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Shen Y, Xi F, Zhao P, Zhang Y, Guo G, Jia X, Wu J, Kuang Y. Development and validation of a prognostic nomogram for ovarian clear cell carcinoma: a study based on the SEER database and a Chinese cohort. Discov Oncol 2025; 16:482. [PMID: 40192950 PMCID: PMC11977087 DOI: 10.1007/s12672-025-02272-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 03/31/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND The clinical prognostic factors for ovarian clear cell carcinoma (OCCC) are limited, and we aim to construct a model to predict the survival of OCCC patients. METHODS Data were extracted from the SEER database for patients diagnosed with OCCC. Cox regression analyses were used to identify independent risk factors for OCCC. Two nomograms were developed, and the results were evaluated comprehensively by C-index, ROC curve, calibration curve, and DCA curve. Patients diagnosed with OCCC were used as the validation set to verify the model. RESULTS A total of 1855 OCCC patients from the SEER database were used as the training set, and 101 patients from our hospital were used as the validation set. Cox regression analysis of the independent risk factors affecting the prognosis of OCCC was used to construct nomograms. The C-index of the training set OS was 0.76, and the validation set OS was 0.75. The AUC of the training set OS is 0.803, 0.794, and 0.802 for 1, 3, and 5 years, and 0.774, 0.800, and 0.923 for the validation set. The calibration curve and DCA curve also showed that OS and CSS have good predictive power. CONCLUSIONS A nomogram based on 8 prognostic factors analyzed by Cox regression can predict the prognosis of OCCC patients effectively.
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Affiliation(s)
- Yao Shen
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education, Harbin Medical University, Harbin, China
- Department of Pathology, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Fei Xi
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education, Harbin Medical University, Harbin, China
| | - Pingge Zhao
- Department of Gynecology and Obstetrics, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center Xiamen Hospital, Xiamen, China
| | - Yuhang Zhang
- Department of Gynecology and Obstetrics, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Guanlin Guo
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education, Harbin Medical University, Harbin, China
| | - Xueyuan Jia
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, China
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education, Harbin Medical University, Harbin, China
| | - Jie Wu
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, China.
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Ministry of Education, Harbin Medical University, Harbin, China.
- Future Medical Laboratory, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Ye Kuang
- Department of Gynecology and Obstetrics, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.
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Prueksaritanond N, Petchsila K, Insin P. The Association of Preoperative Prognostic Nutritional Index With Survival Outcome in Ovarian Clear Cell Cancer. World J Oncol 2024; 15:950-959. [PMID: 39697428 PMCID: PMC11650612 DOI: 10.14740/wjon1963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 10/08/2024] [Indexed: 12/20/2024] Open
Abstract
Background The preoperative prognostic nutritional index (PPNI) has been investigated as a prognostic indicator in various cancers including epithelial ovarian cancer (EOC). However, its prognostic relevance in epithelial ovarian clear cell cancer (EOC-CC) remains uncertain. The objective of the study was to clarify the prognostic values of PPNI in EOC-CC patients. Methods We retrospectively reviewed 290 EOC-CC patients who underwent staging surgery at Rajavithi Hospital between January 2008 and December 2019. The PPNI was calculated using serum albumin × 10 (g/L) + 0.005 × peripheral blood lymphocyte count (per mm3). The association between PPNI and survival outcome was analyzed using the Kaplan-Meier method and the Cox proportional hazard model. Results The optimal cut-off value of PPNI, set at a mean of PPNI as 50, divided the EOC-CC patients into two groups: the low (n = 115) and the high (n = 175) PPNI group. With a median follow-up time of 63 months, patients with high PPNI exhibited significantly superior 5-year overall survival (OS) rates (76.4% vs. 56.8%, P = 0.004) and 5-year progression-free survival (PFS) rates (71.0% vs. 58.7%, P = 0.017) compared to patients with low PPNI. Univariate analysis revealed high PPNI correlated with increased OS (hazard ratio (HR): 0.51; 95% confidence interval (CI): 0.35 - 0.75) and PFS (HR: 0.63; 95% CI: 0.43 - 0.92). Nevertheless, in a multivariate analysis, high PPNI did not retain its status as an independent prognostic factor for a favorable prognosis in EOC-CC patients. Conclusion The present study did not confirm the prognostic significance of PPNI on survival outcomes in EOC-CC patients. Therefore, conducting prospective clinical research with large samples is necessary to illustrate the predictive values of PPNI in this rare disease.
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Affiliation(s)
- Nisa Prueksaritanond
- Gynecologic Oncology Unit, Department of Obstetrics and Gynecology, Rajavithi Hospital, Bangkok, Thailand
- College of Medicine, Rangsit University, Bangkok, Thailand
| | - Kittisak Petchsila
- Gynecologic Oncology Unit, Department of Obstetrics and Gynecology, Rajavithi Hospital, Bangkok, Thailand
| | - Putsarat Insin
- Gynecologic Oncology Unit, Department of Obstetrics and Gynecology, Rajavithi Hospital, Bangkok, Thailand
- College of Medicine, Rangsit University, Bangkok, Thailand
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Xia S, Chen L, Yu M, Li J, Chen J, Xu F, Ni M, Liu C, Wu X, Chen X, Li J. Genetic and therapeutic heterogeneity shape the baseline and longitudinal immune ecosystem of ovarian clear cell carcinoma. J Immunother Cancer 2024; 12:e010069. [PMID: 39608974 PMCID: PMC11603735 DOI: 10.1136/jitc-2024-010069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 11/06/2024] [Indexed: 11/30/2024] Open
Abstract
BACKGROUND Ovarian clear cell carcinoma (OCCC) is a rare and chemo-resistant subtype of ovarian cancer. While immunotherapy has demonstrated effectiveness in some OCCC cases, the mechanisms for heterogeneous immunoreactivity and potential combinatory strategies remain unclear. METHODS Tumor samples from 13 patients with OCCC underwent single-cell mRNA-seq and TCR-seq to generate 1 40 683 cells transcriptome, while additionally 31 formalin-fixed paraffin-embedded samples were used for immunohistochemistry. Spatial transcriptomics of two OCCC samples and bulk RNA-seq of 58 patients were incorporated for spatial and interpatient level explorations. Serum tumor markers and radiologic images of three patients with OCCC who received combinatory VEGF and PD-1 inhibition were retrospectively analyzed. RESULTS OCCC exhibited a dynamic immune architecture shaped by genetic and therapeutic pressure. ARID1A mutation linked to baseline immune activation, correlated with an enrichment of neoantigen-reactive CXCL13+ CTLA4+ CD8+ T cells (p<0.001) and enhanced FASLG-FAS interactions. Recurrent OCCC was fibrotic, angiogenic, and immunosuppressive, exhibiting metabolic reprogramming towards activated activity in fatty acid metabolism. High CD36 (log-rank p=0.012, HR: 4.515) and CD47 expression (log-rank p=0.037, HR: 3.246) indicated worse progression-free survival. Treatment with bevacizumab increased intratumoral T cell infiltration and activated T cell interferon-γ signaling. Retrospective analysis of clinical cases revealed that combination therapy with anti-VEGF (vascular endothelial growth factor) and anti-PD-1 agents exerted clinical benefits in patients with OCCC with persistent, recurrent, and metastatic disease. CONCLUSIONS ARID1A mutation correlated with OCCC baseline immune activation. Stromal reconstruction and tumor metabolic reprogramming functioned as key processes of OCCC dynamic progression. VEGF inhibition remodeled OCCC stroma, restored T cell function and potentiated immunotherapy. CD36 and CD47 might be potential therapeutic targets for recurrent OCCC.
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Affiliation(s)
- Siyu Xia
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Lihua Chen
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Min Yu
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Jiana Li
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Jiaxin Chen
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Fei Xu
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Mengdong Ni
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Chaohua Liu
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Xiaohua Wu
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Xiaojun Chen
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Jiajia Li
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
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Ma Y, Field NR, Xie T, Briscas S, Kokinogoulis EG, Skipper TS, Alghalayini A, Sarker FA, Tran N, Bowden NA, Dickson KA, Marsh DJ. Aberrant SWI/SNF Complex Members Are Predominant in Rare Ovarian Malignancies-Therapeutic Vulnerabilities in Treatment-Resistant Subtypes. Cancers (Basel) 2024; 16:3068. [PMID: 39272926 PMCID: PMC11393890 DOI: 10.3390/cancers16173068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 09/15/2024] Open
Abstract
SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in ARID1A, encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42-67% of ovarian clear cell carcinomas (OCCC). The concomitant somatic or germline mutation and epigenetic silencing of the mutually exclusive ATPase subunits SMARCA4 and SMARCA2, respectively, occurs in Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), with SMARCA4 mutation reported in 69-100% of SCCOHT cases and SMARCA2 silencing seen 86-100% of the time. Somatic ARID1A mutations also occur in endometrioid ovarian cancer (EnOC), as well as in the chronic benign condition endometriosis, possibly as precursors to the development of the endometriosis-associated cancers OCCC and EnOC. Mutation of the ARID1A paralogue ARID1B can also occur in both OCCC and SCCOHT. Mutations in other SWI/SNF complex members, including SMARCA2, SMARCB1 and SMARCC1, occur rarely in either OCCC or SCCOHT. Abrogated SWI/SNF raises opportunities for pharmacological inhibition, including the use of DNA damage repair inhibitors, kinase and epigenetic inhibitors, as well as immune checkpoint blockade.
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Affiliation(s)
- Yue Ma
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Natisha R Field
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Tao Xie
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Sarina Briscas
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Emily G Kokinogoulis
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Tali S Skipper
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Amani Alghalayini
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Farhana A Sarker
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Nham Tran
- School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Nikola A Bowden
- Drug Repurposing and Medicines Research Program, Hunter Medical Research Institute, Newcastle, NSW 2289, Australia
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW 2289, Australia
| | - Kristie-Ann Dickson
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Deborah J Marsh
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
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Mikami M, Tanabe K, Imanishi T, Ikeda M, Hirasawa T, Yasaka M, Machida H, Yoshida H, Hasegawa M, Shimada M, Kato T, Kitamura S, Kato H, Fujii T, Kobayashi Y, Suzuki N, Tanaka K, Murakami I, Katahira T, Hayashi C, Matsuo K. Comprehensive serum glycopeptide spectra analysis to identify early-stage epithelial ovarian cancer. Sci Rep 2024; 14:20000. [PMID: 39198565 PMCID: PMC11358426 DOI: 10.1038/s41598-024-70228-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 08/14/2024] [Indexed: 09/01/2024] Open
Abstract
Epithelial ovarian cancer (EOC) is widely recognized as the most lethal gynecological malignancy; however, its early-stage detection remains a considerable clinical challenge. To address this, we have introduced a new method, named Comprehensive Serum Glycopeptide Spectral Analysis (CSGSA), which detects early-stage cancer by combining glycan alterations in serum glycoproteins with tumor markers. We detected 1712 glycopeptides using liquid chromatography-mass spectrometry from the sera obtained from 564 patients with EOC and 1149 controls across 13 institutions. Furthermore, we used a convolutional neural network to analyze the expression patterns of the glycopeptides and tumor markers. Using this approach, we successfully differentiated early-stage EOC (Stage I) from non-EOC, with an area under the curve (AUC) of 0.924 in receiver operating characteristic (ROC) analysis. This method markedly outperforms conventional tumor markers, including cancer antigen 125 (CA125, 0.842) and human epididymis protein 4 (HE4, 0.717). Notably, our method exhibited remarkable efficacy in differentiating early-stage ovarian clear cell carcinoma from endometrioma, achieving a ROC-AUC of 0.808, outperforming CA125 (0.538) and HE4 (0.557). Our study presents a promising breakthrough in the early detection of EOC through the innovative CSGSA method. The integration of glycan alterations with cancer-related tumor markers has demonstrated exceptional diagnostic potential.
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Affiliation(s)
- Mikio Mikami
- Department of Obstetrics and Gynecology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
| | - Kazuhiro Tanabe
- Medical Solution Promotion Department, Medical Solution Segment, LSI Medience Corporation, Itabashi-ku, Tokyo, Japan.
| | - Tadashi Imanishi
- Genome Diversity Research Center, Graduate School of Medicine, Tokai University, Isehara, Kanagawa, Japan
- Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan
- Institute of Medical Sciences, Tokai University, Isehara, Kanagawa, Japan
| | - Masae Ikeda
- Department of Obstetrics and Gynecology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Takeshi Hirasawa
- Department of Obstetrics and Gynecology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Miwa Yasaka
- Department of Obstetrics and Gynecology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Hiroko Machida
- Department of Obstetrics and Gynecology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Hiroshi Yoshida
- Department of Obstetrics and Gynecology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Masanori Hasegawa
- Department of Urology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Muneaki Shimada
- Department of Obstetrics and Gynecology, Tohoku University School of Medicine, Sendai, Miyagi, Japan
| | - Tomoyasu Kato
- Department of Gynecology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Shoichi Kitamura
- Department of Gynecology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Hisamori Kato
- Department of Gynecologic Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan
| | - Takuma Fujii
- Department of Obstetrics and Gynecology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Yoichi Kobayashi
- Department of Obstetrics and Gynecology, Faculty of Medicine, Kyorin University, Mitaka, Tokyo, Japan
| | - Nao Suzuki
- Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Kyoko Tanaka
- Department of Obstetrics and Gynecology, Toho University Ohashi Medical Center, Meguro-ku, Tokyo, Japan
| | - Isao Murakami
- Department of Obstetrics and Gynecology, Toho University Ohashi Medical Center, Meguro-ku, Tokyo, Japan
| | - Tomoko Katahira
- Medical Solution Promotion Department, Medical Solution Segment, LSI Medience Corporation, Itabashi-ku, Tokyo, Japan
| | - Chihiro Hayashi
- Medical Solution Promotion Department, Medical Solution Segment, LSI Medience Corporation, Itabashi-ku, Tokyo, Japan
| | - Koji Matsuo
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
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Siu WYS, Ding DC. Ischemic stroke with concomitant clear cell carcinoma of the ovary: A case report and review of literature. World J Clin Cases 2024; 12:4397-4404. [PMID: 39015920 PMCID: PMC11235548 DOI: 10.12998/wjcc.v12.i20.4397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/13/2024] [Accepted: 05/24/2024] [Indexed: 06/30/2024] Open
Abstract
BACKGROUND Ischemic stroke is a rare event associated with an elevated risk of blood clot formation owing to an underlying malignancy. Herein, we present a case of ovarian carcinoma that led to cerebral infarction. CASE SUMMARY A 43-year-old woman experienced sudden onset right-sided paralysis and difficulty speaking two days after discovery of a large ovarian tumor measuring approximately 14 cm, which was suspected to be malignant. Further examination revealed left middle cerebral artery infarction. The patient had a history of hypertension and adenomyosis. Following stabilization with heparin treatment and vital signs management, the patient underwent debulking surgery, including total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and bilateral pelvic and para-aortic lymph node dissection. The final diagnosis was clear cell carcinoma of the right ovary (stage IA). Subsequently, the patient completed six rounds of adjuvant chemotherapy while simultaneously undergoing rehabilitation. Presently, the patient is able to walk independently, although she still experiences aphasia. CONCLUSION Prompt medical intervention and interdisciplinary care are crucial in the setting of incidental findings such as a large ovarian tumor.
