HERV-K Hypomethylation in Ovarian Clear Cell Carcinoma Is Associated With a Poor Prognosis and Platinum Resistance

2011 ◽  
Vol 21 (1) ◽  
pp. 51-57 ◽  
Author(s):  
Kanokwan Iramaneerat ◽  
Prakasit Rattanatunyong ◽  
Nipon Khemapech ◽  
Surang Triratanachat ◽  
Apiwat Mutirangura
Keyword(s):  
Overall Survival ◽  
Cell Carcinoma ◽  
Treatment Response ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Platinum Resistance ◽  
Ovarian Clear Cell Carcinoma ◽  
Platinum Based Chemotherapy

Introduction:In general, ovarian clear cell carcinoma (OCCC) has a history of poor response to standard platinum-based chemotherapy regimens, and advanced cases have short survival periods. Therefore, the discovery of a biomarker for the pretreatment prediction of OCCC is crucial. Loss of methylation of a retrotransposable sequence, such as long interspersed repetitive sequence 1 (LINE-1), frequently occurs in cancers, including ovarian cancer, and it has been proven to be associated with poor survival. The expressions of human endogenous retrovirus (HERV) K and E were found to be increased in tissues from patients with OCCC. Here, we propose that methylation levels of HERV are associated with treatment response and prognosis of OCCC.Methods:Twenty-nine patients with OCCC were enrolled. Methylation levels of HERV-K, HERV-E, and LINE-1 were measured from microdissected cancer and normal ovarian tissues. The methylation levels were correlated with stage, treatment response, and prognosis.Results:Methylation levels of HERV-K, HERV-E, and LINE-1 were decreased in tissues from patients with advanced stage cancer (P= 0.0179,P= 0.0021, andP= 0.0307, respectively). Human endogenous retrovirus K demonstrated significantly lower methylation levels in the platinum-resistant group (P= 0.0004). Patients with lower levels of methylated (hypomethylated) HERV-K had a shorter mean overall survival (P= 0.006). In advanced OCCC cases, patients with hypomethylated HERV-K had shorter mean progression-free survival (P= 0.018) and mean overall survival (P= 0.018) than did patients with higher methylation levels of HERV-K.Conclusions:Methylation levels of HERV-K, HERV-E, and LINE-1 are decreased during OCCC multistep carcinogenesis. Moreover, HERV-K hypomethylation is a promising biomarker for predicting OCCC treatment response and prognosis.

scholarly journals Development and validation of Nomograms for predicting overall survival and Cancer-specific survival in patients with ovarian clear cell carcinoma

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Qian Chen ◽  
Shu Wang ◽  
Jing-He Lang
Keyword(s):  
Overall Survival ◽  
Cell Carcinoma ◽  
Cox Regression ◽  
Validation Cohort ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Ovarian Clear Cell Carcinoma ◽  
Cancer Specific Survival ◽  
Training Cohort ◽  
Organ Metastasis

Abstract Background Ovarian clear cell carcinoma (OCCC) is a rare histologic type of ovarian cancer. There is a lack of an efficient prognostic predictive tool for OCCC in clinical work. This study aimed to construct and validate nomograms for predicting the overall survival (OS) and cancer-specific survival (CSS) in patients with OCCC. Methods Data of patients with primary diagnosed OCCC in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2016 was extracted. Prognostic factors were evaluated with LASSO Cox regression and multivariate Cox regression analysis, which were applied to construct nomograms. The performance of the nomogram models was assessed by the concordance index (C-index), calibration plots, decision curve analysis (DCA) and risk subgroup classification. The Kaplan-Meier curves were plotted to compare survival outcomes between subgroups. Results A total of 1541 patients from SEER registries were randomly divided into a training cohort (n = 1079) and a validation cohort (n = 462). Age, laterality, stage, lymph node (LN) dissected, organ metastasis and chemotherapy were independently and significantly associated with OS, while laterality, stage, LN dissected, organ metastasis and chemotherapy were independent risk factors for CSS. Nomograms were developed for the prediction of 3- and 5-year OS and CSS. The C-indexes for OS and CSS were 0.802[95% confidence interval (CI) 0.773–0.831] and 0.802 (0.769–0.835), respectively, in the training cohort, while 0.746 (0.691–0.801) and 0.770 (0.721–0.819), respectively, in the validation cohort. Calibration plots illustrated favorable consistency between the nomogram predicted and actual survival. C-index and DCA curves also indicated better performance of nomogram than the AJCC staging system. Significant differences were observed in the survival curves of different risk subgroups. Conclusions We have constructed predictive nomograms and a risk classification system to evaluate the OS and CSS of OCCC patients. They were validated to be of satisfactory predictive value, and could aid in future clinical practice.

