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Zheng G, Baandrup L, Wang J, Hertzum-Larsen R, Hannibal CG, Faber MT, Sundström K, Kjær SK. Ovarian cancer risk factors in relation to family history. J Natl Cancer Inst 2024; 116:1767-1774. [PMID: 38964345 DOI: 10.1093/jnci/djae164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/07/2024] [Accepted: 07/01/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND Women with a family history of breast and/or ovarian cancer have an increased ovarian cancer risk. Yet it remains uncertain if common ovarian cancer risk factors-especially those that are modifiable-affect this high-risk population similarly to the general population. METHODS Using the Danish and Swedish nationwide registers, we established 2 nested case-control study populations in women with a family history of breast and/or ovarian cancer (2138 ovarian cancers, 85 240 controls) and women without (10 730 ovarian cancers, 429 200 controls). The overall and histology-specific associations were assessed with conditional logistic regression. The country-specific estimates were combined based on a fixed-effect assumption. RESULTS Multiparity, hysterectomy, tubal ligation, salpingectomy, and oral contraceptive (OC) use were associated with a reduced risk of ovarian cancer in women with and without a family history, while endometriosis and menopausal hormone therapy were associated with increased risk. Multiparity and OC use presented protective effects across all histologic subtypes except mucinous ovarian cancer, which was not associated with OC use. Menopausal hormone treatment increased the risk of serous ovarian cancer but decreased the risk of the mucinous and clear cell cancers. Endometriosis was especially related to an increased risk of endometrioid and clear cell ovarian cancer. CONCLUSION Factors associated with a decreased ovarian cancer risk were similar between women with and without a family history of breast and/or ovarian cancer. Given the higher baseline risk for women with a family history, special attention should be paid to risk factors like endometriosis and nulliparity in this high-risk population.
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Affiliation(s)
- Guoqiao Zheng
- Unit of Virus, Lifestyle and Genes, Danish Cancer Institute, Copenhagen, Denmark
| | - Louise Baandrup
- Unit of Virus, Lifestyle and Genes, Danish Cancer Institute, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- D epartment of Pathology, Zealand University Hospital, Roskilde, Denmark
| | - Jiangrong Wang
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | | | | | - Mette Tuxen Faber
- Unit of Virus, Lifestyle and Genes, Danish Cancer Institute, Copenhagen, Denmark
| | - Karin Sundström
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Clinical Pathology and Cancer Diagnostics, Medical Diagnostics Karolinska, Karolinska University Hospital, Stockholm, Sweden
| | - Susanne K Kjær
- Unit of Virus, Lifestyle and Genes, Danish Cancer Institute, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Calmon MS, Lemos FFB, Silva Luz M, Rocha Pinheiro SL, de Oliveira Silva LG, Correa Santos GL, Rocha GR, Freire de Melo F. Immune pathway through endometriosis to ovarian cancer. World J Clin Oncol 2024; 15:496-522. [PMID: 38689629 PMCID: PMC11056862 DOI: 10.5306/wjco.v15.i4.496] [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: 12/15/2023] [Revised: 01/29/2024] [Accepted: 03/18/2024] [Indexed: 04/22/2024] Open
Abstract
Endometriosis is an estrogen-dependent inflammatory disease, defined by the presence of functional endometrial tissue outside of the uterine cavity. This disease is one of the main gynecological diseases, affecting around 10%-15% women and girls of reproductive age, being a common gynecologic disorder. Although endometriosis is a benign disease, it shares several characteristics with invasive cancer. Studies support that it has been linked with an increased chance of developing endometrial ovarian cancer, representing an earlier stage of neoplastic processes. This is particularly true for women with clear cell carcinoma, low-grade serous carcinoma and endometrioid. However, the carcinogenic pathways between both pathologies remain poorly understood. Current studies suggest a connection between endometriosis and endometriosis-associated ovarian cancers (EAOCs) via pathways associated with oxidative stress, inflammation, and hyperestrogenism. This article aims to review current data on the molecular events linked to the development of EAOCs from endometriosis, specifically focusing on the complex relationship between the immune response to endometriosis and cancer, including the molecular mechanisms and their ramifications. Examining recent developments in immunotherapy and their potential to boost the effectiveness of future treatments.