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Affiliation(s)
- Wing Yu Sharon Siu
- Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Hualien 970, Taiwan
| | - Dah-Ching Ding
- Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan
- Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan
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Lee C, Chiang C, Tai Y, Hsu H, Chen Y, Chiang Y, Wu C, Lee W, Hwa H, Cheng W. Outcomes after fertility-sparing surgery of early-stage ovarian cancer: A nationwide population-based study. Cancer Med 2024; 13:e7132. [PMID: 38606892 PMCID: PMC11010646 DOI: 10.1002/cam4.7132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/26/2023] [Accepted: 03/12/2024] [Indexed: 04/13/2024] Open
Abstract
BACKGROUND Fertility-sparing surgery (FSS) is an alternative choice of young patients who have not completed their family planning and still have fertility needs. The aims of this study were to compare the outcomes of early-stage epithelial ovarian cancer (EOC) patients undergoing FSS and radical comprehensive staging surgery (RCS), and the suitability of FSS. METHODS A total of 1297 patients aged between 20 and 44 years with newly diagnosed early-stage EOC were recruited from the Taiwan Cancer Registry database between 2009 and 2017. Site-specific surgery codes were used to distinguish patients in FSS group or RCS group. Cancer-specific survival (CSS) was evaluated using Kaplan-Meier method with log-rank test and Cox regression model. RESULTS There were 401 and 896 patients in FSS and RCS group. Patients in FSS group were with younger age and mostly had Stage I disease. In contrast, patients in RCS group were older. There were more Stage II, high-grade (Grade 3) disease, and adjuvant chemotherapy in RCS group. Stage and tumor grade were two independent factors correlating with CSS and the type of surgery showed no effect on CSS (HR: 1.09, 95% CI: 0.66-1.77, p = 0.73) in multivariable analysis. In multivariable analysis, the clear cell carcinoma group who underwent FSS demonstrated better CSS compared to those in the RCS group (HR: 0.28, 95% CI: 0.06-0.82, p = 0.04). A total of 17 women who underwent FSS developed second malignancies of the uterine corpus or contralateral ovary. CONCLUSION FSS can be a safe alternative procedure in selected young patients of Stage I EOC who have fertility desire. Endometrial biopsy before or during FSS and regular surveillance to detect recurrence are mandatory for ovarian cancer patients undergoing FSS.
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Affiliation(s)
- Chia‐Yi Lee
- Department of Obstetrics and GynecologyNational Taiwan University Hospital, Hsin‐Chu BranchHsinchuTaiwan
- Department of Obstetrics and GynecologyNational Taiwan University HospitalTaipeiTaiwan
| | - Chun‐Ju Chiang
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public HealthNational Taiwan UniversityTaipeiTaiwan
- Taiwan Cancer RegistryTaipeiTaiwan
| | - Yi‐Jou Tai
- Department of Obstetrics and GynecologyNational Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Clinical Medicine, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Heng‐Cheng Hsu
- Department of Obstetrics and GynecologyNational Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Clinical Medicine, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Yu‐Li Chen
- Department of Obstetrics and GynecologyNational Taiwan University HospitalTaipeiTaiwan
- Department of Obstetrics and GynecologyNational Taiwan University HospitalDouliouTaiwan
| | - Ying‐Cheng Chiang
- Department of Obstetrics and GynecologyNational Taiwan University HospitalTaipeiTaiwan
| | - Chia‐Ying Wu
- Department of Obstetrics and GynecologyNational Taiwan University HospitalTaipeiTaiwan
- Department of Obstetrics and GynecologyNantou Hospital of the Ministry of Health and WelfareNantou CityTaiwan
| | - Wen‐Chung Lee
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public HealthNational Taiwan UniversityTaipeiTaiwan
- Taiwan Cancer RegistryTaipeiTaiwan
| | - Hsiao‐Lin Hwa
- Department of Obstetrics and GynecologyNational Taiwan University HospitalTaipeiTaiwan
- Department and Graduate Institute of Forensic Medicine, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Wen‐Fang Cheng
- Department of Obstetrics and GynecologyNational Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of Clinical Medicine, College of MedicineNational Taiwan UniversityTaipeiTaiwan
- Graduate Institute of Oncology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
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Liu Z, Jing C, Kong F. From clinical management to personalized medicine: novel therapeutic approaches for ovarian clear cell cancer. J Ovarian Res 2024; 17:39. [PMID: 38347608 PMCID: PMC10860311 DOI: 10.1186/s13048-024-01359-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 01/26/2024] [Indexed: 02/15/2024] Open
Abstract
Ovarian clear-cell cancer is a rare subtype of epithelial ovarian cancer with unique clinical and biological features. Despite optimal cytoreductive surgery and platinum-based chemotherapy being the standard of care, most patients experience drug resistance and a poor prognosis. Therefore, novel therapeutic approaches have been developed, including immune checkpoint blockade, angiogenesis-targeted therapy, ARID1A synthetic lethal interactions, targeting hepatocyte nuclear factor 1β, and ferroptosis. Refining predictive biomarkers can lead to more personalized medicine, identifying patients who would benefit from chemotherapy, targeted therapy, or immunotherapy. Collaboration between academic research groups is crucial for developing prognostic outcomes and conducting clinical trials to advance treatment for ovarian clear-cell cancer. Immediate progress is essential, and research efforts should prioritize the development of more effective therapeutic strategies to benefit all patients.
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Affiliation(s)
- Zesi Liu
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, Liaoning Province, China
| | - Chunli Jing
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116000, Liaoning Province, China
| | - Fandou Kong
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, Liaoning Province, China.
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Yang SL, Si LH, Lin RX, Gu SY, Li JH, Cui JZ, Yan CH, Farah AM, Jia Y. Prognostic role of the peritoneal cancer index in ovarian cancer patients who undergo cytoreductive surgery: a meta-analysis. Curr Probl Cancer 2023; 47:101014. [PMID: 37718231 DOI: 10.1016/j.currproblcancer.2023.101014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 08/13/2023] [Accepted: 08/24/2023] [Indexed: 09/19/2023]
Abstract
Advanced-stage ovarian cancer is usually associated with peritoneal carcinomatosis. This study evaluates the prognostic role of the Peritoneal Cancer Index (PCI) in predicting the survival of patients with ovarian cancer. A literature search was conducted in electronic databases (Google Scholar, PubMed, Ovid, and Science Direct) and study selection was based on precise eligibility criteria. Random-effects meta-analyses were performed to estimate survival with low and high PCI scores and to pool hazard ratios (HR) of survival between lower and higher PCI scores. A total of 20 studies (2588 patients) were included. Median follow-up was 39 months [95%CI: 25, 54]. Complete cytoreduction rate was 80% [95% CI: 73, 87]. The median PCI score was 11.3 [95% CI: 9.9, 12.7]. Median survival was 56.7 months [95% CI: 45.2, 68.2] with below and 28.8 months [95% CI: 23.0, 34.6] with above any PCI cutoff. Most studies used PCI cutoffs between 10 and 20. The median progression-free survival was 23.7 months [95% CI: 16.5, 30.8] with below and 11.9 months [95% CI: 5.9, 17.9] with above any PCI cutoff. 5-year survival rates were 61.3% [95% CI: 49.9, 72.8] with PCI<10 cutoffs, 21.7% [95% CI: 11.6, 31.8] with PCI>10 cutoffs, 50.1% [95% CI: 39.0, 61.2] with PCI<20 cutoffs, and 21.7% [95% CI: 16.2, 27.1] with PCI>20 cutoffs. Pooled analysis of HRs showed that a higher PCI score was associated with worse survival in both univariate (HR 2.14 [95%CI: 1.63, 2.66]) and multivariate (HR 1.10 [95% CI: 1.02, 1.18]) analyses. In a set of studies that used varying PCI cutoffs, the PCI has been found to have a significant inverse association with the survival of patients with advanced ovarian cancer who underwent cytoreductive surgery.
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Affiliation(s)
- Shu-Li Yang
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, ChangChun City, Jilin Province, China
| | - Li-Hui Si
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, ChangChun City, Jilin Province, China
| | - Rui-Xin Lin
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, ChangChun City, Jilin Province, China
| | - Shi-Yu Gu
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, ChangChun City, Jilin Province, China
| | - Jia-Hui Li
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, ChangChun City, Jilin Province, China
| | - Jun-Ze Cui
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, ChangChun City, Jilin Province, China
| | - Chu-Han Yan
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, ChangChun City, Jilin Province, China
| | - Abdulkarim Mohamed Farah
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, ChangChun City, Jilin Province, China
| | - Yan Jia
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, ChangChun City, Jilin Province, China.
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10
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Fujiwara S. Clinical perspectives of rare ovarian tumors: clear cell ovarian cancer. Jpn J Clin Oncol 2023; 53:664-672. [PMID: 37288485 DOI: 10.1093/jjco/hyad057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 05/16/2023] [Accepted: 05/20/2023] [Indexed: 06/09/2023] Open
Abstract
Ovarian clear cell carcinoma (OCCC) is a rare and distinct histological type of epithelial ovarian carcinoma in terms of its histopathological, clinical and genetic features. Patients with OCCC are younger and diagnosed at earlier stages than those with the most common histological type-high-grade serous carcinoma. Endometriosis is considered a direct precursor of OCCC. Based on preclinical data, the most frequent gene alternations in OCCC are mutations of AT-rich interaction domain 1A and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha. The prognosis of patients with early-stage OCCC is favorable, whereas patients at an advanced stage or who have the recurrent disease have a dismal prognosis due to OCCC's resistance to standard platinum-based chemotherapy. Despite a lower rate of response due to its resistance to standard platinum-based chemotherapy, the treatment strategy for OCCC resembles that of high-grade serous carcinoma, which includes aggressive cytoreductive surgery and adjuvant platinum-based chemotherapy. Alternative treatment strategies, including biological agents based on molecular characteristics specific to OCCC, are urgently needed. Furthermore, due to its rarity, well-designed collaborative international clinical trials are needed to improve oncologic outcomes and the quality of life in patients with OCCC.
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Affiliation(s)
- Satoe Fujiwara
- Department of Obstetrics and Gynecology, Osaka Medical and Pharmaceutical University, Osaka, Japan
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11
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Batista MDP, Roffé M, Romero I, López-Guerrero JA, Illueca C, Lopez R, Balieiro Anastácio da Costa AA, De Brot L, Molina JP, Barboza L, Peria FM, Chaud F, Gouvêa Yamada AS, Poveda A, Rego EM. Genomic landscapes of ovarian clear cell carcinoma from latin countries reveal aberrations linked to survival and progression. BMC Cancer 2023; 23:613. [PMID: 37400764 DOI: 10.1186/s12885-023-11095-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 06/21/2023] [Indexed: 07/05/2023] Open
Abstract
BACKGROUND Ovarian clear cell carcinomas (OCCCs) are rare, aggressive and chemoresistant tumors. Geographical and ethnic differences in the incidence of OCCC have been reported with a higher incidence in Asiatic countries. There is a paucity of information regarding OCCC in Latin America (LA) and other countries. METHODS Here, we characterized two cohorts of 33 patients with OCCC from LA (24 from Brazil and 9 from Costa Rica) and a cohort of 27 patients from Spain. Genomic analysis was performed for 26 OCCC using the OncoScan platform. Tumors were classified according to their genomic landscapes into subgroups. Clinical parameters were related to the frequency of genomic aberrations. RESULTS The median overall survival (OS) was not significantly different between the cohorts. Genomic landscapes were characterized by different homologous recombination deficiency (HRD) levels. No difference in the distribution of genomic landscapes profiles was detected between patients from the different cohorts. OCCCs with MYC-amplified tumors harboring a concomitant loss of a region in chromosome 13q12-q13 that includes the BRCA2 gene had the longest OS. In contrast, patients carrying a high number (> 30) of total copy number (CN) aberrations with no concomitant alterations in MYC and BRCA2 genes presented the shortest OS. Furthermore, amplification of the ASH1L gene was also associated with a shorter OS. Initial-stage OCCCs with early progression were characterized by gains in the JNK1 and MKL1 genes. CONCLUSIONS Our results provide new data from understudied OCCC populations and reveal new potential markers for OCCCs.
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Affiliation(s)
- Mariana de Paiva Batista
- Department of Internal Medicine, Medical School of Ribeirão Preto and Center for Cell Based Therapy, University of São Paulo, 14051-140, Tenente Catao Roxo, 2501, Ribeirão Preto, Brazil.
| | - Martín Roffé
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
| | - Ignacio Romero
- Gynecological Oncology Area, Valencian Institute of Oncology Foundation, Valencia, Spain
| | | | - Carmen Illueca
- Gynecological Oncology Area, Valencian Institute of Oncology Foundation, Valencia, Spain
| | - Raquel Lopez
- Gynecological Oncology Area, Valencian Institute of Oncology Foundation, Valencia, Spain
| | | | - Louise De Brot
- Department of Pathology, A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Juan Pablo Molina
- Medical Oncology Service, México Hospital, CCSS, San José, Costa Rica
| | - Laura Barboza
- Pathological Anatomy Service, San Juan de Dios Hospital, San José, Costa Rica
| | - Fernanda Maris Peria
- Department of Internal Medicine, Medical School of Ribeirão Preto and Center for Cell Based Therapy, University of São Paulo, 14051-140, Tenente Catao Roxo, 2501, Ribeirão Preto, Brazil
| | - Fernando Chaud
- Department of Internal Medicine, Medical School of Ribeirão Preto and Center for Cell Based Therapy, University of São Paulo, 14051-140, Tenente Catao Roxo, 2501, Ribeirão Preto, Brazil
| | - Ana Silvia Gouvêa Yamada
- Department of Internal Medicine, Medical School of Ribeirão Preto and Center for Cell Based Therapy, University of São Paulo, 14051-140, Tenente Catao Roxo, 2501, Ribeirão Preto, Brazil
| | - Andres Poveda
- Oncogynecologic Department, Quironsalud Hospital, Valencia, Spain
| | - Eduardo Magalhães Rego
- Department of Internal Medicine, Medical School of Ribeirão Preto and Center for Cell Based Therapy, University of São Paulo, 14051-140, Tenente Catao Roxo, 2501, Ribeirão Preto, Brazil
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12
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Ren J, Mao L, Zhao J, Li XL, Wang C, Liu XY, Jin ZY, He YL, Li Y, Xue HD. Seeing beyond the tumor: computed tomography image-based radiomic analysis helps identify ovarian clear cell carcinoma subtype in epithelial ovarian cancer. LA RADIOLOGIA MEDICA 2023:10.1007/s11547-023-01666-x. [PMID: 37368228 DOI: 10.1007/s11547-023-01666-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 06/14/2023] [Indexed: 06/28/2023]
Abstract
OBJECTIVE To develop and validate a model that can preoperatively identify the ovarian clear cell carcinoma (OCCC) subtype in epithelial ovarian cancer (EOC) using CT imaging radiomics and clinical data. MATERIAL AND METHODS We retrospectively analyzed data from 282 patients with EOC (training set = 225, testing set = 57) who underwent pre-surgery CT examinations. Patients were categorized into OCCC or other EOC subtypes based on postoperative pathology. Seven clinical characteristics (age, cancer antigen [CA]-125, CA-199, endometriosis, venous thromboembolism, hypercalcemia, stage) were collected. Primary tumors were manually delineated on portal venous-phase images, and 1218 radiomic features were extracted. The F-test-based feature selection method and logistic regression algorithm were used to build the radiomic signature, clinical model, and integrated model. To explore the effects of integrated model-assisted diagnosis, five radiologists independently interpreted images in the testing set and reevaluated cases two weeks later with knowledge of the integrated model's output. The diagnostic performances of the predictive models, radiologists, and radiologists aided by the integrated model were evaluated. RESULTS The integrated model containing the radiomic signature (constructed by four wavelet radiomic features) and three clinical characteristics (CA-125, endometriosis, and hypercalcinemia), showed better diagnostic performance (AUC = 0.863 [0.762-0.964]) than the clinical model (AUC = 0.792 [0.630-0.953], p = 0.295) and the radiomic signature alone (AUC = 0.781 [0.636-0.926], p = 0.185). The diagnostic sensitivities of the radiologists were significantly improved when using the integrated model (p = 0.023-0.041), while the specificities and accuracies were maintained (p = 0.074-1.000). CONCLUSION Our integrated model shows great potential to facilitate the early identification of the OCCC subtype in EOC, which may enhance subtype-specific therapy and clinical management.