scholarly journals Development and Validation of Nomograms for Predicting Overall Survival and Cancer-Specific Survival in Patients with Ovarian Clear Cell Carcinoma

2020 ◽  
Author(s):  
Qian Chen ◽  
Shu Wang ◽  
Jing-he Lang
Keyword(s):  
Overall Survival ◽  
Cell Carcinoma ◽  
Cox Regression ◽  
Validation Cohort ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Ovarian Clear Cell Carcinoma ◽  
Cancer Specific Survival ◽  
Training Cohort ◽  
Organ Metastasis

Abstract Background: Ovarian clear cell carcinoma (OCCC) is a rare histologic type of ovarian cancer. There is a lack of an efficient prognostic predictive tool for OCCC in clinical work. This study aimed to construct and validate nomograms for predicting the overall survival (OS) and cancer-specific survival (CSS) in patients with OCCC.Methods: Data of patients with primary diagnosed OCCC in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2016 was extracted. Prognostic factors were evaluated with LASSO Cox regression and multivariate Cox regression analysis, which were applied to construct nomograms. The performance of the nomogram models was assessed by the concordance index (C-index), calibration plots, decision curve analysis (DCA) and risk subgroup classification. The Kaplan-Meier curves were plotted to compare survival outcomes between subgroups.Results: A total of 1541 patients from SEER registries were randomly divided into a training cohort (n=1079) and a validation cohort (n=462). Age, laterality, stage, lymph node (LN) dissected, organ metastasis and chemotherapy were independently and significantly associated with OS, while laterality, stage, LN dissected, organ metastasis and chemotherapy were independent risk factors for CSS. Nomograms were developed for the prediction of 3‐ and 5‐year OS and CSS. The C-indexes for OS and CSS were 0.802[95% confidence interval (CI) 0.773-0.831] and 0.802 (0.769-0.835), respectively, in the training cohort, while 0.746 (0.691-0.801) and 0.770 (0.721-0.819), respectively, in the validation cohort. Calibration plots illustrated favorable consistency between the nomogram predicted and actual survival. C-index and DCA curves also indicated better performance of nomogram than the AJCC staging system. Significant differences were observed in the survival curves of different risk subgroups.Conclusions: We have constructed predictive nomograms and a risk classification system to evaluate the OS and CSS of OCCC patients. They were validated to be of satisfactory predictive value, and could aid in future clinical practice.

Fertility sparing surgery for patients with FIGO stage I clear cell ovarian carcinoma: a database analysis and systematic review of the literature

2020 ◽  
Vol 30 (9) ◽  
pp. 1372-1377 ◽  
Author(s):  
Dimitrios Nasioudis ◽  
Lakeisha Mulugeta-Gordon ◽  
Erin McMinn ◽  
Melissa K Frey ◽  
Eloise Chapman-Davis ◽  
...  
Keyword(s):  
Systematic Review ◽  
Overall Survival ◽  
Cell Carcinoma ◽  
Clear Cell ◽  
Radical Surgery ◽  
Clear Cell Carcinoma ◽  
Stage I ◽  
Ovarian Clear Cell Carcinoma ◽  
Fertility Sparing Surgery ◽  
Fertility Sparing

ObjectiveFertility sparing surgery for patients with early stage ovarian clear cell carcinoma is controversial. We aimed to investigate the impact of fertility sparing surgery on the oncologic outcomes of young patients with stage I ovarian clear cell carcinoma.MethodsThe National Cancer Database was accessed and patients with pathological stage IA or IC ovarian clear cell carcinoma, aged <45 years, were selected. Based on site specific surgery codes, patients who underwent fertility sparing or radical surgery were identified. Overall survival was evaluated following generation of Kaplan–Meier curves, and compared with the log rank test. Multivariate Cox analysis was performed to control for possible confounders. A systematic review of literature of the Pubmed, EMBASE and Web of Science databases was also performed to summarize all reported cases.ResultsA total of 57 (35.8%) and 102 (64.2%) patients underwent fertility sparing and radical surgery. There was no difference in overall survival between patients who had fertility sparing and radical surgery (p=0.92); 5 year overall survival rates were 89% and 87.9%, respectively. After controlling for the performance of lymphadenectomy and disease substage, fertility sparing surgery was not associated with worse survival (hazard ratio 0.83, 95% confidence interval 0.30 to 2.32). A systematic review of the literature identified 132 patients with stage I disease who underwent fertility sparing surgery; a total of 20 patients (15.2%) experienced a relapse at a median of 18 months from surgery.ConclusionsIn a large cohort of young patients with stage I ovarian clear cell carcinoma, fertility sparing surgery was not associated with worse survival.