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Affiliation(s)
- Mariana Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Gabriel Lima Correa Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Zheng G, Faber MT, Baandrup L, Kjaer SK. Paracetamol use and risk of epithelial ovarian cancer: A nationwide nested case-control study. BJOG 2024; 131:290-299. [PMID: 37551038 DOI: 10.1111/1471-0528.17632] [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: 03/02/2023] [Revised: 07/11/2023] [Accepted: 07/23/2023] [Indexed: 08/09/2023]
Abstract
OBJECTIVE To investigate whether paracetamol use is associated with a reduced risk of epithelial ovarian cancer (EOC). DESIGN A nationwide nested case-control study. SETTING Danish female population. POPULATION A total of 9589 EOC cases diagnosed from 2000 to 2019 were age-matched with 383 549 randomly selected female controls using risk set sampling. METHODS Paracetamol use, reproductive history, history of medication and history of surgery were retrieved from Danish national registers. Paracetamol use was defined as at least two prescriptions for up to 1 year before the index date, and was further classified according to recency, duration, cumulative dose and intensity of dose. MAIN OUTCOME MEASURES Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals for the association between paracetamol and EOC risk, overall and by histological subtypes. RESULTS 'Ever' use of paracetamol was associated with a reduced EOC risk after adjusting for potential confounding factors (OR 0.92, 95% CI 0.87-0.97). The association was only significant among recent users (OR 0.89, 95% CI 0.84-0.95). The risk declined further with the increasing level of cumulative dose and intensity; women from the group with a high cumulative dose and a high intensity had a 13% (OR 0.87, 95% CI 0.80-0.94) and 14% (OR 0.86, 95% CI 0.79-0.93) reduced risk, respectively. In the histological subtype analysis, reduced risk with 'ever' use was most pronounced for serous and clear cell tumours. CONCLUSIONS Paracetamol use was associated with a decreased risk of EOC in a dose-response manner. Future studies are needed to validate the findings and investigate the mechanisms behind the association.
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Affiliation(s)
- Guoqiao Zheng
- Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Mette Tuxen Faber
- Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Louise Baandrup
- Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Susanne K Kjaer
- Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
- Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Ring LL, Baandrup L, Zheng G, Gottschau M, Dehlendorff C, Mellemkjær L, Kjaer SK. Hysterectomy and risk of epithelial ovarian cancer by histologic type, endometriosis, and menopausal hormone therapy. Cancer Epidemiol 2023; 84:102359. [PMID: 37054550 DOI: 10.1016/j.canep.2023.102359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 03/21/2023] [Accepted: 03/27/2023] [Indexed: 04/15/2023]
Abstract
BACKGROUND This nationwide, register-based case-control study investigated the association between hysterectomy and risk of epithelial ovarian cancer according to histology and by history of endometriosis and menopausal hormone therapy (MHT) use. METHODS From the Danish Cancer Registry, all women registered with epithelial ovarian cancer at age 40-79 years during 1998-2016 were identified (n = 6738). Each case was sex- and age-matched to 15 population controls using risk-set sampling. Information on previous hysterectomy on benign indication and potential confounders was retrieved from nationwide registers. Conditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between hysterectomy and ovarian cancer according to histology, endometriosis, and use of MHT. RESULTS Hysterectomy was not associated with risk of epithelial ovarian cancer overall (OR=0.99; 95% CI 0.91 -1.09) but was associated with reduced risk of clear cell ovarian cancer (OR=0.46; 95% CI 0.28-0.78). In stratified analyses, decreased ORs associated with hysterectomy were seen in women with endometriosis (OR=0.74; 95% CI 0.50-1.10) and in non-users of MHT (OR=0.87; 95% CI 0.76-1.01). In contrast, among long-term MHT users, hysterectomy was associated with increased odds for ovarian cancer (OR=1.20; 95% CI 1.03-1.39). CONCLUSION Hysterectomy was not associated with epithelial ovarian cancer overall but with reduced risk of clear cell ovarian cancer. Our findings may suggest a reduced risk of ovarian cancer after hysterectomy in women with endometriosis and in MHT non-users. Interestingly our data pointed to an increased ovarian cancer risk associated with hysterectomy among long-term users of MHT.
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Affiliation(s)
- Linea Landgrebe Ring
- Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Louise Baandrup
- Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Guoqiao Zheng
- Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Mathilde Gottschau
- Unit of Diet, Cancer and Health, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Christian Dehlendorff
- Statistics and Data Analysis, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Lene Mellemkjær
- Unit of Diet, Cancer and Health, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Susanne K Kjaer
- Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Gynecology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
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Di Palma T, Zannini M. PAX8 as a Potential Target for Ovarian Cancer: What We Know so Far. Onco Targets Ther 2022; 15:1273-1280. [PMID: 36275185 PMCID: PMC9584354 DOI: 10.2147/ott.s361511] [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: 06/30/2022] [Accepted: 10/13/2022] [Indexed: 11/22/2022] Open
Abstract
The Fallopian tube epithelium harbors the origin cells for the majority of high-grade serous ovarian carcinomas (HGSCs), the most lethal form of gynecologic malignancies. PAX8 belongs to the paired-box gene family of transcription factors and it is a marker of the FTE secretory cell lineage. Its role has been investigated in migration, invasion, proliferation, cell survival, stem cell maintenance, angiogenesis and tumor growth. In this review, we focus on the pro-tumorigenic role of PAX8 in ovarian cancer; in this context, PAX8 possibly continues to exert its transcriptional activity on its physiological targets but may also function on newly available targets after the tumorigenic hits. Acquiring new insights into the different PAX8 mechanism(s) of action in the tumor microenvironment could uncover new viable therapeutic targets and thus improve the current treatment regimen.