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Affiliation(s)
- Jing Ren
- Department of Radiology, Chinese Academy of Medical Sciences & Peking Union Medical College, Peking Union Medical College Hospital, Shuai Fu Yuan 1, Dongcheng District, Beijing, 100730, People's Republic of China
| | - Li Mao
- AI Lab, Deepwise Healthcare, Beijing, People's Republic of China
| | - Jia Zhao
- Department of Radiology, Chinese Academy of Medical Sciences & Peking Union Medical College, Peking Union Medical College Hospital, Shuai Fu Yuan 1, Dongcheng District, Beijing, 100730, People's Republic of China
| | - Xiu-Li Li
- AI Lab, Deepwise Healthcare, Beijing, People's Republic of China
| | - Chen Wang
- Department of Radiology, Chinese Academy of Medical Sciences & Peking Union Medical College, Peking Union Medical College Hospital, Shuai Fu Yuan 1, Dongcheng District, Beijing, 100730, People's Republic of China
| | - Xin-Yu Liu
- Department of Radiology, Chinese Academy of Medical Sciences & Peking Union Medical College, Peking Union Medical College Hospital, Shuai Fu Yuan 1, Dongcheng District, Beijing, 100730, People's Republic of China
| | - Zheng-Yu Jin
- Department of Radiology, Chinese Academy of Medical Sciences & Peking Union Medical College, Peking Union Medical College Hospital, Shuai Fu Yuan 1, Dongcheng District, Beijing, 100730, People's Republic of China
| | - Yong-Lan He
- Department of Radiology, Chinese Academy of Medical Sciences & Peking Union Medical College, Peking Union Medical College Hospital, Shuai Fu Yuan 1, Dongcheng District, Beijing, 100730, People's Republic of China.
| | - Yuan Li
- Department of Obstetrics and Gynecology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Beijing, People's Republic of China.
| | - Hua-Dan Xue
- Department of Radiology, Chinese Academy of Medical Sciences & Peking Union Medical College, Peking Union Medical College Hospital, Shuai Fu Yuan 1, Dongcheng District, Beijing, 100730, People's Republic of China.
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13
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Huang RYJ, Huang KJ, Chen KC, Hsiao SM, Tan TZ, Wu CJ, Hsu C, Chang WC, Pan CY, Sheu BC, Wei LH. Immune-Hot tumor features associated with recurrence in early-stage ovarian clear cell carcinoma. Int J Cancer 2023; 152:2174-2185. [PMID: 36629283 DOI: 10.1002/ijc.34428] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/03/2022] [Accepted: 12/16/2022] [Indexed: 01/12/2023]
Abstract
Ovarian clear cell carcinoma (OCCC) is a distinct histotype of ovarian cancer, which usually presages a worse prognosis upon recurrence. Identifying patients at risk for relapse is an unmet need to improve outcomes. A retrospective cohort analysis of 195 early-stage OCCC patients diagnosed between January 2011 and December 2019 at National Taiwan University Hospital was conducted to identify prognostic factors for recurrence, progression-free survival (PFS) and overall survival (OS). Molecular profiling of tumors was performed in a case-controlled cohort matched for adjuvant therapy for biomarker discovery. Multivariate Cox proportional hazard model revealed that paclitaxel-based chemotherapy was associated with better PFS than nonpaclitaxel chemotherapy (HR = 0.19, P = .006). The addition of bevacizumab was associated with better PFS, compared to no bevacizumab (HR = 0.09, P = .02). Neither showed significant improvement in OS. Recurrence is associated with an Immune-Hot tumor feature (P = .03), the CTLA-4-high subtype (P = .01) and increased infiltration of immune cells in general. The Immune-Hot feature (HR = 3.39, P = .005) and the CTLA-4-high subtype (HR = 2.13, P = .059) were associated with worse PFS. Immune-Hot tumor features could prognosticate recurrence in early-stage OCCC.
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Affiliation(s)
- Ruby Yun-Ju Huang
- School of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Kuan-Ju Huang
- Department of Obstetrics and Gynecology, National Taiwan University Hospital & National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Hospital Yunlin Branch, Douliu City, Taiwan
| | - Ko-Chen Chen
- School of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Sheng-Mou Hsiao
- Department of Obstetrics and Gynecology, Far Eastern Memorial Hospital, New Taipei, Taiwan.,Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan, Taiwan
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, Singapore
| | - Chin-Jui Wu
- National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan
| | - Ching Hsu
- Department of Obstetrics and Gynecology, National Taiwan University Hospital & National Taiwan University College of Medicine, Taipei, Taiwan
| | - Wen-Chun Chang
- Department of Obstetrics and Gynecology, National Taiwan University Hospital & National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chen-Yu Pan
- Department of Obstetrics and Gynecology, National Taiwan University Hospital & National Taiwan University College of Medicine, Taipei, Taiwan
| | - Bor-Ching Sheu
- Department of Obstetrics and Gynecology, National Taiwan University Hospital & National Taiwan University College of Medicine, Taipei, Taiwan
| | - Lin-Hung Wei
- Department of Obstetrics and Gynecology, National Taiwan University Hospital & National Taiwan University College of Medicine, Taipei, Taiwan
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14
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Abstract
Ovarian clear cell carcinoma is a rare subtype of epithelial ovarian cancer with unique clinicopathological features. The most common genetic aberration observed is loss of function ARID1A mutations. Advanced and recurrent ovarian clear cell carcinoma is characterized by resistance to standard-of-care cytotoxic chemotherapy and a poor prognosis. Despite the distinct molecular features of ovarian clear cell carcinoma, current treatments for this subtype of epithelial ovarian cancer are based on clinical trials which predominantly recruited patients with high grade serous ovarian carcinoma. These factors have encouraged researchers to develop novel treatment strategies specifically for ovarian clear cell carcinoma which are currently being tested in the context of clinical trials. These new treatment strategies currently focus on three key areas: immune checkpoint blockade, targeting angiogenesis, and exploiting ARID1A synthetic lethal interactions. Rational combinations of these strategies are being assessed in clinical trials. Despite the progress made in identifying new treatments for ovarian clear cell carcinoma, predictive biomarkers to better define those patients likely to respond to new treatments remain to be elucidated. Additional future challenges which may be addressed through international collaboration include the need for randomized trials in a rare disease and establishing the relative sequencing of these novel treatments.
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Affiliation(s)
- James Stewart
- Royal Marsden Hospital NHS Trust, London, UK
- Gene Function Laboratory, Insitute of Cancer Research, London, UK
| | | | - Susana Banerjee
- Royal Marsden Hospital NHS Trust, London, UK
- Division of Clinical Studies, Institute of Cancer Research, London, UK
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15
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Devlin MJ, Miller RE. Disparity in the era of personalized medicine for epithelial ovarian cancer. Ther Adv Med Oncol 2023; 15:17588359221148024. [PMID: 36643655 PMCID: PMC9837277 DOI: 10.1177/17588359221148024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 12/12/2022] [Indexed: 01/13/2023] Open
Abstract
The treatment of high-grade serous ovarian cancer and high-grade endometrioid ovarian cancer has seen significant improvements in recent years, with BRCA1/2 and homologous recombination status guiding a personalized approach which has resulted in improved patient outcomes. However, for other epithelial ovarian cancer subtypes, first-line treatment remains unchanged from the platinum-paclitaxel trials of the early 2000s. In this review, we explore novel therapeutic approaches being adopted in the treatment of clear cell, mucinous, carcinosarcoma and low-grade serous ovarian cancer and the biological rational behind them. We discuss why such disparities exist, the challenges faced in conducting dedicated trials in these rarer histologies and look towards new approaches being adopted to overcome them.
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Affiliation(s)
| | - Rowan E. Miller
- Department of Medical Oncology, St Bartholomew’s Hospital, London, UK,Department of Medical Oncology, University College London Hospital, London, UK
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16
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Zhuang Y, Yang H. The Significance of Radiotherapy in Ovarian Clear Cell Carcinoma: A Systematic Review and Meta-Analysis. Cancer Control 2023; 30:10732748231179291. [PMID: 37236911 DOI: 10.1177/10732748231179291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2023] Open
Abstract
OBJECTIVE To assess the response rate and survival effect of adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) during ovarian clear cell carcinoma (OCCC). METHODS We searched Web of Science, PubMed, Cochrane library electronic databases, Clinical Trials, WanFang Data and Chinese National Knowledge Infrastructure (CNKI) up to October 2022. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. RESULTS We identified a total of 4259 patients from 14 studies met the inclusion criteria. The pooled response rate of residual tumors for RT/CRT was 80.0%, the pooled 5-year progression-free survival (PFS) ratio during RT/CRT group was 61.0%, and the pooled 5-year overall survival (OS) ratio during RT/CRT group was 68.0%; heterogeneity tests demonstrated significant difference between studies (I2 >50%). Cumulative results suggested adjuvant RT/CRT improved 5-year PFS ratio of OCCC patients (OR: 0.51 (95% CI: 0.42-.88), I2 = 22%, P = .009), had no impact on 5-year OS ratio (OR: 0.52 (95% CI: 0.19-1.44), I2 = 87%, P = .21); meta-regression of studies before and after 2000 found consistent results. Sub-analysis observed that adjuvant RT/CRT had no impact on 5-year OS ratio of early-stage (stage I + II) OCCC patients (OR: 0.67 (95% CI: 0.25-1.83), I2 = 85%, P = .44), but might improve 5-year OS ratio of advanced and recurrent OCCC patients (OR: 0.13(95% CI: 0.04-.44), P = .001). CONCLUSION This analysis suggested that adjuvant RT/CRT might improve oncologic outcomes of OCCC, especially for advanced and recurrent cases. Due to the inherent selective biases of retrospective studies enrolled in the meta-analysis, more convincing evidences based on prospective randomized controlled trials (RCTs) are urgently needed.
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Affiliation(s)
- Yuan Zhuang
- Department of Gynecology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Hua Yang
- Department of Gynecology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
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17
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Atiya HI, Frisbie L, Goldfeld E, Orellana T, Donnellan N, Modugno F, Calderon M, Watkins S, Zhang R, Elishaev E, Soong TR, Vlad A, Coffman L. Endometriosis-Associated Mesenchymal Stem Cells Support Ovarian Clear Cell Carcinoma through Iron Regulation. Cancer Res 2022; 82:4680-4693. [PMID: 36219681 PMCID: PMC9755968 DOI: 10.1158/0008-5472.can-22-1294] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 08/31/2022] [Accepted: 10/07/2022] [Indexed: 01/24/2023]
Abstract
Ovarian clear cell carcinoma (OCCC) is a deadly and treatment-resistant cancer, which arises within the unique microenvironment of endometriosis. In this study, we identified a subset of endometriosis-derived mesenchymal stem cells (enMSC) characterized by loss of CD10 expression that specifically support OCCC growth. RNA sequencing identified alterations in iron export in CD10-negative enMSCs and reciprocal changes in metal transport in cocultured OCCC cells. CD10-negative enMSCs exhibited elevated expression of iron export proteins hephaestin and ferroportin and donate iron to associated OCCCs, functionally increasing the levels of labile intracellular iron. Iron is necessary for OCCC growth, and CD10-negative enMSCs prevented the growth inhibitory effects of iron chelation. In addition, enMSC-mediated increases in OCCC iron resulted in a unique sensitivity to ferroptosis. In vitro and in vivo, treatment with the ferroptosis inducer erastin resulted in significant death of cancer cells grown with CD10-negative enMSCs. Collectively, this work describes a novel mechanism of stromal-mediated tumor support via iron donation. This work also defines an important role of endometriosis-associated MSCs in supporting OCCC growth and identifies a critical therapeutic vulnerability of OCCC to ferroptosis based on stromal phenotype. SIGNIFICANCE Endometriosis-derived mesenchymal stem cells support ovarian clear cell carcinoma via iron donation necessary for cancer growth, which also confers sensitivity to ferroptosis-inducing therapy.
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Affiliation(s)
- Huda I. Atiya
- Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Leonard Frisbie
- Department of Integrative Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ester Goldfeld
- University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Taylor Orellana
- Division of Gynecologic Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Nicole Donnellan
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Francesmary Modugno
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Michael Calderon
- Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Simon Watkins
- Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Rugang Zhang
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Esther Elishaev
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Thing Rinda Soong
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Anda Vlad
- Division of Gynecologic Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Lan Coffman
- Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.,Division of Gynecologic Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Corresponding Author: Lan Coffman, Department of Medicine, University of Pittsburgh Medical Center, 204 Craft Avenue, Pittsburgh, PA, 15213. E-mail:
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18
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Farley JH, Brady WE, O'Malley D, Fujiwara K, Yonemori K, Bonebrake A, Secord AA, Stephan JM, Walker JL, Nam JH, Birrer MJ, Gershenson DM. A phase II evaluation of temsirolimus with carboplatin and paclitaxel followed by temsirolimus consolidation in clear cell ovarian cancer: An NRG oncology trial. Gynecol Oncol 2022; 167:423-428. [PMID: 36244829 PMCID: PMC9789681 DOI: 10.1016/j.ygyno.2022.10.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/06/2022] [Accepted: 10/07/2022] [Indexed: 11/04/2022]
Abstract
OBJECTIVE The primary objective of the study was to estimate the 12-month progression-free survival (PFS) for carboplatin/paclitaxel + temsirolimus in women with newly diagnosed clear cell ovarian cancer (CCOC), compared to historical controls in this patient population. METHODS Patients with Stage III or IV CCOC were treated with Paclitaxel 175 mg/m2 on Day 1, Carboplatin AUC 6 Day 1, and temsirolimus (CCI-779) 25 mg IV Days 1 and 8 every 3 weeks for Cycles 1-6 or disease progression, followed by consolidation therapy with temsirolimus 25 mg Days 1, 8, and 15 every 3 weeks cycles 7-17 or until disease progression. RESULTS Ninety patients were accrued to the study: 45 in the US and Korea (US/Korea) and 45 in Japan. Twenty-two percent received ≤6 cycles of therapy while 28% completed all 17 cycles of chemotherapy. Median PFS (OS) was 11 (23) months for US/Korea and 12 (26) months for Japan. In the US, none of suboptimally debulked patients had PFS >12 months, and 49% of optimal patients did, compared to 25% and 59% in Japan. Most common grade 3-4 adverse events were neutropenia, leukopenia, anemia, thrombocytopenia, hypertension, hypertriglyceridemia, and oral mucositis. CONCLUSION The carboplatin/paclitaxel + temsirolimus regimen was well tolerated. In optimally debulked patients, 54% had a PFS >12 months. This regimen did not statistically significantly increase PFS at 12 months compared to historical controls. No statistically significant differences in PFS or OS were observed between US/Korea vs Japan, or Asians vs non-Asians.