scholarly journals Development and Validation of Nomograms for Predicting Overall Survival and Cancer-Specific Survival in Patients with Ovarian Clear Cell Carcinoma

2020 ◽  
Author(s):  
Qian Chen ◽  
Shu Wang ◽  
Jing-he Lang
Keyword(s):  
Overall Survival ◽  
Cell Carcinoma ◽  
Cox Regression ◽  
Validation Cohort ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Ovarian Clear Cell Carcinoma ◽  
Cancer Specific Survival ◽  
Training Cohort ◽  
Organ Metastasis

Abstract Background Ovarian clear cell carcinoma (OCCC) is a rare histologic type of ovarian cancer. There is a lack of useful prognostic predictive tool for OCCC in clinical work. This study aimed to construct and validate nomograms for predicting the overall survival (OS) and cancer-specific survival (CSS) in patients with OCCC. Methods Data of patients with primary diagnosed OCCC in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2016 was extracted. Prognostic factors were evaluated with LASSO COX regression and multivariate Cox regression analysis, which were applied to construct nomograms. The performance of the nomogram models was assessed by concordance index (C-index), calibration plots, decision curve analysis (DCA) and risk subgroup classification. The Kaplan-Meier curves were plotted to compare survival outcomes between subgroups. Results A total of 1541 patients from SEER registries were randomly divided into a training cohort (n = 1079) and a validation cohort (n = 462). Age, laterality, stage, lymph node (LN) dissected, organ metastasis and chemotherapy were independently and significantly associated with OS, while laterality, stage, LN dissected, organ metastasis and chemotherapy were independent risk factors for CSS. Nomograms were developed for prediction of 3- and 5‐year OS and CSS. The C-indexes for OS and CSS were 0.802[95% confidence interval (CI) 0.773–0.831] and 0.802 (0.769–0.835), respectively, in the training cohort, while 0.746 (0.691–0.801) and 0.770 (0.721–0.819), respectively, in the validation cohort. Calibration plots illustrated favorable consistency between the nomogram predicted and actual survival. C-index and DCA curves also indicated better performance of nomogram than the AJCC staging system. Significant differences were observed in survival curves of different risk subgroups. Conclusions We constructed predictive nomograms and a risk classification system to evaluate the OS and CSS of OCCC patients. They were validated to be of satisfactory predictive value, and could aid in future clinical practice.

scholarly journals Treatment Strategies for ARID1A-Deficient Ovarian Clear Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1769
Author(s):  
Kazuaki Takahashi ◽  
Masataka Takenaka ◽  
Aikou Okamoto ◽  
David D. L. Bowtell ◽  
Takashi Kohno
Keyword(s):  
Ovarian Cancer ◽  
Cell Carcinoma ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Immune Checkpoint Blockade ◽  
Serous Carcinoma ◽  
Histological Subtype ◽  
Ovarian Clear Cell Carcinoma ◽  
Chemotherapeutic Regimen ◽  
Platinum Based Chemotherapy

Ovarian clear cell carcinoma (OCCC) is a histological subtype of ovarian cancer that is more frequent in Asian countries (~25% of ovarian cancers) than in US/European countries (less than 10%). OCCC is refractory to conventional platinum-based chemotherapy, which is effective against high-grade serous carcinoma (HGSC), a major histological subtype of ovarian cancer. Notably, deleterious mutations in SWI/SNF chromatin remodeling genes, such as ARID1A, are common in OCCC but rare in HGSC. Because this complex regulates multiple cellular processes, including transcription and DNA repair, molecularly targeted therapies that exploit the consequences of SWI/SNF deficiency may have clinical efficacy against OCCC. Three such strategies have been proposed to date: prioritizing a gemcitabine-based chemotherapeutic regimen, synthetic lethal therapy targeting vulnerabilities conferred by SWI/SNF deficiency, and immune checkpoint blockade therapy that exploits the high mutational burden of ARID1A-deficient tumor. Thus, ARID1A deficiency has potential as a biomarker for precision medicine of ovarian cancer.