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Affiliation(s)
- Tina Di Palma
- IEOS - Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, National Research Council, Napoli, 80131, Italy
| | - Mariastella Zannini
- IEOS - Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, National Research Council, Napoli, 80131, Italy,Correspondence: Mariastella Zannini, IEOS - Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, National Research Council, via S. Pansini 5, Napoli, 80131, Italy, Tel +39-081-5465530, Fax +39-081-2296674, Email
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Liang X, Harris HR, Hendryx M, Shadyab AH, Hale L, Li Y, Crane TE, Cespedes Feliciano EM, Stefanick ML, Luo J. Sleep Characteristics and Risk of Ovarian Cancer Among Postmenopausal Women. Cancer Prev Res (Phila) 2021; 14:55-64. [PMID: 32917642 PMCID: PMC7947032 DOI: 10.1158/1940-6207.capr-20-0174] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 08/01/2020] [Accepted: 09/02/2020] [Indexed: 11/16/2022]
Abstract
Several studies have assessed the relationship between sleep duration and ovarian cancer risk, but the results are conflicting. Importantly, no studies addressed the relationship between sleep disturbance or sleep quality and ovarian cancer incidence. Moreover, few studies have examined the relationships between sleep measures and subtypes of ovarian cancer. This study included 109,024 postmenopausal women ages 50-79 from the Women's Health Initiative during 1993-1998 and followed through 2018. The Cox proportional hazards model was used to estimate adjusted HRs for the associations between sleep habits and the incidence of ovarian cancer and its subtypes. No association was observed between sleep duration, sleep quality, sleep disturbance, or insomnia and risk of overall ovarian cancer, serous/nonserous, or type I/type II ovarian cancer subtype. However, compared with women with average sleep quality, women with restful or very restful sleep quality had a significantly lower risk of invasive serous subtype [HR: 0.73, 95% confidence interval (CI): 0.60-0.90] while insomnia was associated with a higher risk of invasive serous subtype (HR: 1.36, 95% CI: 1.12-1.66). Associations with insomnia differed significantly by serous and nonserous subtypes, and type I and type II subtypes (P heterogeneity = 0.001 and P heterogeneity <0.001, respectively). This study provides no evidence on association between sleep habits and overall ovarian cancer risk among postmenopausal women. However, restful or very restful sleep quality was associated with a lower risk of invasive serous ovarian cancer, and insomnia was associated with a higher risk of invasive serous ovarian cancer. Associations with insomnia differed by subtypes. PREVENTION RELEVANCE: This study shows no association between sleep duration, sleep quality, or insomnia with the risk of overall ovarian cancer among postmenopausal women. However, restful sleep quality was associated with a lower risk of invasive serous ovarian cancer, and insomnia was associated with a higher risk of invasive serous ovarian cancer.
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Affiliation(s)
- Xiaoyun Liang
- School of Social Development and Public Policy, Beijing Normal University, Beijing, China.
| | - Holly R Harris
- Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Michael Hendryx
- Department of Environmental and Occupational Health, School of Public Health, Indiana University Bloomington, Bloomington, Indiana
| | - Aladdin H Shadyab
- Department of Family Medicine and Public Health, University of California, San Diego School of Medicine, La Jolla, California
| | - Lauren Hale
- Program in Public Health, Renaissance School of Medicine at Stony Brook University, Stony Brook, New York
| | - Yueyao Li
- Department of Dermatology, Brown Alpert Medical School, Providence, Rhode Island
| | - Tracy E Crane
- Biobehavioral Health Science Division, College of Nursing, University of Arizona, Tucson, Arizona
| | | | - Marcia L Stefanick
- Department of Medicine, Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, California
| | - Juhua Luo
- Department of Epidemiology and Biostatistics, School of Public Health, Indiana University Bloomington, Bloomington, Indiana
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7
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Plasticity in Ovarian Cancer: The Molecular Underpinnings and Phenotypic Heterogeneity. J Indian Inst Sci 2020. [DOI: 10.1007/s41745-020-00174-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Endometriosis and ovarian cancer: Their association and relationship. Eur J Obstet Gynecol Reprod Biol X 2019; 3:100053. [PMID: 31404281 PMCID: PMC6687431 DOI: 10.1016/j.eurox.2019.100053] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 05/17/2019] [Accepted: 05/18/2019] [Indexed: 02/07/2023] Open
Abstract
Objectives To study endometriosis-associated borderline or malignant ovarian epithelial tumors by analyzing their differential clinical features, as well as the histological pattern, survival and immunohistochemical data compared with those without associated endometriosis. Study design Setting: Hospital Marina Baixa and San Juan University Hospital, Alicante, Spain. This retrospective study included clinical and pathological data from 36 operated cases with endometriosis-associated ovarian epithelial tumors and 305 cases of ovarian epithelial tumors without endometriosis, including borderline and invasive tumors. We also studied hormonal receptors and p53 protein expression in 13 cases with endometriosis-associated endometrioid and clear cell tumors, and report two cases with histologically-confirmed previous endometriosis. Results Associated endometriosis was observed in 10.5% of patients with borderline or invasive ovarian epithelial tumor, 53% of those with endometrioid, and 22% with clear cell tumors. Patients with endometriosis-associated ovarian epithelial tumors were younger, had lower parity, were more frequently premenopausal, had a lower tumor stage or were borderline, and in general had better prognosis and longer survival, although they also more frequently had an associated endometrial carcinoma. Associated endometriosis and endometrioid tumors were generally estrogen-receptor positive, whereas they were negative in the clear cell tumor component. p53 protein positivity was generally observed in clear cell tumors and in associated endometriosis. Two reported cases with previous, known endometriosis were followed in their evolution to borderline endometrioid carcinoma and clear cell carcinoma, respectively. Conclusions Our results and review of the literature suggest that the association of ovarian epithelial tumors and endometriosis is a factor for good prognosis for ovarian cancer and that this association might correspond in many cases to an intermediate stage in the development of endometriosis to endometrioid, clear cell, or other invasive carcinomas.