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Affiliation(s)
- John H Farley
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
| | - William E Brady
- NRG Oncology, Clinical Trial Development Division, Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | | | | | - Kan Yonemori
- National Cancer Center Hospital, 5 Chome-1 - 1 Tsukiji, Chuo City, Tokyo 104-0045, Japan.
| | - Albert Bonebrake
- Cancer Research for the Ozarks-Cox Health, Springfield, MO, USA.
| | | | | | - Joan L Walker
- University of Oklahoma, Oklahoma City, OK 73104, USA.
| | - Joo-Hyun Nam
- Asan Medical Center, University of Ulsan, Seoul 13876 05505, KR, Republic of Korea.
| | | | - David M Gershenson
- Dept. of Gynecologic Oncology, University of Texas, MD, USA; Anderson Cancer Center, Unit 1362, PO Box 301439, Houston, TX 77230-1439, USA.
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19
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Bolton KL, Chen D, Corona de la Fuente R, Fu Z, Murali R, Köbel M, Tazi Y, Cunningham JM, Chan IC, Wiley BJ, Moukarzel LA, Winham SJ, Armasu SM, Lester J, Elishaev E, Laslavic A, Kennedy CJ, Piskorz A, Sekowska M, Brand AH, Chiew YE, Pharoah P, Elias KM, Drapkin R, Churchman M, Gourley C, DeFazio A, Karlan B, Brenton JD, Weigelt B, Anglesio MS, Huntsman D, Gayther S, Konner J, Modugno F, Lawrenson K, Goode EL, Papaemmanuil E. Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes. Clin Cancer Res 2022; 28:4947-4956. [PMID: 35816189 PMCID: PMC9777703 DOI: 10.1158/1078-0432.ccr-21-3817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 02/24/2022] [Accepted: 07/07/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. EXPERIMENTAL DESIGN We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival. RESULTS We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy. CONCLUSIONS Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838.
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Affiliation(s)
- Kelly L. Bolton
- Washington University School of Medicine, St. Louis, Missouri
| | - Denise Chen
- Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania
| | | | - Zhuxuan Fu
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | | | - Martin Köbel
- The University of Calgary, Calgary, Alberta, Canada
| | - Yanis Tazi
- Memorial Sloan-Kettering Cancer Center, New York, New York
| | | | | | - Brian J. Wiley
- Washington University School of Medicine, St. Louis, Missouri
| | | | | | | | - Jenny Lester
- David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, California
| | - Esther Elishaev
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | - Angela Laslavic
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | - Catherine J. Kennedy
- Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia
- Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
| | - Anna Piskorz
- University of Cambridge, Cambridge, United Kingdom
| | | | - Alison H. Brand
- Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia
- The University of Sydney, Sydney, New South Wales, Australia
| | - Yoke-Eng Chiew
- Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia
- Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
| | - Paul Pharoah
- University of Cambridge, Cambridge, United Kingdom
| | | | - Ronny Drapkin
- University of Pennsylvania, Philadelphia, Pennsylvania
| | | | | | - Anna DeFazio
- Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia
- Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
- The University of Sydney, Sydney, New South Wales, Australia
- The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, New South Wales, Australia
| | - Beth Karlan
- David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, California
| | | | - Britta Weigelt
- Memorial Sloan-Kettering Cancer Center, New York, New York
| | | | - David Huntsman
- University of British Columbia, Vancouver, British Columbia, Canada
| | - Simon Gayther
- Cedars-Sinai Medical Center, Los Angeles, California
| | - Jason Konner
- Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Francesmary Modugno
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
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20
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Ma B, Zhao L, Zhang Y, Zhang F, Gao Q. Complete remission of ovarian clear cell carcinoma achieved after pseudoprogression during PD-1 inhibitor therapy. Immunotherapy 2022; 14:1205-1209. [PMID: 36043370 DOI: 10.2217/imt-2021-0328] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background: Ovarian clear cell carcinoma (OCCC), which is resistant to traditional treatment, has a poor prognosis. Immune checkpoint inhibitors (ICIs) have been emerged in the past decade and are now widely used in clinics. However, OCCC reportedly responds poorly to ICIs, and ICI monotherapy is rarely used for patients with OCCC. Methodology & Results: We report the case of a patient with refractory OCCC who received an ICI (nivolumab) monotherapy treatment and achieved a complete response despite the occurrence of pseudoprogression. Nivolumab was discontinued after 2 years, and the patient remained in complete remission more than a year after treatment withdrawal. Conclusion: This is the first report of complete remission being achieved in a case of refractory OCCC after pseudoprogression during nivolumab monotherapy.
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Affiliation(s)
- Baozhen Ma
- Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Lingdi Zhao
- Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Yong Zhang
- Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Fang Zhang
- Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Quanli Gao
- Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
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21
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Wu L, Shi S, Sun H, Zhang H. Tumor Size Is an Independent Prognostic Factor for Stage I Ovarian Clear Cell Carcinoma: A Large Retrospective Cohort Study of 1,000 Patients. Front Oncol 2022; 12:862944. [PMID: 35651798 PMCID: PMC9149085 DOI: 10.3389/fonc.2022.862944] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
Objective The aim of this study was to investigate the prognostic value and stratification cutoff point for tumor size in stage I ovarian clear cell carcinoma (OCCC). Methods This was a retrospective cohort study using the Surveillance, Epidemiology, and End Results database (version: SEER 8.3.9). Patients diagnosed with stage I OCCC from 1988 to 2018 were included for further analysis. X-Tile software was used to identify the potential cutoff point for tumor size. Stratification analysis, propensity score matching, and inverse probability weighting analysis were used to balance the potential confounding factors. Results A total of 1,000 stage I OCCC patients were included. Of these 1,000 patients, median follow-up was 106 months (95% confidence interval [CI]: 89-112 months). Multivariate analysis showed that tumor size, age at diagnosis, and stage IC were significantly associated with stage I OCCC patients. Eight centimeters is a promising cutoff point that can divide stage I OCCC patients into a good or a poor prognosis group. After controlling potential confounding factors with propensity score matching and inverse probability weighting, we demonstrated that stage I OCCC patients with tumor size ≤ 8 cm enjoyed a significantly better 5-year overall survival (OS, 89.8% vs. 81%, p < 0.0001). Tumor size ≤ 8 cm was an independent prognostic factor of stage I OCCC patients (hazard ratio [HR] 0.5608, 95% CI: 0.4126-0.7622, p = 0.0002). Conclusions Tumor size is an independent prognostic factor for stage I OCCC, and 8 cm is a promising cutoff point for tumor size for risk stratification. However, using tumor size in the stratification management of stage I OCCC patients warrants further investigation.
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Affiliation(s)
| | | | - Hong Sun
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Haiyan Zhang
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
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22
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Kim SI, Ha HI, Eoh KJ, Lim J, Won YJ, Lim MC. Trends in the Incidence and Survival Rates of Primary Ovarian Clear Cell Carcinoma Compared to Ovarian Serous Carcinoma in Korea. Front Oncol 2022; 12:874037. [PMID: 35463304 PMCID: PMC9021727 DOI: 10.3389/fonc.2022.874037] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 03/14/2022] [Indexed: 02/03/2023] Open
Abstract
Objective To compare the incidence and survival rates of primary ovarian clear cell carcinoma (OCCC) and ovarian serous carcinoma (OSC) from a nationwide collected database. Methods We extracted information of patients with primary OCCC and OSC from the Korea Central Cancer Registry recorded between 1999 and 2018, including age at diagnosis and the Surveillance, Epidemiology, and End Results summary stage. Age-standardized incidence rates (ASRs) and annual percent changes (APCs) were calculated. Baseline characteristics and overall survival (OS) were compared between the OCCC and OSC groups. Results Overall, the incidence rate of primary OCCC increased markedly from 1999 (ASR, 0.16/100,000) to 2018 (0.76/100,000) (APC, 7.85%; P<0.0001). Patients with OCCC were significantly younger and had early-stage disease more frequently than those with OSC. Patients diagnosed with OCCC before the age of 50 showed better OS than those diagnosed after the age of 50 (P=0.0048). The 5-year OS of the OCCC group did not differ by study period [73.5% (1999–2008) vs. 75.4% (2009–2018), P=0.3187], whereas the 5-year OS of the OSC group improved from 54.4% to 58% (P=0.0003). Conclusions Our nationwide registry-based study demonstrated that the incidence of OCCC in Korea increased significantly from 1999 to 2018. Early-stage OCCC had a relatively good prognosis, but advanced-stage OCCC had a worse OS than advanced-stage OSC. Therefore, the development of optimal treatment strategies for OCCC is warranted.
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Affiliation(s)
- Se Ik Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, South Korea
| | - Hyeong In Ha
- Department of Obstetrics and Gynecology, Pusan National University Yangsan Hospital, Yangsan, South Korea
| | - Kyung Jin Eoh
- Department of Obstetrics and Gynecology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, South Korea
| | - Jiwon Lim
- Division of Cancer Registration and Surveillance, National Cancer Center, Goyang, South Korea
| | - Young-Joo Won
- Division of Cancer Registration and Surveillance, National Cancer Center, Goyang, South Korea.,Department of Health Administration, Yonsei University, Wonju, South Korea
| | - Myong Cheol Lim
- Center for Gynecologic Cancer and Center for Clinical Trial, Hospital, National Cancer Center, Goyang, South Korea.,Department of Cancer Control and Policy, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, South Korea.,Rare & Pediatric Cancer Branch and Immuno-oncology Branch, Division of Rare and Refractory Cancer, Research Institute, National Cancer Center, Goyang, South Korea
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23
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Tamura R, Yoshihara K, Enomoto T. Therapeutic Strategies Focused on Cancer-Associated Hypercoagulation for Ovarian Clear Cell Carcinoma. Cancers (Basel) 2022; 14:2125. [PMID: 35565252 PMCID: PMC9099459 DOI: 10.3390/cancers14092125] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 04/22/2022] [Accepted: 04/23/2022] [Indexed: 02/04/2023] Open
Abstract
Ovarian clear cell carcinoma (OCCC) is associated with chemotherapy resistance and poor prognosis, especially in advanced cases. Although comprehensive genomic analyses have clarified the significance of genomic alterations such as ARID1A and PIK3CA mutations in OCCC, therapeutic strategies based on genomic alterations have not been confirmed. On the other hand, OCCC is clinically characterized by a high incidence of thromboembolism. Moreover, OCCC specifically shows high expression of tissue factor and interleukin-6, which play a critical role in cancer-associated hypercoagulation and may be induced by OCCC-specific genetic alterations or the endometriosis-related tumor microenvironment. In this review, we focused on the association between cancer-associated hypercoagulation and molecular biology in OCCC. Moreover, we reviewed the effectiveness of candidate drugs targeting hypercoagulation, such as tissue factor- or interleukin-6-targeting drugs, anti-inflammatory drugs, anti-hypoxia signaling drugs, anticoagulants, and combined immunotherapy with these drugs for OCCC. This review is expected to contribute to novel basic research and clinical trials for the prevention, early detection, and treatment of OCCC focused on hypercoagulation.
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Affiliation(s)
| | - Kosuke Yoshihara
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; (R.T.); (T.E.)
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24
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Incidence and predictive factors for recurrent clear cell ovarian carcinoma: results from a single center in Thailand. Obstet Gynecol Sci 2022; 65:188-196. [PMID: 35193175 PMCID: PMC8942748 DOI: 10.5468/ogs.21313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 01/05/2022] [Indexed: 12/02/2022] Open
Abstract
Objective We aimed to study the incidence and predictive factors of recurrent clear cell ovarian carcinoma (CCC) and evaluate the oncological outcomes after recurrence. Methods This was a retrospective study of 134 CCC cases diagnosed between 2005 and 2020. Clinicopathological data and oncological outcomes were extracted and evaluated. Patients with co-malignancy, mixed pathological type, or incomplete data were excluded. Descriptive statistics, univariate and multivariable analyses, and Kaplan-Meier survival probability estimates were completed. A proportional hazards model was used to assess the association between the prognostic factors with progression-free survival (PFS), overall survival (OS), and post-recurrence survival. Results A total of 134 patients with CCC were enrolled. The incidence of recurrent CCC was 33.6% (45/134). The median PFS was 12.8 months (95% confidence interval [CI], 9.66–18.9) in the recurrence group and 3.3 months (95% CI, 1.15–4.4) in the refractory group. Residual tumor from surgical outcome, ascites cytology, and lymphovascular space invasion (LVSI) were independent prognostic factors for PFS. The significant variables were residual tumor (sub-optimal surgery vs. optimal surgery) (hazard ratio [HR], 2.68; 95% CI, 1.48–4.87; P=0.002), ascites cytology (positive vs. negative) (HR, 2.8; 95% CI, 1.58–4.98; P=0.002), and LVSI (positive vs. negative) (HR, 2.14; 95% CI, 1.18–3.86; P=0.04). The median post-recurrence survival was 13.96 months (95% CI, 10.61–26.2) in the recurrence group. Conclusion CCC has a high rate of recurrence. Sub-optimal surgery, positive ascites cytology, and LVSI indicated a worse prognosis for PFS. Optimal cytoreductive surgery is an important part of primary treatment to improve survival in patients with CCC.
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25
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Lee EJ, Park SJ, Lee C, Yim GW, Kim JW, Kim HS. Hypoxia-induced Maspin Expression Affects the Prognosis of Ovarian Clear Cell Carcinoma. In Vivo 2022; 36:212-220. [PMID: 34972717 DOI: 10.21873/invivo.12693] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND/AIM To investigate the role of the expression of hypoxia-related genes on the prognosis of ovarian clear cell carcinoma (OCCC). MATERIALS AND METHODS Basal mRNA levels of eight hypoxia-related genes were compared. Cell viability was assayed after treating ES-2 cells under hypoxic conditions. The mRNA and protein levels were evaluated after the induction of hypoxia and administration of increased doses of N-acetylcysteine (NAC). Finally, the prognostic role of their expression levels was evaluated in 61 patients with OCCC. RESULTS The mRNA and protein levels of maspin increased gradually with the induction of hypoxia. Maspin protein expression decreased after treatment with paclitaxel and NAC. High expression of maspin was related to poor progression-free and overall survival in patients with OCCC (adjusted hazard ratios, 3.97 and 7.47; 95% confidence intervals=1.34-11.81, and 1.98-28.13). CONCLUSION High expression of maspin induced by hypoxia might be associated with poor prognosis of OCCC.
