-EPMC9535101 | biostudies-literature