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9
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Carvalho VPD, Grassi ML, Palma CDS, Carrara HHA, Faça VM, Candido Dos Reis FJ, Poersch A. The contribution and perspectives of proteomics to uncover ovarian cancer tumor markers. Transl Res 2019; 206:71-90. [PMID: 30529050 DOI: 10.1016/j.trsl.2018.11.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 11/07/2018] [Accepted: 11/13/2018] [Indexed: 12/13/2022]
Abstract
Despite all the advances in understanding the mechanisms involved in ovarian cancer (OC) development, many aspects still need to be unraveled and understood. Tumor markers (TMs) are of special interest in this disease. Some aspects of clinical management of OC might be improved by the use of validated TMs, such as differentiating subtypes, defining the most appropriate treatment, monitoring the course of the disease, or predicting clinical outcome. The Food and Drug Administration (FDA) has approved a few TMs for OC: CA125 (cancer antigen 125; monitoring), HE4 (Human epididymis protein; monitoring), ROMA (Risk Of Malignancy Algorithm; HE4+CA125; prediction of malignancy) and OVA1 (Vermillion's first-generation Multivariate Index Assay [MIA]; prediction of malignancy). Proteomics can help advance the research in the field of TMs for OC. A variety of biological materials are being used in proteomic analysis, among them tumor tissues, interstitial fluids, tumor fluids, ascites, plasma, and ovarian cancer cell lines. However, the discovery and validation of new TMs for OC is still very challenging. The enormous heterogeneity of histological types of samples and the individual variability of patients (lifestyle, comorbidities, drug use, and family history) are difficult to overcome in research protocols. In this work, we sought to gather relevant information regarding TMs, OC, biological samples for proteomic analysis, as well as markers and algorithms approved by the FDA for use in clinical routine.
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Affiliation(s)
| | - Mariana Lopes Grassi
- Department of Biochemistry and Immunology, FMRP, University of São Paulo, Ribeirão Preto, SP, Brazil; Center for Cell Based Therapy, Hemotherapy Center of Ribeirão Preto, Ribeirão Preto, SP, Brazil
| | - Camila de Souza Palma
- Department of Biochemistry and Immunology, FMRP, University of São Paulo, Ribeirão Preto, SP, Brazil; Center for Cell Based Therapy, Hemotherapy Center of Ribeirão Preto, Ribeirão Preto, SP, Brazil
| | | | - Vitor Marcel Faça
- Department of Biochemistry and Immunology, FMRP, University of São Paulo, Ribeirão Preto, SP, Brazil; Center for Cell Based Therapy, Hemotherapy Center of Ribeirão Preto, Ribeirão Preto, SP, Brazil
| | | | - Aline Poersch
- Department of Biochemistry and Immunology, FMRP, University of São Paulo, Ribeirão Preto, SP, Brazil; Center for Cell Based Therapy, Hemotherapy Center of Ribeirão Preto, Ribeirão Preto, SP, Brazil.
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10
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Abstract
Endometriosis-associated cancers include clear cell and endometrioid ovarian carcinoma. A history of endometriosis has long been considered to be a risk factor for later development of these malignancies; however, recent molecular genetic evidence has provided unequivocal evidence that these lesions are in fact the precursors for endometriosis-associated cancers. Herein, we will explore the relationship between endometriosis and ovarian carcinomas, similarities between the premalignant lesions and their cancerous counterparts, and the potential role of mutations and the ovarian microenvironment that may contribute to malignant transformation.