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Affiliation(s)
- Eun Ji Lee
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Soo Jin Park
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Cheol Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ga Won Yim
- Department of Obstetrics and Gynecology, Dongguk University College of Medicine, Goyang, Republic of Korea
| | - Jae Weon Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hee Seung Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea;
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26
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Yokomizo R, Lopes TJS, Takashima N, Hirose S, Kawabata A, Takenaka M, Iida Y, Yanaihara N, Yura K, Sago H, Okamoto A, Umezawa A. O3C Glass-Class: A Machine-Learning Framework for Prognostic Prediction of Ovarian Clear-Cell Carcinoma. Bioinform Biol Insights 2022. [DOI: 10.1177/11779322221134312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Ovarian clear cell carcinoma (OCCC), one of the histopathological types of ovarian cancer, has a poor prognosis when it recurs; however, it is difficult to precisely predict the risk of recurrence. Here, we analyzed pathological images of OCCC to elucidate the relationship between pathological findings and recurrence, and using machine learning, we established a classifier to predict the recurrence and several other prognosis indicators of this disease. In total, 110 patients with OCCC treated with primary surgery at a single institution were enrolled in this study. We used the deep-learning neural networks to process the whole slide images of OCCC obtained by digitally scanning the original hematoxylin and eosin-stained glass slides. The images were preprocessed and used as input to the machine learning pipeline. We fine-tuned its parameters to predict the recurrence, progression-free survival, and the overall survival days of all patients. We predicted the recurrence of OCCC with an overall accuracy of 93%, area under the receiver operating characteristic curve of 0.98, and sensitivity/specificity above 0.92 using Resnet 34. Furthermore, we predicted progression-free survival/overall survival of the patients with ~90% accuracy. In conclusion, our study demonstrates the feasibility of using a machine learning system to predict different features of OCCC samples using histopathological images as input. This novel application provides accurate prognosis information and aids in the development of personalized treatment strategies.
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Affiliation(s)
- Ryo Yokomizo
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Setagaya-ku, Japan
- Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Setagaya-ku, Japan
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Minato-ku, Japan
| | - Tiago JS Lopes
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Setagaya-ku, Japan
| | - Nagisa Takashima
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Setagaya-ku, Japan
- Divison of Life Sciences, Graduate School of Humanities and Sciences, Ochanomizu University, Bunkyo-ku, Japan
| | - Sou Hirose
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Minato-ku, Japan
| | - Ayako Kawabata
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Minato-ku, Japan
| | - Masataka Takenaka
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Minato-ku, Japan
| | - Yasushi Iida
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Minato-ku, Japan
| | - Nozomu Yanaihara
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Minato-ku, Japan
| | - Kei Yura
- Divison of Life Sciences, Graduate School of Humanities and Sciences, Ochanomizu University, Bunkyo-ku, Japan
- Department of Life Science & Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Shinjuku-ku, Japan
| | - Haruhiko Sago
- Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Setagaya-ku, Japan
| | - Aikou Okamoto
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Minato-ku, Japan
| | - Akihiro Umezawa
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Setagaya-ku, Japan
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27
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Sun Y, Liu G. Endometriosis-associated Ovarian Clear Cell Carcinoma: A Special Entity? J Cancer 2021; 12:6773-6786. [PMID: 34659566 PMCID: PMC8518018 DOI: 10.7150/jca.61107] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 09/12/2021] [Indexed: 02/06/2023] Open
Abstract
Endometriosis is an estrogen-dependent disease, which serves as a precursor of ovarian cancer, especially clear cell carcinoma (OCCC) and endometrial carcinoma. Although micro-environmental factors such as oxidative stress, immune cell dysfunction, inflammation, steroid hormones, and stem cells required for malignant transformation have been found in endometriosis, the exact carcinogenic mechanism remains unclear. Recent research suggest that many putative driver genes and aberrant pathways including ARID1A mutations, PIK3CA mutations, MET activation, HNF-1β activation, and miRNAs dysfunction, play crucial roles in the malignant transformation of endometriosis to OCCC. The clinical features of OCCC are different from other histological types. Patients usually present with a large, unilateral pelvic mass, and occasionally have thromboembolic vascular complications. OCCC patients are easier to be resistant to chemotherapy, have a worse prognosis, and are usually difficult to treat. To improve the survival of OCCC patients, it is necessary to better understand its specific carcinogenic mechanism and explore new treatment strategy, including molecular target.
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Affiliation(s)
- Yue Sun
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin, 300052, China
| | - Guoyan Liu
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin, 300052, China
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28
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Iida Y, Okamoto A, Hollis RL, Gourley C, Herrington CS. Clear cell carcinoma of the ovary: a clinical and molecular perspective. Int J Gynecol Cancer 2021; 31:605-616. [PMID: 32948640 DOI: 10.1136/ijgc-2020-001656] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 08/13/2020] [Accepted: 08/17/2020] [Indexed: 12/14/2022] Open
Abstract
Clear cell carcinoma of the ovary has distinct biology and clinical behavior. There are significant geographical and racial differences in the incidence of clear cell carcinoma compared with other epithelial ovarian tumors. Patients with clear cell carcinoma are younger, tend to present at an early stage, and their tumors are commonly associated with endometriosis, which is widely accepted as a direct precursor of clear cell carcinoma and has been identified pathologically in approximately 50% of clear cell carcinoma cases. The most frequent and important specific gene alterations in clear cell carcinoma are mutations of AT-rich interaction domain 1A (ARID1A) (~50% of cases) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (~50% cases). More broadly, subgroups of clear cell carcinoma have been identified based on C-APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) and C-AGE (age-related) mutational signatures. Gene expression profiling shows upregulation of hepatocyte nuclear factor 1-beta (HNF1β) and oxidative stress-related genes, and has identified epithelial-like and mesenchymal-like tumor subgroups. Although the benefit of platinum-based chemotherapy is not clearly defined it remains the mainstay of first-line therapy. Patients with early-stage disease have a favorable clinical outcome but the prognosis of patients with advanced-stage or recurrent disease is poor. Alternative treatment strategies are required to improve patient outcome and the development of targeted therapies based on molecular characteristics is a promising approach. Improved specificity of the histological definition of this tumor type is helping these efforts but, due to the rarity of clear cell carcinoma, international collaboration will be essential to design appropriately powered, large-scale clinical trials.
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Affiliation(s)
- Yasushi Iida
- Department of Obstetrics and Gynecology, Jikei University School of Medicine, Tokyo, Japan
| | - Aikou Okamoto
- Department of Obstetrics and Gynecology, Jikei University School of Medicine, Tokyo, Japan
| | - Robert L Hollis
- University of Edinburgh Cancer Research UK Centre, Edinburgh, UK
| | - Charlie Gourley
- University of Edinburgh Cancer Research UK Centre, Edinburgh, UK
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29
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Chelariu-Raicu A, Cobb LP, Gershenson DM. Fertility preservation in rare ovarian tumors. Int J Gynecol Cancer 2021; 31:432-441. [PMID: 33649010 DOI: 10.1136/ijgc-2020-001775] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 09/30/2020] [Indexed: 12/22/2022] Open
Abstract
Although gynecologic cancers usually affect older women, a significant proportion of patients with rare ovarian tumors are of reproductive age. In a young patient who presents with a pelvic mass, a primary consideration should be the probability of a malignancy. If there is any suspicion of a cancer diagnosis, the patient should be referred to a gynecologic oncologist. Key factors in clinical management include assessment of preoperative studies (physical examination, tumor markers, and imaging) to determine the likelihood of a malignancy, appropriate preoperative counseling (including discussion of fertility preservation), choice of surgical approach (minimally invasive vs open), frozen section examination by a gynecologic pathologist, and intraoperative decision making. Fortunately, the clinical features of several rare ovarian tumors are compatible with fertility preservation. These characteristics include a high proportion of stage I disease and unilateral ovarian involvement for most rare histotypes. Once a final diagnosis of a rare ovarian tumor is determined, further clinical management may include the need for further studies, possible referral to a fertility expert, consideration of further surgery (if the initial surgery was incomplete), and recommendations for postoperative therapy. This article reviews the literature on fertility preservation in the context of the treatment of several rare ovarian tumor subtypes, including malignant germ cell tumors, sex cord-stromal tumors, borderline tumors, low grade serous carcinoma, clear cell carcinoma, mucinous carcinoma, and small cell carcinoma of the hypercalcemic type.
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Affiliation(s)
- Anca Chelariu-Raicu
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany
| | - Lauren P Cobb
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - David M Gershenson
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Zhu C, Xu Z, Zhang T, Qian L, Xiao W, Wei H, Jin T, Zhou Y. Updates of Pathogenesis, Diagnostic and Therapeutic Perspectives for Ovarian Clear Cell Carcinoma. J Cancer 2021; 12:2295-2316. [PMID: 33758607 PMCID: PMC7974897 DOI: 10.7150/jca.53395] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 01/30/2021] [Indexed: 12/15/2022] Open
Abstract
Ovarian clear cell carcinoma (OCCC) is a special pathological type of epithelial ovarian carcinoma (EOC) and has a high prevalence in Asia without specific molecular subtype classification. Endometriosis is a recognized precancerous lesion that carries 3-fold increased risk of OCCC. Ovarian endometrioid carcinoma, which also originates from endometriosis, shares several features with OCCC, including platinum resistance and younger age at diagnosis. Patients with OCCC have about a 2.5 to 4 times greater risk of having a venous thromboembolism (VTE) compared with other EOC, and OCCC tends to metastasize through lymphatic vesicular and peritoneal spread as opposed to hematogenous metastasis. There is only mild elevation of the conventional biomarker CA125. Staging surgery or optimal cytoreduction combined with chemotherapy is a common therapeutic strategy for OCCC. However, platinum resistance commonly portends a poor prognosis, so novel treatments are urgently needed. Targeted therapy and immunotherapy are currently being studied, including PARP, EZH2, and ATR inhibitors combined with the synthetic lethality of ARID1A-dificiency, and MAPK/PI3K/HER2, VEGF/bFGF/PDGF, HNF1β, and PD-1/PD-L1 inhibitors. Advanced stage, suboptimal cytoreduction, platinum resistance, lymph node metastasis, and VTE are major prognostic predictors for OCCC. We focus on update pathogenesis, diagnostic methods and therapeutic approaches to provide future directions for clinical diagnosis and treatment of OCCC.
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Affiliation(s)
- Chenchen Zhu
- Department of Obstetrics and Gynecology, Anhui Provincial Hospital, Anhui Medical University, Hefei, 230001, China
| | - Zhihao Xu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Tianjiao Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Lili Qian
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Weihua Xiao
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Haiming Wei
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Tengchuan Jin
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Ying Zhou
- Department of Obstetrics and Gynecology, Anhui Provincial Hospital, Anhui Medical University, Hefei, 230001, China.,Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
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Kusumoto S, Kurashige M, Ohshima K, Tahara S, Matsui T, Nojima S, Hattori S, Morii E. An immature inhibin-α-expressing subpopulation of ovarian clear cell carcinoma cells is related to an unfavorable prognosis. Cancer Med 2021; 10:1485-1500. [PMID: 33611864 PMCID: PMC7940216 DOI: 10.1002/cam4.3801] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 11/05/2020] [Accepted: 02/05/2021] [Indexed: 11/20/2022] Open
Abstract
Inhibin‐α, a member of transforming growth factor‐β, is elevated in multiple tumors, but its specific roles are poorly understood. Here, we examined the feature of inhibin‐α‐expressing cells in ovarian tumors. Immunohistochemically, inhibin‐α‐expressing tumor cells were detected only in ovarian clear cell carcinoma (OCCC) among various types of ovarian tumors. By comparing the expression of inhibin‐α and Ki‐67, inhibin‐α‐expressing tumor cells were revealed to be less proliferative. When spheroids and chemoresistant cells were derived from OCCC cell lines, the expression level of inhibin‐α was elevated, and that of an immature marker, aldehyde dehydrogenase, was also elevated. In consistent with this, inhibin‐α expression was correlated with other immature markers, such as OCT3/4 and SOX2, and inversely correlated with proliferative marker MKI67 in public database on OCCC. Knockdown of inhibin‐α in OCCC cell decreased chemoresistance. Moreover, prognostic analysis with 69 surgically resected OCCC cases revealed that the increased inhibin‐α expression was an independent unfavorable prognostic factor. These findings suggested that inhibin‐α‐expressing subpopulation of OCCC tumor cells appeared to be less proliferative, immature, and angiogenic and to be related to acceleration of malignant progression.
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Affiliation(s)
- Shinya Kusumoto
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Masako Kurashige
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kenji Ohshima
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shinichiro Tahara
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takahiro Matsui
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Satoshi Nojima
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Satoshi Hattori
- Division of Biomedical Statistics, Department of Integrated Medicine, Graduate School of Medicine, and Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan
| | - Eiichi Morii
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
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32
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Xia Y, Ye S, Yang Y, Liu Y, Tong G. Over-expression of RALYL suppresses the progression of ovarian clear cell carcinoma through inhibiting MAPK and CDH1 signaling pathways. Int J Med Sci 2021; 18:785-791. [PMID: 33437214 PMCID: PMC7797558 DOI: 10.7150/ijms.51488] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/30/2020] [Indexed: 12/01/2022] Open
Abstract
Background: The molecular mechanism in the progression of ovarian clear cell carcinoma (OCCC) remains unclear. Objective: This study aimed to investigate the potential function of RAYLY in OCCC. Methods: To validate RAYLY expression, immunohistochemistry, quantitative real-time PCR and western blotting were performed in OCCC tissues and the cell lines of OCCC and epithelial ovarian carcinoma (EOC). Subsequently, the biological effects of RALYL were evaluated through colony formation, and cell proliferation, migration and invasion assays. Finally, RNA-sequencing and gene set enrichment analysis (GSEA) were conducted to explore potential mechanism of RALYL in OCCC. Results: In our study, RALYL was significantly down-regulated in a majority of OCCC tissues compared to adjacent non-tumorous tissues, and OCCC cells had a lower expression level of RALYL than that of EOC cells. OCCC patients with high RALYL expression had a better pathological stage and prognosis. In vitro, over-expression of RALYL inhibited cell proliferation, migration and invasion in OCCC. GSEA analysis and western blot indicated an enrichment of MAPK and CDH1 signaling pathways in OCCC cells without RALYL over-expression. Conclusions: RALYL played an important role in the progression of OCCC, and might serve as a potential prognostic biomarker and novel therapeutic target for OCCC.
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Affiliation(s)
- Ye Xia
- Reproductive Medicine Center, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Shanting Ye
- Department of Hepatobiliary Surgery, Shenzhen Second People's Hospital, Clinical Institute of Guangzhou Medical University, Shenzhen 518035, Guangdong Province, China
| | - Yang Yang
- Reproductive Medicine Center, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yuchen Liu
- Department of Hepatobiliary Surgery, Shenzhen Second People's Hospital, Clinical Institute of Guangzhou Medical University, Shenzhen 518035, Guangdong Province, China
| | - Guoqing Tong
- Reproductive Medicine Center, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Novera W, Lee ZW, Nin DS, Dai MZY, Binte Idres S, Wu H, Damen JMA, Tan TZ, Sim AYL, Long YC, Wu W, Huang RYJ, Deng LW. Cysteine Deprivation Targets Ovarian Clear Cell Carcinoma Via Oxidative Stress and Iron-Sulfur Cluster Biogenesis Deficit. Antioxid Redox Signal 2020; 33:1191-1208. [PMID: 32336105 PMCID: PMC8697566 DOI: 10.1089/ars.2019.7850] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Aims: Current treatment options for ovarian clear cell carcinoma (OCCC) are limited to combination of platinum-based and other cytotoxic agents to which patients respond poorly due to intrinsic chemoresistance. There is therefore an urgent need to develop alternative therapeutic strategies for OCCC. Results: Cysteine deprivation suppresses OCCC growth in vitro and in vivo with no apparent toxicity. Modes of cell death induced by cysteine deprivation in OCCC are determined by their innate metabolic profiles. Cysteine-deprived glycolytic OCCC is abolished primarily by oxidative stress-dependent necrosis and ferroptosis, which can otherwise be prevented by pretreatment with antioxidative agents. Meanwhile, OCCC that relies on mitochondria respiration for its bioenergetics is suppressed through apoptosis, which can otherwise be averted by pretreatment with cysteine precursor alone, but not with antioxidative agents. Cysteine deprivation induces apoptosis in respiring OCCC by limiting iron-sulfur (Fe-S) cluster synthesis in the mitochondria, without which electron transport chain may be disrupted. Respiring OCCC responds to Fe-S cluster deficit by increasing iron influx into the mitochondria, which leads to iron overload, mitochondria damage, and eventual cell death. Innovation/Conclusion: This study demonstrates the importance of cysteine availability in OCCC that is for its antioxidative property and its less appreciated role in mitochondria respiration. Regardless of OCCC metabolic profiles, cysteine deprivation abolishes both glycolytic and respiring OCCC growth in vitro and in vivo. Conclusion: This study highlights the therapeutic potential of cysteine deprivation for OCCC.