scholarly journals Mismatch Repair Status as a Predictor of Benefit From Platinum-Based Adjuvant Therapy in Ovarian Clear Cell Carcinoma

2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 217s-217s
Author(s):  
J. Zhu ◽  
X. Wu ◽  
X. Ju
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Cell Carcinoma ◽  
Mismatch Repair ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Progression Free Survival ◽  
Ovarian Clear Cell Carcinoma ◽  
Free Survival ◽  
Pathologic Features

Background: Previous studies have indicated that patients with colorectal cancer who demonstrate defective DNA mismatch repair (dMMR) have clinical and pathologic features that distinguish them from patients who have proficient mismatch repair (pMMR) tumors. However, the influence of mismatch repair (MMR) status in ovarian clear cell carcinoma (OCCC) is still unknown. Aim: To evaluate the MMR statuses in OCCC and its correlation with clinicopathological and prognostic characteristics. Methods: MMR statuses were measured by tissue microarray–based immunohistochemistry from 120 OCCC patients. The associations of clinicopathologic features with progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier method and multivariate analysis was further performed by Cox regression model. Results: Overall, 120 OCCC patients met the entry criteria and their MMR status were detected, consisting of 24 patients with dMMR and 96 patients with pMMR. Tumors with dMMR were strongly associated with platinum-sensitive disease ( P = 0.008) and large tumor volume ( P = 0.028). Among all the patients who have received surgery, tumors with dMMR had a better progression-free survival and overall survival (OS) than those with pMMR (hazard ratio [HR] for recurrence, 0.459 [95% confidence interval (95% CI), 0.224-0.940]; P = 0.029; HR for death, 0.381 [95% CI, 0.170-0.853]; P = 0.015). In subgroup analysis, dMMR patients experienced a better PFS (HR, 0.242; P = 0.055) and OS (HR, 0.141; P = 0.039) than pMMR cases among early stages (I-II), but this difference was not observed in advanced stage (III-IV) patients. Meanwhile, pMMR was associated with more favorable prognosis than dMMR in platinum-resistant patients (PFS, HR: 0.317, P = 0.052; OS, HR: 0.370, P = 0.046). Multivariate analysis revealed that only advanced stages (III-IV) were adverse independent prognosticators for both PFS (HR, 5.938; [95% CI, 2.804-12.574], P < 0.001) and OS (HR, 6.209; [95% CI, 2.724-14.156], P < 0.001). Conclusion: MMR status in ovarian clear cell carcinoma is not only a prognostic indicator, but also appears to be a possible predictor for the use of platinum-based adjuvant chemotherapy.

scholarly journals Complete remission of heavily treated ovarian clear cell carcinoma with ARID1A mutations after pembrolizumab and bevacizumab combination therapy: a case report

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Yu-Chien Lin ◽  
Kuo-Chang Wen ◽  
Pi-Lin Sung ◽  
Yu-Ting Chou ◽  
Phui-Ly Liew ◽  
...  
Keyword(s):  
Complete Remission ◽  
Cell Carcinoma ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Checkpoint Inhibitors ◽  
Genomic Analysis ◽  
Angiogenesis Inhibitors ◽  
Ca 125 ◽  
Ovarian Clear Cell Carcinoma ◽  
Platinum Based Chemotherapy

Abstract Background Patients with ovarian clear cell carcinoma (OCCC) have a poor prognosis because they show low sensitivity to platinum-based chemotherapy. New treatments for refractory OCCC are urgently needed. Case presentation We present a patient with refractory OCCC in whom conventional chemotherapy failed. Cachexia was induced by the disseminating recurrent tumors. Tumor tissue staining and genomic analysis revealed PD-L1 negativity, a low tumor burden, stable microsatellite instability, and two mutations in ARID1A. The patient was administered pembrolizumab combined with bevacizumab triweekly. Her serum CA-125 level decreased dramatically after the first cycle. A computerized tomography scan showed marked regression of the recurrent masses after 3 cycles, and the patient reached complete remission after 9 cycles. She showed good recovery from cachexia. We observed no marked side effects except for mild polyarthritis of the small joints. Conclusions The therapeutic effect of checkpoint inhibitors combined with angiogenesis inhibitors is very promising in our patient with OCCC. Further clinical trials of tumors including ARID1A mutations are warranted.

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