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11
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Oral E, Aydin O, Kumbak BA, İlvan S, Yilmaz H, Tustas E, Bese T, Demirkiran F, Arvas M. Concomitant endometriosis in malignant and borderline ovarian tumours. J OBSTET GYNAECOL 2018; 38:1104-1109. [DOI: 10.1080/01443615.2018.1441815] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Engin Oral
- Department of Obstetrics and Gynecology, Cerrahpasa Medical School, İstanbul University, İstanbul, Turkey
| | - Ovgu Aydin
- Department of Pathology, Cerrahpasa Medical School, İstanbul University, İstanbul, Turkey
| | - Banu Aygun Kumbak
- Department of Obstetrics and Gynecology, İstanbul Aydin University, İstanbul, Turkey
| | - Sennur İlvan
- Department of Pathology, Cerrahpasa Medical School, İstanbul University, İstanbul, Turkey
| | - Handan Yilmaz
- Department of Obstetrics and Gynecology, Cerrahpasa Medical School, İstanbul University, İstanbul, Turkey
| | - Esra Tustas
- Umraniye Education and Research Hospital, İstanbul, Turkey
| | - Tugan Bese
- Department of Obstetrics and Gynecology, Cerrahpasa Medical School, İstanbul University, İstanbul, Turkey
| | - Fuat Demirkiran
- Department of Obstetrics and Gynecology, Cerrahpasa Medical School, İstanbul University, İstanbul, Turkey
| | - Macit Arvas
- Department of Obstetrics and Gynecology, Cerrahpasa Medical School, İstanbul University, İstanbul, Turkey
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13
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Hanley GE, McAlpine JN, Miller D, Huntsman D, Schrader KA, Blake Gilks C, Mitchell G. A population-based analysis of germline BRCA1 and BRCA2 testing among ovarian cancer patients in an era of histotype-specific approaches to ovarian cancer prevention. BMC Cancer 2018; 18:254. [PMID: 29506471 PMCID: PMC5838948 DOI: 10.1186/s12885-018-4153-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 02/20/2018] [Indexed: 01/09/2023] Open
Abstract
Background Identifying female carriers of BRCA1 and BRCA2 mutations is imperative for prevention of ovarian cancer and breast cancer. There are five major histologic subtypes of ovarian cancer and high grade serous cancer (the most common) is reported in 75–100% of BRCA1 and BRCA2 mutation carriers. We examined histology-based referral to the Hereditary Cancer Program following an educational prevention campaign recommending BRCA1 and BRCA2 mutation screening for all high-grade serous cancer patients. Methods We conducted a population-based retrospective study in the province of British Columbia, Canada that included all patients visiting the Hereditary Cancer Program for genetic counselling for BRCA1 and BRCA2 mutation between 2001 and 2014. We examined the difference in rates of BRCA1 and BRCA2 testing between serous cancer patients and endometrioid and clear cell cancer patients using a differences in differences analysis. We also calculated the mean number of family members tested for every BRCA1 and BRCA2 identified ovarian cancer patient before and after the educational campaign. Results There were 5712 women tested for a BRCA1 and BRCA2 mutation at the HCP between 2001 and 2014, 887 of which had previously received a diagnosis of ovarian cancer. By 2013, 43% of serous cancer patients were being tested for BRCA1 and BRCA2 mutations compared with 20% of endometrioid and clear cell patients (p < 0.001). The mean number of family members tested for each BRCA1 and BRCA2 positive ovarian cancer patient increased after the educational campaign from 2.54 to 3.27 (p = 0.071), and the number of family members identified as BRCA positive also increased significantly. Conclusions Recommendations for histology-based referral significantly increased the likelihood of serous cancer patients being tested for BRCA mutations. There was also an increase in the number of carrier tests performed for each BRCA1 and BRCA2 index ovarian cancer patient. Electronic supplementary material The online version of this article (10.1186/s12885-018-4153-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Gillian E Hanley
- Department of Obstetrics & Gynaecology, University of British Columbia, Vancouver, BC, Canada.
| | - Jessica N McAlpine
- Department of Obstetrics & Gynaecology, University of British Columbia, Vancouver, BC, Canada
| | - Dianne Miller
- Department of Obstetrics & Gynaecology, University of British Columbia, Vancouver, BC, Canada
| | - David Huntsman
- Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Kasmintan A Schrader
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - C Blake Gilks
- Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Gillian Mitchell
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
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14
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Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer. Nat Commun 2017; 8:14470. [PMID: 28262727 PMCID: PMC5343481 DOI: 10.1038/ncomms14470] [Citation(s) in RCA: 244] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 01/03/2017] [Indexed: 12/19/2022] Open
Abstract
Advanced ovarian cancers are highly metastatic due to frequent peritoneal dissemination, resulting in dismal prognosis. Here we report the functions of cancer-derived extracellular vesicles (EVs), which are emerging as important mediators of tumour metastasis. The EVs from highly metastatic cells strongly induce metastatic behaviour in moderately metastatic tumours. Notably, the cancer EVs efficiently induce apoptotic cell death in human mesothelial cells in vitro and in vivo, thus resulting in the destruction of the peritoneal mesothelium barrier. Whole transcriptome analysis shows that MMP1 is significantly elevated in mesothelial cells treated with highly metastatic cancer EVs and intact MMP1 mRNAs are selectively packaged in the EVs. Importantly, MMP1 expression in ovarian cancer is tightly correlated with a poor prognosis. Moreover, MMP1 mRNA-carrying EVs exist in the ascites of cancer patients and these EVs also induce apoptosis in mesothelial cells. Our findings elucidate a previously unknown mechanism of peritoneal dissemination via EVs. Ovarian cancer is particularly deadly because it is difficult to detect at the pre-metastatic stage; extracellular vesicles (EVs) on the other hand are involved in the pre-metastatic niche preparation. Here the authors show that EVs mediate ovarian cancer metastasis in the peritoneal area by targeting the mesothelium.