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Affiliation(s)
- Wisna Novera
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Zheng-Wei Lee
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Dawn Sijin Nin
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Melvin Zi-Yu Dai
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Shabana Binte Idres
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Hui Wu
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - J Mirjam A Damen
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Arthur Yi Loong Sim
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yun Chau Long
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Wei Wu
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Ruby Yun-Ju Huang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.,Department of Obstetrics and Gynaecology, National University of Singapore, Singapore, Singapore.,Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Lih-Wen Deng
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,National University Cancer Institute, National University Health System, Singapore, Singapore
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Mandelbaum RS, Klar M, Takiuchi T, Bainvoll L, Matsuzaki S, Paulson RJ, Matsuo K. Fertility-sparing treatment for early-stage epithelial ovarian cancer: Contemporary oncologic, reproductive and endocrinologic perspectives. J Obstet Gynaecol Res 2020; 46:1263-1281. [PMID: 32500605 DOI: 10.1111/jog.14302] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/21/2020] [Accepted: 04/30/2020] [Indexed: 12/11/2022]
Abstract
AIM Epithelial ovarian cancer (EOC) can be a devastating diagnosis in women of reproductive age who desire future fertility. However, in early-stage disease, fertility-sparing surgery (FSS) can be considered in appropriately selected patients. METHODS This is a narrative descriptive review of the recent literature on FSS for EOC from oncologic, reproductive and endocrinologic perspectives. RESULTS The recurrence rate following FSS performed for stage I EOC in published retrospective studies collectively is 13% but ranges from 5 to 29%, while mortality ranges from 0 to 18%. Five-year disease-free survival following FSS is over 90% but decreases with higher stage and grade. Recurrences following FSS are more likely to be localized with a more favorable prognosis compared to recurrences following radical surgery. Adjuvant chemotherapy is recommended in women with high-risk disease, and strategies to minimize gonadotoxicity during chemotherapy such as gonadotropin-releasing hormone (GnRH) agonists may be considered. Oocyte, embryo and/or ovarian cryopreservation can also be offered to patients desiring future biologic children. Reproductive outcomes following FSS, including pregnancy and miscarriage rates, resemble those of the general population, with a chance of successful pregnancy of nearly 80%. CONCLUSION In retrospective data, FSS appears to be oncologically safe in stage IA and IC grade 1-2 non-clear cell EOC. In patients with grade 3 tumors or clear cell histology, treatment can be individualized, weighing a slightly higher risk of recurrence with fertility goals. A multidisciplinary approach with oncology and reproductive endocrinology may be of utility to help these patients achieve their fertility goals.
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Affiliation(s)
- Rachel S Mandelbaum
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA.,Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA
| | - Maximilian Klar
- Department of Obstetrics and Gynecology, University of Freiburg, Freiburg, Germany
| | - Tsuyoshi Takiuchi
- Department of Obstetrics and Gynecology, Osaka University, Osaka, Japan
| | - Liat Bainvoll
- Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Shinya Matsuzaki
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA
| | - Richard J Paulson
- Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA
| | - Koji Matsuo
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA.,Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA
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35
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Liu H, Zeng Z, Afsharpad M, Lin C, Wang S, Yang H, Liu S, Kelemen LE, Xu W, Ma W, Xiang Q, Mastriani E, Wang P, Wang J, Liu SL, Johnston RN, Köbel M. Overexpression of IGF2BP3 as a Potential Oncogene in Ovarian Clear Cell Carcinoma. Front Oncol 2020; 9:1570. [PMID: 32083017 PMCID: PMC7002550 DOI: 10.3389/fonc.2019.01570] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 12/27/2019] [Indexed: 11/13/2022] Open
Abstract
Ovarian Clear Cell Carcinoma (OCCC) displays distinctive clinical and molecular characteristics and confers the worst prognosis among all ovarian carcinoma histotypes when diagnosed at advanced stage, because of the lack of effective therapy. IGF2BP3 is an RNA binding protein that modulates gene expression by post-transcriptional action. In this study, we investigated the roles of IGF2BP3 in the progression of OCCC. We used 328 OCCCs from the AOVT (the Alberta Ovarian Tumor Type study) and the COEUR (the Canadian Ovarian Experimental Unified Resource) cohorts to elucidate the associations between IGF2BP3 expression and clinicopathological parameters, with positive IGF2BP3 expression defined as diffuse block staining, being more frequently observed at stage III (P = 0.0056) and significantly associated with unfavorable overall survival (HR = 1.59, 95% CI 1.09-2.33) in multivariate analysis. IGF2BP3 mRNA gene expression was markedly increased in OCCC cell lines compared to normal tissues such as ovarian surface epithelium. We chose two IGF2BP3-overexpressing cell lines ES2 and OVMANA for in vitro and in vivo knockdown experiments. The proliferation and viability of both cell lines were significantly inhibited by two IGF2BP3 siRNAs and similar suppression was observed in cell migration and invasion by Wound Healing and Transwell assays. The percentage of apoptotic cancer cells was enhanced by both IGF2BP3 siRNAs. In vivo experiments showed significantly reduced sizes of tumors when treated with IGF2BP3 siRNA compared to controls. Furthermore, cancer metastasis-indicators MMP2 and MMP9 proteins were down-regulated. In conclusion, our study shows that IGF2BP3 expression is a promising biomarker for prognostication of women diagnosed with OCCC with multiple effects on key cell functions, supporting its role as an important cellular regulator with potential oncogenic activity, and as a potential target for future intervention strategies.
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Affiliation(s)
- Huidi Liu
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China.,Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada.,Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Zheng Zeng
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Mitra Afsharpad
- Pathology and Laboratory Medicine, Calgary Laboratory Service, University of Calgary, Calgary, AB, Canada
| | - Caiji Lin
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Siwen Wang
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Hao Yang
- Department of Pathology, Harbin Chest Hospital, Harbin, China
| | - Shuhong Liu
- Pathology and Laboratory Medicine, Calgary Laboratory Service, University of Calgary, Calgary, AB, Canada
| | - Linda E Kelemen
- Hollings Cancer Center and Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, United States
| | - Wenwen Xu
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Wenqing Ma
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Qian Xiang
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Emilio Mastriani
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Pengfei Wang
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Jiali Wang
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Shu-Lin Liu
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, China.,HMU-UCCSM Centre for Infection and Genomics, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China.,Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, Canada
| | - Randal N Johnston
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada.,Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
| | - Martin Köbel
- Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada.,Pathology and Laboratory Medicine, Calgary Laboratory Service, University of Calgary, Calgary, AB, Canada
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Current Position of the Molecular Therapeutic Targets for Ovarian Clear Cell Carcinoma: A Literature Review. Healthcare (Basel) 2019; 7:healthcare7030094. [PMID: 31366141 PMCID: PMC6787681 DOI: 10.3390/healthcare7030094] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 07/27/2019] [Accepted: 07/29/2019] [Indexed: 12/12/2022] Open
Abstract
Ovarian clear cell carcinoma (OCCC) shows low sensitivity to conventional chemotherapy and has a poor prognosis, especially in advanced stages. Therefore, the development of innovative therapeutic strategies and precision medicine for the treatment of OCCC are important. Recently, several new molecular targets have been identified for OCCC, which can be broadly divided into four categories: (a) downstream pathways of receptor tyrosine kinases, (b) anti-oxidative stress molecules, (c) AT-rich interactive domain 1A-related chromatin remodeling errors, and (d) anti-programmed death ligand 1/programmed cell death 1 agents. Several inhibitors have been discovered for these targets, and the suppression of OCCC cells has been demonstrated both in vitro and in vivo. However, no single inhibitor has shown a sufficient effectiveness in clinical pilot studies. This review outlines recent progress regarding the molecular biological characteristics of OCCC to identify future directions for the development of precision medicine and combinatorial therapies to treat OCCC.
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Prognostic Factors of Early Stage Epithelial Ovarian Carcinoma. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16040637. [PMID: 30795566 PMCID: PMC6406698 DOI: 10.3390/ijerph16040637] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Revised: 02/02/2019] [Accepted: 02/18/2019] [Indexed: 11/17/2022]
Abstract
We aimed to determine prognostic factors of early stage (I/II) epithelial ovarian carcinoma (EOC) including clinicopathologic and chemotherapeutic regimens. Four hundred and thirty-seven women who underwent primary staging surgery with adjuvant chemotherapy between January 1, 2000 and December 31, 2010 were retrospectively reviewed and analyzed from two medical centers. The prognostic factors were determined from multivariate survival analyses using Cox regression models. The majority of women were diagnosed with stage Ic (244/437, 55.8%). The histopathologic types were clear cell (37.5%), endometrioid (27.2%), serous (14.0%), and mucinous (13.3%). Fifty-seven percent (249/437) of the women received taxane-based (platinum plus paclitaxel) regimens and 43.0% received non-taxane (platinum plus cyclophosphamide) regimens as frontline adjuvant chemotherapy. Clear cell tumors (adjusted Hazard ratio (aHR) 0.37, 95% confidence interval (CI) 0.21–0.73, p = 0.001) showed better 5-year disease-free survival (DFS) than serous tumors. Women diagnosed at FIGO (International Federation of Gynecology and Obstetrics) stage II (aHR 5.97, 95% CI = 2.47–14.39, p < 0.001), grade 3 tumor without clear cell (aHR 2.28, 95% CI = 1.02–5.07, p = 0.004) and who received 3–5 cycles of non-taxane regimens (aHR 3.29, 95% CI = 1.47–7.34, p = 0.004) had worse 5-year overall survival (OS). Clear cell histology treated with taxane-based regimens showed significantly higher 5-year DFS (91.2% vs. 82.0%, aHR = 0.45, 95% CI = 0.21–0.93, p = 0.043) and 5-year OS (93.5% vs. 79.0%, aHR = 0.30, 95% CI = 0.13–0.70, p = 0.005) than those treated with non-taxane-based regimens. We conclude that stage, tumor grade, and chemotherapeutic regimens/cycles are independent prognostic factors for early stage ovarian cancer.
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Missing information in statewide and national cancer databases: Correlation with health risk factors, geographic disparities, and outcomes. Gynecol Oncol 2018; 152:119-126. [PMID: 30376964 DOI: 10.1016/j.ygyno.2018.10.029] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 10/17/2018] [Accepted: 10/22/2018] [Indexed: 11/22/2022]
Abstract
OBJECTIVE The objectives of this study were to analyze factors associated with outcomes and missing data in women with epithelial ovarian cancer using institutional, state and national databases. METHODS Data were abstracted from the University of Virginia cancer registry, Virginia Department of Health (VDH) database, and Surveillance, Epidemiology, and End Results (SEER) Program and analyzed for correlations with demographics, cancer characteristics, and outcomes. Statewide spatial associations between health risk factors such as smoking, obesity, and missing grade/stage were evaluated using bivariate LiSA in Geoda. RESULTS There were 524 institutional, 3544 VDH, and 44,464 SEER cases of epithelial ovarian cancer. Institutional cases were younger, most often of white race, had increased grade 1, and decreased unknown grade and stage (all p < 0.001). Significant predictors of unknown grade were non-white race, older age, no surgery, unknown stage/stage IV, and unknown histology/adenocarcinoma. Unknown grade correlated with a significant survival disadvantage. Missing stage and grade correlated with county-level obesity and smoking, as rural regions in Southwest and Southside Virginia had high rates of health risk factors and missing stage/grade compared to urban, affluent regions in Northern Virginia. CONCLUSIONS Over a third of nationally reported cases have an unknown grade and 10-20% have an unknown stage which correlates with the worst survival. Predictors of unknown grade include insurance, age, race, smoking status, obesity, and rural setting. Missing data may represent geographical differences or disparities in cancer care available as significantly fewer cases had an unknown grade/stage at a tertiary academic medical center compared to VDH and SEER.
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Nunes SC, Ramos C, Lopes-Coelho F, Sequeira CO, Silva F, Gouveia-Fernandes S, Rodrigues A, Guimarães A, Silveira M, Abreu S, Santo VE, Brito C, Félix A, Pereira SA, Serpa J. Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity. Sci Rep 2018; 8:9513. [PMID: 29934500 PMCID: PMC6015047 DOI: 10.1038/s41598-018-27753-y] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 06/01/2018] [Indexed: 01/13/2023] Open
Abstract
Ovarian cancer is the second most common gynaecologic malignancy and the main cause of death from gynaecologic cancer, due to late diagnosis and chemoresistance. Studies have reported the role of cysteine in cancer, by contributing for hydrogen sulphide (H2S) generation and as a precursor of glutathione (GSH). However, the role of cysteine in the adaptation to hypoxia and therapy response remains unclear. We used several ovarian cancer cell lines, ES2, OVCAR3, OVCAR8, A2780 and A2780cisR, to clarify cysteine relevance in ovarian cancer cells survival upon hypoxia and carboplatin. Results show that ES2 and OVCAR8 cells presented a stronger dependence on cysteine availability upon hypoxia and carboplatin exposure than OVCAR3 cells. Interestingly, the A2780 cisR, but not A2780 parental cells, benefits from cysteine upon carboplatin exposure, showing that cysteine is crucial for chemoresistance. Moreover, GSH degradation and subsequent cysteine recycling pathway is associated with ovarian cancer as seen in peripheral blood serum from patients. Higher levels of total free cysteine (Cys) and homocysteine (HCys) were found in ovarian cancer patients in comparison with benign tumours and lower levels of GSH were found in ovarian neoplasms patients in comparison with healthy individuals. Importantly, the total and S-Homocysteinylated levels distinguished blood donors from patients with neoplasms as well as patients with benign from patients with malignant tumours. The levels of S-cysteinylated proteins distinguish blood donors from patients with neoplasms and the free levels of Cys in serum distinguish blood from patients with benign tumours from patients with malignant tumours. Herein we disclosed that cysteine contributes for a worse disease prognosis, allowing faster adaptation to hypoxia and protecting cells from carboplatin. The measurement of serum cysteine levels can be an effective tool for early diagnosis, for outcome prediction and follow up of disease progression.