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Brüggmann D, Pulch K, Klingelhöfer D, Pearce CL, Groneberg DA. Ovarian cancer: density equalizing mapping of the global research architecture. Int J Health Geogr 2017; 16:3. [PMID: 28086974 PMCID: PMC5237222 DOI: 10.1186/s12942-016-0076-2] [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: 02/29/2016] [Accepted: 12/08/2016] [Indexed: 12/22/2022] Open
Abstract
Background Despite its impact on female health worldwide, no efforts have been made to depict the global architecture of ovarian cancer research and to understand the trends in the related literature. Hence, it was the objective of this study to assess the global scientific performance chronologically, geographically and in regards to economic benchmarks using bibliometric tools and density equalizing map projections. Methods The NewQIS platform was employed to identify all ovarian cancer related articles published in the Web of Science since 1900. The items were analyzed regarding quantitative aspects (e.g. publication date, country of origin) and parameters describing the recognition of the work by the scientific community (e.g. citation rates). Results 23,378 articles on ovarian cancer were analyzed. The USA had the highest activity of ovarian cancer research with a total of n = 9312 ovarian cancer-specific publications, followed by the UK (n = 1900), China (n = 1813), Germany (n = 1717) and Japan (n = 1673). Ovarian cancer-specific country h-index also showed a leading position of the USA with an h-index (HI) of 207, followed by the UK (HI = 122), Canada (HI = 99), Italy (HI = 97), Germany (HI = 84), and Japan (HI = 81). In the socio-economic analysis, the USA were ranked first with an average of 175.6 ovarian cancer-related publications per GDP per capita in 1000 US-$, followed by Italy with an index level of 46.85, the UK with 45.48, and Japan with 43.3. Overall, the USA and Western European nations, China and Japan constituted the scientific power players publishing the majority of highly cited ovarian cancer-related articles and dominated international collaborative efforts. African, Asian and South American countries played almost no visible role in the scientific community. Conclusions The quantity and scientific recognition of publications related to ovarian cancer are continuously increasing. The research endeavors in the field are concentrated in high-income countries with no involvement of lower-resource nations. Hence, worldwide collaborative efforts with the aim to exchange epidemiologic data, resources and knowledge have to be strengthened in the future to successfully alleviate the global burden related to ovarian cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12942-016-0076-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Dörthe Brüggmann
- Department of Obstetrics and Gynecology, Keck School of Medicine of USC, Los Angeles, CA, USA. .,Department of Female Health and Preventive Medicine, Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe-University, Theodor-Stern Kai 7, 60590, Frankfurt, Germany.
| | - Katharina Pulch
- Department of Female Health and Preventive Medicine, Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe-University, Theodor-Stern Kai 7, 60590, Frankfurt, Germany
| | - Doris Klingelhöfer
- Department of Female Health and Preventive Medicine, Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe-University, Theodor-Stern Kai 7, 60590, Frankfurt, Germany
| | - Celeste Leigh Pearce
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - David A Groneberg
- Department of Female Health and Preventive Medicine, Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe-University, Theodor-Stern Kai 7, 60590, Frankfurt, Germany
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Kondrashova O, Love CJ, Lunke S, Hsu AL, Waring PM, Taylor GR. High-Throughput Amplicon-Based Copy Number Detection of 11 Genes in Formalin-Fixed Paraffin-Embedded Ovarian Tumour Samples by MLPA-Seq. PLoS One 2015; 10:e0143006. [PMID: 26569395 PMCID: PMC4646639 DOI: 10.1371/journal.pone.0143006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 10/29/2015] [Indexed: 11/19/2022] Open
Abstract
Whilst next generation sequencing can report point mutations in fixed tissue tumour samples reliably, the accurate determination of copy number is more challenging. The conventional Multiplex Ligation-dependent Probe Amplification (MLPA) assay is an effective tool for measurement of gene dosage, but is restricted to around 50 targets due to size resolution of the MLPA probes. By switching from a size-resolved format, to a sequence-resolved format we developed a scalable, high-throughput, quantitative assay. MLPA-seq is capable of detecting deletions, duplications, and amplifications in as little as 5ng of genomic DNA, including from formalin-fixed paraffin-embedded (FFPE) tumour samples. We show that this method can detect BRCA1, BRCA2, ERBB2 and CCNE1 copy number changes in DNA extracted from snap-frozen and FFPE tumour tissue, with 100% sensitivity and >99.5% specificity.
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Affiliation(s)
- Olga Kondrashova
- Department of Pathology, University of Melbourne, Melbourne, VIC, Australia
| | - Clare J. Love
- Department of Pathology, University of Melbourne, Melbourne, VIC, Australia
| | - Sebastian Lunke
- Department of Pathology, University of Melbourne, Melbourne, VIC, Australia
| | - Arthur L. Hsu
- Department of Pathology, University of Melbourne, Melbourne, VIC, Australia
| | - Australian Ovarian Cancer Study (AOCS) Group
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, and Departments of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Paul M. Waring
- Department of Pathology, University of Melbourne, Melbourne, VIC, Australia
| | - Graham R. Taylor
- Department of Pathology, University of Melbourne, Melbourne, VIC, Australia
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17
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Hanley GE, McAlpine JN, Kwon JS, Mitchell G. Opportunistic salpingectomy for ovarian cancer prevention. GYNECOLOGIC ONCOLOGY RESEARCH AND PRACTICE 2015; 2:5. [PMID: 27231565 PMCID: PMC4881168 DOI: 10.1186/s40661-015-0014-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 09/09/2015] [Indexed: 04/29/2023]
Abstract
Recently accumulated evidence has strongly indicated that the fallopian tube is the site of origin for the majority of high-grade serous ovarian or peritoneal carcinomas. As a result, recommendations have been made to change surgical practice in women at general population risk for ovarian cancer and perform bilateral salpingectomy at the time of hysterectomy without oophorectomy and in lieu of tubal ligation, a practice that has been termed opportunistic salpingectomy (OS). Despite suggestions that bilateral salpingectomy may be used as an interim procedure in women with BRCA1/2 mutations, enabling them to delay oophorectomy, there is insufficient evidence to support this practice as a safe alternative and risk-reducing bilateral salpingo-oophorectomy remains the recommended standard of care for high-risk women. While evidence on uptake of OS is sparse, it points toward increasing practice of OS during hysterectomy. The practice of OS for sterilization purposes, although expanding, appears to be less common. Operative and perioperative complications as measured by administered blood transfusions, hospital length of stay and readmissions were not increased with the addition of OS either at time of hysterectomy or for sterilization. Additional operating room time was 16 and 10 min for OS with hysterectomy and OS for sterilization, respectively. Short-term studies of the consequences of OS on ovarian function indicate no difference between women undergoing hysterectomy alone and hysterectomy with OS, but no long-term data exist. There is emerging evidence of effectiveness of excisional sterilization on reducing ovarian cancer rates from Rochester (OR = 0.36 95 % CI 0.13, 1.02), and bilateral salpingectomy from Denmark (OR = 0.58 95 % CI 0.36, 0.95) and Sweden (HR = 0.35, 95 % CI 0.17, 0.73), but these studies suffer from limitations, including that they were performed for pathological rather than prophylactic purposes. Initial cost-effectiveness modeling indicates that OS is cost-effective over a wide range of costs and risk estimates. While preliminary safety, efficacy, and cost-effectiveness data are promising, further research is needed (particularly long-term data on ovarian function) to firmly establish the safety of the procedure. The marginal benefit of OS compared with tubal ligation or hysterectomy alone needs to be established through large prospective studies of OS done for prophylaxis.
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Affiliation(s)
- Gillian E Hanley
- Department of Gynaecology and Obstetrics, Division of Gynaecologic Oncology, University of British Columbia, Vancouver, BC Canada
| | - Jessica N McAlpine
- Department of Gynaecology and Obstetrics, Division of Gynaecologic Oncology, University of British Columbia, Vancouver, BC Canada
| | - Janice S Kwon
- Department of Gynaecology and Obstetrics, Division of Gynaecologic Oncology, University of British Columbia, Vancouver, BC Canada
| | - Gillian Mitchell
- Hereditary Cancer Program, BC Cancer Agency, Vancouver, BC Canada ; Department of Medicine, University of British Columbia, Vancouver, BC Canada
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18
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Crane EK, Kwan SY, Izaguirre DI, Tsang YTM, Mullany LK, Zu Z, Richards JS, Gershenson DM, Wong KK. Nutlin-3a: A Potential Therapeutic Opportunity for TP53 Wild-Type Ovarian Carcinomas. PLoS One 2015; 10:e0135101. [PMID: 26248031 PMCID: PMC4527847 DOI: 10.1371/journal.pone.0135101] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 07/16/2015] [Indexed: 11/20/2022] Open
Abstract
Epithelial ovarian cancer is a diverse molecular and clinical disease, yet standard treatment is the same for all subtypes. TP53 mutations represent a node of divergence in epithelial ovarian cancer histologic subtypes and may represent a therapeutic opportunity in subtypes expressing wild type, including most low-grade ovarian serous carcinomas, ovarian clear cell carcinomas and ovarian endometrioid carcinomas, which represent approximately 25% of all epithelial ovarian cancer. We therefore sought to investigate Nutlin-3a--a therapeutic which inhibits MDM2, activates wild-type p53, and induces apoptosis--as a therapeutic compound for TP53 wild-type ovarian carcinomas. Fifteen epithelial ovarian cancer cell lines of varying histologic subtypes were treated with Nutlin-3a with determination of IC50 values. Western Blot (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) analyses quantified MDM2, p53, and p21 expression after Nutlin-3a treatment. DNA from 15 cell lines was then sequenced for TP53 mutations in exons 2-11 including intron-exon boundaries. Responses to Nutlin-3a were dependent upon TP53 mutation status. By qRT-PCR and WB, levels of MDM2 and p21 were upregulated in wild-type TP53 sensitive cell lines, and p21 induction was reduced or absent in mutant cell lines. Annexin V assays demonstrated apoptosis in sensitive cell lines treated with Nutlin-3a. Thus, Nutlin-3a could be a potential therapeutic agent for ovarian carcinomas expressing wild-type TP53 and warrants further investigation.