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Affiliation(s)
- Sofia C Nunes
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal
- Unidade de Investigação em Patobiologia Molecular do Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023, Lisboa, Portugal
| | - Cristiano Ramos
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal
- Unidade de Investigação em Patobiologia Molecular do Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023, Lisboa, Portugal
| | - Filipa Lopes-Coelho
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal
- Unidade de Investigação em Patobiologia Molecular do Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023, Lisboa, Portugal
| | - Catarina O Sequeira
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal
| | - Fernanda Silva
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal
- Unidade de Investigação em Patobiologia Molecular do Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023, Lisboa, Portugal
| | - Sofia Gouveia-Fernandes
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal
- Unidade de Investigação em Patobiologia Molecular do Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023, Lisboa, Portugal
| | - Armanda Rodrigues
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal
- Unidade de Investigação em Patobiologia Molecular do Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023, Lisboa, Portugal
| | - António Guimarães
- Serviço de Oncologia Médica do Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023, Lisbon, Portugal
| | - Margarida Silveira
- Serviço de Patologia Clinica do Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023, Lisbon, Portugal
| | - Sofia Abreu
- Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901, Oeiras, Portugal
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157, Oeiras, Portugal
| | - Vítor E Santo
- Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901, Oeiras, Portugal
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157, Oeiras, Portugal
| | - Catarina Brito
- Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901, Oeiras, Portugal
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157, Oeiras, Portugal
| | - Ana Félix
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal
- Serviço de Anatomia Patológica do Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023, Lisbon, Portugal
| | - Sofia A Pereira
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal
| | - Jacinta Serpa
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal.
- Unidade de Investigação em Patobiologia Molecular do Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023, Lisboa, Portugal.
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Nunes SC, Lopes-Coelho F, Gouveia-Fernandes S, Ramos C, Pereira SA, Serpa J. Cysteine boosters the evolutionary adaptation to CoCl 2 mimicked hypoxia conditions, favouring carboplatin resistance in ovarian cancer. BMC Evol Biol 2018; 18:97. [PMID: 29921232 PMCID: PMC6011206 DOI: 10.1186/s12862-018-1214-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 06/07/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Ovarian cancer is the second most common gynaecologic malignancy and the most common cause of death from gynaecologic cancer, especially due to diagnosis at an advanced stage, when a cure is rare. As ovarian tumour grows, cancer cells are exposed to regions of hypoxia. Hypoxia is known to be partially responsible for tumour progression, metastasis and resistance to therapies. These suggest that hypoxia entails a selective pressure in which the adapted cells not only have a fitness increase under the selective environment, but also in non-selective adverse environments. In here, we used two different ovarian cancer cell lines - serous carcinoma (OVCAR3) and clear cell carcinoma (ES2) - in order to address the effect of cancer cells selection under normoxia and hypoxia mimicked by cobalt chloride on the evolutionary outcome of cancer cells. RESULTS Our results showed that the adaptation to normoxia and CoCl2 mimicked hypoxia leads cells to display opposite strategies. Whereas cells adapted to CoCl2 mimicked hypoxia conditions tend to proliferate less but present increased survival in adverse environments, cells adapted to normoxia proliferate rapidly but at the cost of increased mortality in adverse environments. Moreover, results suggest that cysteine allows a quicker response and adaptation to hypoxic conditions that, in turn, are capable of driving chemoresistance. CONCLUSIONS We showed that cysteine impacts the adaptation of cancer cells to a CoCl2 mimicked hypoxic environment thus contributing for hypoxia-drived platinum-based chemotherapeutic agents' resistance, allowing the selection of more aggressive phenotypes. These observations support a role of cysteine in cancer progression, recurrence and chemoresistance.
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Affiliation(s)
- Sofia C. Nunes
- Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisbon, Portugal
- Unidade de Investigação em Patobiologia Molecular do Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
| | - Filipa Lopes-Coelho
- Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisbon, Portugal
- Unidade de Investigação em Patobiologia Molecular do Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
| | - Sofia Gouveia-Fernandes
- Unidade de Investigação em Patobiologia Molecular do Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
| | - Cristiano Ramos
- Unidade de Investigação em Patobiologia Molecular do Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
| | - Sofia A. Pereira
- Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisbon, Portugal
| | - Jacinta Serpa
- Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisbon, Portugal
- Unidade de Investigação em Patobiologia Molecular do Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
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Mercier F, Bakrin N, Bartlett DL, Goere D, Quenet F, Dumont F, Heyd B, Abboud K, Marolho C, Villeneuve L, Glehen O. Peritoneal Carcinomatosis of Rare Ovarian Origin Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Multi-Institutional Cohort from PSOGI and BIG-RENAPE. Ann Surg Oncol 2018; 25:1668-1675. [PMID: 29637438 DOI: 10.1245/s10434-018-6464-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Indexed: 02/06/2023]
Abstract
PURPOSE Ovarian cancer is the most common deadly cancer of gynecologic origin. Patients often are diagnosed at advanced stage with peritoneal metastasis. There are many rare histologies of ovarian cancer; some have outcomes worse than serous ovarian cancer. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) can be considered for patients with recurrence. This study was designed to assess the impact of CRS and HIPEC on survival of patient with peritoneal metastasis from rare ovarian malignancy. METHODS A prospective, multicentric, international database was retrospectively searched to identify all patients with rare ovarian tumor (mucinous, clear cells, endometrioid, small cell hypercalcemic, and other) and peritoneal metastasis who underwent CRS and HIPEC through the Peritoneal Surface Oncology Group International (PSOGI) and BIG-RENAPE working group. The postoperative complications, long-term results, and principal prognostic factors were analyzed. RESULTS The analysis included 210 patients with a median follow-up of 43.5 months. Median overall survival (OS) was 69.3 months, and the 5-year OS was 57.7%. For mucinous tumors, median OS and DFS were not reached at 5 years. For granulosa tumors, median overall survival was not reached at 5 years, and median DFS was 34.6 months. Teratoma or germinal tumor showed median overall survival and DFS that were not reached at 5 years. Differences in OS were not statistically significant between histologies (p = 0.383), whereas differences in DFS were (p < 0.001). CONCLUSIONS CRS and HIPEC may increases long-term survival in selected patients with peritoneal metastasis from rare ovarian tumors especially in mucinous, granulosa, or teratoma histological subtypes.
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MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Carcinoma, Endometrioid/secondary
- Carcinoma, Endometrioid/therapy
- Cytoreduction Surgical Procedures/adverse effects
- Disease-Free Survival
- Female
- Follow-Up Studies
- Granulosa Cell Tumor/secondary
- Granulosa Cell Tumor/therapy
- Humans
- Hyperthermia, Induced
- Lymphatic Metastasis
- Middle Aged
- Neoplasms, Cystic, Mucinous, and Serous/secondary
- Neoplasms, Cystic, Mucinous, and Serous/therapy
- Neoplasms, Germ Cell and Embryonal/secondary
- Neoplasms, Germ Cell and Embryonal/therapy
- Ovarian Neoplasms/pathology
- Peritoneal Neoplasms/secondary
- Peritoneal Neoplasms/therapy
- Rare Diseases/pathology
- Rare Diseases/therapy
- Retrospective Studies
- Survival Rate
- Teratoma/secondary
- Teratoma/therapy
- Treatment Outcome
- Young Adult
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Affiliation(s)
- Frédéric Mercier
- Department of Surgical Oncology, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.
| | - Naoual Bakrin
- Department of Surgical Oncology, Centre Hospitalier Lyon Sud, Pierre-Bénite, France
- EMR 3738, Lyon 1 University, Lyon, France
| | - David L Bartlett
- Department of Surgical Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Diane Goere
- Department of Surgical Oncology, Gustave Roussy, Villejuif Cedex, France
| | - François Quenet
- Department of Surgery, Institut Du Cancer de Montpellier, Montpellier, France
| | - Frédéric Dumont
- Department of Surgical Oncology, ICO René Gauducheau Cancer Center, Saint-Herblain, France
| | - Bruno Heyd
- Department of Digestive Surgery, Minjoz University Hospital, Besançon, France
| | - Karine Abboud
- Department of General Surgery, St Etienne University Hospital, Saint-Étienne, France
| | - Christelle Marolho
- Unité de Recherche Clinique, Hospices Civils de Lyon, Pôle Information Médicale Evaluation Recherche, Lyon, France
| | - Laurent Villeneuve
- EMR 3738, Lyon 1 University, Lyon, France
- Unité de Recherche Clinique, Hospices Civils de Lyon, Pôle Information Médicale Evaluation Recherche, Lyon, France
| | - Olivier Glehen
- Department of Surgical Oncology, Centre Hospitalier Lyon Sud, Pierre-Bénite, France
- EMR 3738, Lyon 1 University, Lyon, France
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Cuylan ZF, Meydanli MM, Sari ME, Akbayir O, Celik H, Dede M, Sahin H, Gungorduk K, Kuscu E, Ozgul N, Gungor T, Ayhan A. Prognostic factors for maximally or optimally cytoreduced stage III nonserous epithelial ovarian carcinoma treated with carboplatin/paclitaxel chemotherapy. J Obstet Gynaecol Res 2018; 44:1284-1293. [DOI: 10.1111/jog.13663] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 03/23/2018] [Indexed: 12/20/2022]
Affiliation(s)
- Zeliha F. Cuylan
- Department of Gynecologic Oncology, Zekai Tahir Burak Women's Health Training and Research Hospital, Faculty of Medicine; University of Health Sciences; Ankara Turkey
| | - Mehmet M. Meydanli
- Department of Gynecologic Oncology, Zekai Tahir Burak Women's Health Training and Research Hospital, Faculty of Medicine; University of Health Sciences; Ankara Turkey
| | - Mustafa E. Sari
- Department of Gynecologic Oncology, Zekai Tahir Burak Women's Health Training and Research Hospital, Faculty of Medicine; University of Health Sciences; Ankara Turkey
| | - Ozgur Akbayir
- Department of Gynecologic Oncology, Kanuni Sultan Suleyman Teaching and Research Hospital, Faculty of Medicine; University of Health Sciences; Istanbul Turkey
| | - Husnu Celik
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine; Baskent University; Adana Turkey
| | - Murat Dede
- Department of Obstetrics and Gynecology, Gulhane Training and Research Hospital, Faculty of Medicine; University of Health Sciences; Ankara Turkey
| | - Hanifi Sahin
- Department of Gynecologic Oncology, Zekai Tahir Burak Women's Health Training and Research Hospital, Faculty of Medicine; University of Health Sciences; Ankara Turkey
| | - Kemal Gungorduk
- Department of Gynecologic Oncology, Tepecik Education and Research Hospital, Faculty of Medicine; University of Health Sciences; Izmir Turkey
| | - Esra Kuscu
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine; Baskent University; Ankara Turkey
| | - Nejat Ozgul
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine; Hacettepe University; Ankara Turkey
| | - Tayfun Gungor
- Department of Gynecologic Oncology, Zekai Tahir Burak Women's Health Training and Research Hospital, Faculty of Medicine; University of Health Sciences; Ankara Turkey
| | - Ali Ayhan
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine; Baskent University; Ankara Turkey
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Wilkerson PM, Dedes KJ, Samartzis EP, Dedes I, Lambros MB, Natrajan R, Gauthier A, Piscuoglio S, Töpfer C, Vukovic V, Daley F, Weigelt B, Reis-Filho JS. Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer. Oncotarget 2018; 8:6057-6066. [PMID: 28002809 PMCID: PMC5351612 DOI: 10.18632/oncotarget.14011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 12/10/2016] [Indexed: 12/18/2022] Open
Abstract
Purpose To determine if models of ovarian clear cell carcinomas (OCCCs) harbouring defects in homologous recombination (HR) DNA repair of double strand breaks (DSBs) are sensitive to cisplatin and/or PARP inhibition. Experimental Design The HR status of 12 OCCC cell lines was determined using RAD51/γH2AX foci formation assays. Sensitivity to cisplatin and the PARP inhibitor BMN-673 was correlated with HR status. BRCA1, BRCA2, MRE11 and PTEN loss of expression was investigated as a potential determinant of BMN-673 sensitivity. A tissue microarray containing 50 consecutive primary OCCC was assessed for PTEN expression using immunohistochemistry. Results A subset of OCCC cells displayed reduced RAD51 foci formation in the presence of DNA DSBs, suggestive of HR defects. HR-defective OCCC cells, with the exception of KOC-7c, had higher sensitivity to cisplatin/ BMN-673 than HR-competent OCCC cell lines (Log10 SF50 –9.4 (SD +/− 0.29) vs –8.1 (SD +/− 0.35), mean difference 1.3, p < 0.01). Of the cell lines studied, two, TOV-21G and KOC-7c, showed loss of PTEN expression. In primary OCCCs, loss of PTEN expression was observed in 10% (5/49) of cases. Conclusions A subset of OCCC cells are sensitive to PARP inhibition in vitro, which can be predicted by HR defects as defined by γH2AX/RAD51 foci formation. These results provide a rationale for the testing of HR deficiency and PARP inhibitors as a targeted therapy in a subset of OCCCs.
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Affiliation(s)
- Paul M Wilkerson
- The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
| | - Konstantin J Dedes
- The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.,Department of Gynaecology, University Hospital of Zurich, 8091 Zurich, Switzerland
| | | | - Ioannis Dedes
- Department of Gynaecology, University Hospital of Zurich, 8091 Zurich, Switzerland
| | - Maryou B Lambros
- The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
| | - Rachael Natrajan
- The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
| | - Arnaud Gauthier
- The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
| | - Salvatore Piscuoglio
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Chantal Töpfer
- The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
| | - Vesna Vukovic
- The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
| | - Frances Daley
- The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
| | - Britta Weigelt
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Jorge S Reis-Filho
- The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.,Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
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Dietary fat intake and ovarian cancer risk: a meta-analysis of epidemiological studies. Oncotarget 2018; 7:37390-37406. [PMID: 27119509 PMCID: PMC5095084 DOI: 10.18632/oncotarget.8940] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 04/10/2016] [Indexed: 12/11/2022] Open
Abstract
Observational studies assessing the association of dietary fat and risk of ovarian cancer yield discrepant results. Pertinent prospective cohort studies were identified by a PubMed search from inception to December 2015. Sixteen independent case-control and nine cohort studies on dietary fat intake were included, with approximately 900,000 subjects in total. Relative risks (RRs) with 95% confidence intervals were pooled using a random effects model. Heterogeneity, sensitivity analysis and publication bias were assessed; subgroup analysis and analysis stratified by EOC histology were conducted. The reported studies showed a significant increase of ovarian cancer risk with high consumption of total-, saturated-, and trans-fats, while serous ovarian cancer was more susceptible to dietary fat consumption than other pathological subtypes. No evidence of positive association between dietary fat intake and ovarian cancer risk was provided by cohort studies. Menopausal status, hormone replacement therapy, body mass index (BMI), and pregnancy times, modified the objective associations. In conclusion, the meta-analysis findings indicate that high consumption of total, saturated and trans-fats increase ovarian cancer risk, and different histological subtypes have different susceptibility to dietary fat.
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Nasioudis D, Chapman-Davis E, Frey MK, Witkin SS, Holcomb K. Could fertility-sparing surgery be considered for women with early stage ovarian clear cell carcinoma? J Gynecol Oncol 2017; 28:e71. [PMID: 28758377 PMCID: PMC5641522 DOI: 10.3802/jgo.2017.28.e71] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 04/17/2017] [Accepted: 06/19/2017] [Indexed: 11/30/2022] Open
Abstract
Objective The aim of the present retrospective population-based study was to investigate the oncologic impact of uterine and ovarian preservation (OP) in premenopausal women with stage IA or IC ovarian clear cell carcinoma (OCCC). Methods The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database was accessed and a cohort of surgically-staged premenopausal women (age <50 years) diagnosed with unilateral stage IA or IC OCCC was drawn. Based on site-specific surgery codes, women who did not undergo hysterectomy and/or bilateral salpingo-oophorectomy (BSO) were identified. Overall survival (OS) and cancer-specific survival (CSS) rates were calculated following generation of Kaplan-Meier curves; comparisons were made with the log-rank test. Multivariate Cox analysis was performed to control for possible confounders. Results A total of 741 premenopausal women who met the inclusion criteria were identified. Based on available information, rate of uterine preservation was 14.5% (96/663) while the rate of OP was 28.1% (71/253). Five-year CSS rates were 90.8% for women who did not undergo hysterectomy compared with 87.7% for those who did (p=0.290). Similarly, 5-year CSS rates in the OP and BSO groups were 92.6% and 85%, respectively (p=0.060). After controlling for disease sub-stage (IA vs. IC), uterine or OP was not associated with a worse overall or cancer-specific mortality. Conclusion In the present cohort, uterine and OP did not have a negative impact on oncologic outcomes. Selection criteria for fertility-sparing surgery (FSS) could be expanded to include women with stage IA OCCC.
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Affiliation(s)
- Dimitrios Nasioudis
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA. ,
| | - Eloise Chapman-Davis
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
| | - Melissa K Frey
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
| | - Steven S Witkin
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
| | - Kevin Holcomb
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
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González-Palomares B, Coronado Martín PJ, Maestro de Las Casas ML, Veganzones de Castro S, Rafael Fernández S, Vidaurreta Lázaro M, De la Orden García V, Vidart Aragon JA. Vascular Endothelial Growth Factor (VEGF) Polymorphisms and Serum VEGF Levels in Women With Epithelial Ovarian Cancer, Benign Tumors, and Healthy Ovaries. Int J Gynecol Cancer 2017; 27:1088-1095. [PMID: 28574932 DOI: 10.1097/igc.0000000000001006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
OBJECTIVE This study analyzed the relation of 5 single-nucleotide polymorphisms (SNPs) in the VEGF (vascular endothelial growth factor) gene in patients with epithelial ovarian cancer (EOC), compared with patients carrying benign tumors or healthy ovaries. We studied serum VEGF levels and the relation with SNPs and association between VEGF SNPs and haplotypes with progression-free survival (PFS) in patients with cancer. METHODS The genotyping of VEGF gene polymorphisms (-2578 C/A, -1154 G/A, -460 T/C, +405 G/C, +936 C/T) was performed in DNA isolated from blood samples of 100 women. The different genotypes were evaluated by quantitative real-time polymerase chain reaction. Vascular endothelial growth factor protein concentration was assessed in serum using solid-phase sandwich enzyme-linked immunosorbent assay. RESULTS We found statistically significant differences in the distribution of VEGF genotypes among the 3 groups of patients: -2578 C/A between those with EOC and healthy ovary (P = 0.04), -460 T/C between those with EOC and healthy ovary (P = 0.03), and -460 T/C between those with benign tumors and healthy ovary (P = 0.02). Vascular endothelial growth factor serum levels were analyzed in patients with EOC. Higher levels were found in patients with clear cell carcinoma compared with those with serous, mucinous, or endometrioid tumors (P < 0.05). No clear association was observed between VEGF SNPs and serum VEGF levels. There was no significant correlation between VEGF SNPs and PFS. In haplotype analysis, CGTCT and CGTGT showed worse prognosis without reaching the statistical significance. CGCGC and AGTGC haplotypes had statistically significant differences among patients with EOC, benign tumors, and healthy ovaries (Ps = 0.046 and 0.041, respectively). CONCLUSIONS The distribution of VEGF genotypes was different in patients with EOC, compared with those with benign tumors or women with healthy ovaries. Vascular endothelial growth factor serum levels were higher in patients with clear cell carcinoma. No correlation was found with improved PFS, but CGTCT and CGTGT haplotypes showed worse prognosis.
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Affiliation(s)
- Blanca González-Palomares
- *Department of Obstetrics and Gynecology and †Service of Clinical Analyses, Hospital Clínico San Carlos, Complutense University of Madrid, Madrid, Spain
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Kawabata A, Yanaihara N, Nagata C, Saito M, Noguchi D, Takenaka M, Iida Y, Takano H, Yamada K, Iwamoto M, Kiyokawa T, Okamoto A. Prognostic impact of interleukin-6 expression in stage I ovarian clear cell carcinoma. Gynecol Oncol 2017; 146:609-614. [PMID: 28673661 DOI: 10.1016/j.ygyno.2017.06.027] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 06/12/2017] [Accepted: 06/20/2017] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Ovarian clear cell carcinoma (OCCC) frequently presents at an early stage. In stage I OCCC, the prognosis differs according to substage. In particular, predictive biomarkers and new treatment strategies are needed for stage IC2/IC3 disease. We investigated tumor biology and prognostic factors for stage I OCCC from a clinicopathological perspective, including the expression of ARID1A and IL-6, which are considered critical for OCCC carcinogenesis. METHODS A retrospective cohort study of 192 patients with stage I OCCC treated at a single institution was performed. We calculated overall survival (OS) with respect to 12 clinicopathological parameters that included the unique and diverse histological features of OCCC. RESULTS The estimated 5-year OS rate in patients with all stage I OCCC was 88.9% during a median of 91months of follow-up. The multivariate analysis indicated that substage classification and IL-6 expression status were associated with poor OS (p=0.010 and p=0.027, respectively). Loss of ARID1A expression had no impact on survival; however, it was associated with substage (p=0.001), capsule rupture status (p=0.011), and ascites cytology (p=0.016). No clear association was found between ARID1A and IL-6 expressions. Histological findings, including the presence of endometriosis, adenofibroma, architectural pattern, and tumor cell type, showed no prognostic effects. CONCLUSIONS Both substage classification and IL-6 expression status may be independent prognostic factors in stage I OCCC. Therefore, IL-6 molecular stratification may be crucial in optimizing therapeutic strategies for early stage OCCC to improve survival.
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Affiliation(s)
- Ayako Kawabata
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Nozomu Yanaihara
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
| | - Chie Nagata
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan; Department of Education for Clinical Research, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
| | - Misato Saito
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Daito Noguchi
- Department of Obstetrics and Gynecology, The Jikei University Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa-shi, Chiba 277-0004, Japan
| | - Masataka Takenaka
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Yasushi Iida
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Hirokuni Takano
- Department of Obstetrics and Gynecology, The Jikei University Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa-shi, Chiba 277-0004, Japan
| | - Kyosuke Yamada
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Masami Iwamoto
- Department of Pathology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Takako Kiyokawa
- Department of Pathology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan
| | - Aikou Okamoto
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan
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Arildsen NS, Jönsson JM, Bartuma K, Ebbesson A, Westbom-Fremer S, Måsbäck A, Malander S, Nilbert M, Hedenfalk IA. Involvement of Chromatin Remodeling Genes and the Rho GTPases RhoB and CDC42 in Ovarian Clear Cell Carcinoma. Front Oncol 2017; 7:109. [PMID: 28611940 PMCID: PMC5447048 DOI: 10.3389/fonc.2017.00109] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 05/10/2017] [Indexed: 12/31/2022] Open
Abstract
Objective Ovarian clear cell carcinomas (OCCCs) constitute a rare ovarian cancer subtype with distinct clinical features, but may nonetheless be difficult to distinguish morphologically from other subtypes. There is limited knowledge of genetic events driving OCCC tumorigenesis beyond ARID1A, which is reportedly mutated in 30–50% of OCCCs. We aimed to further characterize OCCCs by combined global transcriptional profiling and targeted deep sequencing of a panel of well-established cancer genes. Increased knowledge of OCCC-specific genetic aberrations may help in guiding development of targeted treatments and ultimately improve patient outcome. Methods Gene expression profiling of formalin-fixed, paraffin-embedded (FFPE) tissue from a cohort of the major ovarian cancer subtypes (cohort 1; n = 67) was performed using whole-genome cDNA-mediated Annealing, Selection, extension and Ligation (WG-DASL) bead arrays, followed by pathway, gene module score, and gene ontology analyses, respectively. A second FFPE cohort of 10 primary OCCCs was analyzed by targeted DNA sequencing of a panel of 60 cancer-related genes (cohort 2). Non-synonymous and non-sense variants affecting single-nucleotide variations and insertions or deletions were further analyzed. A tissue microarray of 43 OCCCs (cohort 3) was used for validation by immunohistochemistry and chromogenic in situ hybridization. Results Gene expression analyses revealed a distinct OCCC profile compared to other histological subtypes, with, e.g., ERBB2, TFAP2A, and genes related to cytoskeletal actin regulation being overexpressed in OCCC. ERBB2 was, however, not overexpressed on the protein level and ERBB2 amplification was rare in the validation cohort. Targeted deep sequencing revealed non-synonymous variants or insertions/deletions in 11/60 cancer-related genes. Genes involved in chromatin remodeling, including ARID1A, SPOP, and KMT2D were frequently mutated across OCCC tumors. Conclusion OCCCs appear genetically heterogeneous, but harbor frequent alterations in chromatin remodeling genes. Overexpression of TFAP2A and ERBB2 was observed on the mRNA level in relation to other ovarian cancer subtypes. However, overexpression of ERBB2 was not reflected by HER2 amplification or protein overexpression in the OCCC validation cohort. In addition, Rho GTPase-dependent actin organization may also play a role in OCCC pathogenesis and warrants further investigation. The distinct biological features of OCCC discovered here may provide a basis for novel targeted treatment strategies.
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Affiliation(s)
- Nicolai Skovbjerg Arildsen
- Division of Oncology and Pathology, Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden
| | - Jenny-Maria Jönsson
- Division of Oncology and Pathology, Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden
| | - Katarina Bartuma
- Division of Oncology and Pathology, Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden
| | - Anna Ebbesson
- Division of Oncology and Pathology, Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden.,CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden
| | - Sofia Westbom-Fremer
- Department of Clinical Pathology, Division of Laboratory Medicine, Skåne University Hospital, Lund, Sweden
| | - Anna Måsbäck
- Department of Clinical Pathology, Division of Laboratory Medicine, Skåne University Hospital, Lund, Sweden
| | - Susanne Malander
- Division of Oncology and Pathology, Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden
| | - Mef Nilbert
- Division of Oncology and Pathology, Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden.,Clinical Research Centre, Hvidovre University Hospital, Copenhagen University, Hvidovre, Denmark
| | - Ingrid A Hedenfalk
- Division of Oncology and Pathology, Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden.,CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden
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Choi JY, Han HH, Kim YT, Lee JH, Kim BG, Kang S, Cho NH. Ovarian Clear Cell Carcinoma Sub-Typing by ARID1A Expression. Yonsei Med J 2017; 58:59-66. [PMID: 27873496 PMCID: PMC5122653 DOI: 10.3349/ymj.2017.58.1.59] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 06/03/2016] [Accepted: 06/08/2016] [Indexed: 01/27/2023] Open
Abstract
PURPOSE Loss of AT-rich DNA-interacting domain 1A (ARID1A) has been identified as a driving mutation of ovarian clear cell carcinoma (O-CCC), a triple-negative ovarian cancer that is intermediary between serous and endometrioid subtypes, in regards to molecular and clinical behaviors. However, about half of O-CCCs still express BAF250a, the protein encoded by ARID1A. Herein, we aimed to identify signatures of ARID1A-positive O-CCC in comparison with its ARID1A-negative counterpart. MATERIALS AND METHODS Seventy cases of O-CCC were included in this study. Histologic grades and patterns of primary tumor, molecular marker immunohistochemistry profiles, and clinical outcomes were analyzed. RESULTS Forty-eight (69%) O-CCCs did not express BAF250a, which were designated as "ARID1A-negative." The other 22 (31%) O-CCCs were designated as "ARID1A-positive." ARID1A-positive tumors were more likely to be histologically of high grades (41% vs. 10%, p=0.003), ERβ-positive (45% vs. 17%, p=0.011), and less likely to be HNF1β-positive (77% vs. 96%, p=0.016) and E-cadherin-positive (59% vs. 83%, p=0.028) than ARID1A-negative tumors. Patient age, parity, tumor stage were not significantly different in between the two groups. Cancer-specific survival was not significantly different either. CONCLUSION We classified O-CCCs according to ARID1A expression status. ARID1A-positive O-CCCs exhibited distinct immunohistochemical features from ARID1A-negative tumors, suggesting a different underlying molecular event during carcinogenesis.
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Affiliation(s)
- Jae Yoon Choi
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Hyun Ho Han
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Young Tae Kim
- Department of Gynecology, Yonsei University College of Medicine, Seoul, Korea
| | - Joo Hyun Lee
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Baek Gil Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Suki Kang
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
- Severance Biomedical Science Institute (SBSI), Yonsei University College of Medicine, Seoul, Korea
| | - Nam Hoon Cho
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
- Severance Biomedical Science Institute (SBSI), Yonsei University College of Medicine, Seoul, Korea.
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Kim HJ, Yoon A, Ryu JY, Cho YJ, Choi JJ, Song SY, Bang H, Lee JS, Cho WC, Choi CH, Lee JW, Kim BG, Bae DS. c-MET as a Potential Therapeutic Target in Ovarian Clear Cell Carcinoma. Sci Rep 2016; 6:38502. [PMID: 27917934 PMCID: PMC5137074 DOI: 10.1038/srep38502] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 11/10/2016] [Indexed: 12/30/2022] Open
Abstract
In this study, we investigated the therapeutic effects of c-MET inhibition in ovarian clear cell carcinoma (OCCC). Expression levels of c-MET in the epithelial ovarian cancers (EOCs) and normal ovarian tissues were evaluated using real-time PCR. To test the effects of c-MET inhibitors in OCCC cell lines, we performed MTT and apoptosis assays. We used Western blots to evaluate the expression of c-MET and its down-stream pathway. In vivo experiments were performed to test the effects of c-MET inhibitor on tumor growth in orthotopic mouse xenografts of OCCC cell line RMG1 and a patient-derived tumor xenograft (PDX) model of OCCC. c-MET expression was significantly greater in OCCCs compared with serous carcinomas and normal ovarian tissues (p < 0.001). In in vitro study, inhibition of c-MET using c-MET inhibitors (SU11274 or crizotinib) significantly decreased the proliferation, and increased the apoptosis of OCCC cells. SU11274 decreased expression of the p-c-MET proteins and blocked the phosphorylation of down-stream proteins Akt and Erk. Furthermore, SU11274 treatment significantly decreased the in vivo tumor weight in xenograft models of RMG1 cell and a PDX model for OCCC compared to control (p = 0.004 and p = 0.009, respectively).
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Affiliation(s)
- Ha-Jeong Kim
- Department of Obstetrics and Gynecology, Institute of Wonkwang Medical Science, College of Medicine, Wonkwang University, Iksan, Korea
| | - Aera Yoon
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji-Yoon Ryu
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young-Jae Cho
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jung-Joo Choi
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang Yong Song
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Heejin Bang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji Soo Lee
- Health promotion center Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - William Chi Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
| | - Chel Hun Choi
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jeong-Won Lee
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea
- Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Byoung-Gie Kim
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Duk-Soo Bae
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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