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Affiliation(s)
- Erin K. Crane
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Suet-Yan Kwan
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Cancer Biology Program, The University of Texas at Houston Graduate School of Biomedical Sciences, Houston, Texas, United States of America
| | - Daisy I. Izaguirre
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Cancer Biology Program, The University of Texas at Houston Graduate School of Biomedical Sciences, Houston, Texas, United States of America
| | - Yvonne T. M. Tsang
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Lisa K. Mullany
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Zhifei Zu
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - JoAnne S. Richards
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
| | - David M. Gershenson
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Kwong-Kwok Wong
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Cancer Biology Program, The University of Texas at Houston Graduate School of Biomedical Sciences, Houston, Texas, United States of America
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19
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McCluggage WG, Judge MJ, Clarke BA, Davidson B, Gilks CB, Hollema H, Ledermann JA, Matias-Guiu X, Mikami Y, Stewart CJR, Vang R, Hirschowitz L. Data set for reporting of ovary, fallopian tube and primary peritoneal carcinoma: recommendations from the International Collaboration on Cancer Reporting (ICCR). Mod Pathol 2015; 28:1101-22. [PMID: 26089092 DOI: 10.1038/modpathol.2015.77] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 02/24/2015] [Accepted: 02/25/2015] [Indexed: 12/20/2022]
Abstract
A comprehensive pathological report is essential for optimal patient management, cancer staging and prognostication. In many countries, proforma reports are used but these vary in their content. The International Collaboration on Cancer Reporting (ICCR) is an alliance formed by the Royal College of Pathologists of Australasia, the Royal College of Pathologists of the United Kingdom, the College of American Pathologists, the Canadian Partnership Against Cancer and the European Society of Pathology, with the aim of developing an evidence-based reporting data set for each cancer site. This will reduce the global burden of cancer data set development and reduplication of effort by different international institutions that commission, publish and maintain standardised cancer reporting data sets. The resultant standardisation of cancer reporting will benefit not only those countries directly involved in the collaboration but also others not in a position to develop their own data sets. We describe the development of a cancer data set by the ICCR expert panel for the reporting of primary ovarian, fallopian tube and peritoneal carcinoma and present the 'required' and 'recommended' elements to be included in the report with an explanatory commentary. This data set encompasses the recent International Federation of Obstetricians and Gynaecologists staging system for these neoplasms and the updated World Health Organisation Classification of Tumours of the Female Reproductive Organs. The data set also addresses issues about site assignment of the primary tumour in high-grade serous carcinomas and proposes a scoring system for the assessment of tumour response to neoadjuvant chemotherapy. The widespread implementation of this data set will facilitate consistent and accurate data collection, comparison of epidemiological and pathological parameters between different populations, facilitate research and hopefully will result in improved patient management.
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Affiliation(s)
- W Glenn McCluggage
- Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK
| | - Meagan J Judge
- Royal College of Pathologists of Australasia, Sydney, NSW, Australia
| | - Blaise A Clarke
- Department of Pathology and Laboratory Medicine, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Ben Davidson
- 1] Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway [2] Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - C Blake Gilks
- Department of Pathology, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Harry Hollema
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Xavier Matias-Guiu
- Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLleida, Lleida, Spain
| | - Yoshiki Mikami
- Department of Diagnostic Pathology, Kumamoto University Hospital, Kumamoto, Japan
| | - Colin J R Stewart
- 1] Department of Histopathology, King Edward Memorial Hospital, Perth, WA, Australia [2] School for Women's and Infant's Health, University of Western Australia, Crawley, WA, Australia
| | - Russell Vang
- Department of Pathology (Division of Gynecologic Pathology), The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lynn Hirschowitz
- Department of Cellular Pathology, Birmingham Women's Hospital, Birmingham, UK
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20
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Inhibition of adhesion, proliferation, and invasion of primary endometriosis and endometrial stromal and ovarian carcinoma cells by a nonhyaluronan adhesion barrier gel. BIOMED RESEARCH INTERNATIONAL 2015; 2015:450468. [PMID: 25785270 PMCID: PMC4345068 DOI: 10.1155/2015/450468] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Revised: 01/23/2015] [Accepted: 01/28/2015] [Indexed: 11/17/2022]
Abstract
Endometriosis is a chronic disease of women in the reproductive age, defined as endometrial cells growing outside of the uterine cavity and associated with relapses. Relapses are hypothesized to correlate with incomplete surgical excision or result from nonrandom implantation of new endometrial implants in adjacent peritoneum. Thus, surgical excision could lead to free endometriotic cells or tissue residues, which readhere, grow, and invade into recurrent lesions. Barrier agents are frequently used to prevent postoperative adhesions. We tested if the absorbable cell adhesion barrier gel Intercoat consisting of polyethylene oxide and sodium carboxymethyl cellulose could inhibit cellular adhesion, proliferation, and invasion of primary endometriosis and endometrial cells. Due to an association of endometriosis with ovarian carcinoma, we tested two ovarian carcinoma cell lines. Prior to cell seeding, a drop of the barrier gel was placed in cell culture wells in order to test inhibition of adherence and proliferation or coated over a polymerized collagen gel to assay for prevention of invasion. Results showed that the barrier gel significantly inhibited cell adherence, proliferation, and invasion of endometriosis and endometrial stromal cells as well as ovarian carcinoma cells in culture. Our findings could help to prevent local cell growth/invasion and possible consequent recurrences.
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21
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Cancer genomics: why rare is valuable. J Mol Med (Berl) 2015; 93:369-81. [PMID: 25676695 PMCID: PMC4366545 DOI: 10.1007/s00109-015-1260-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 12/26/2014] [Accepted: 01/29/2015] [Indexed: 02/07/2023]
Abstract
Rare conditions are sometimes ignored in biomedical research because of difficulties in obtaining specimens and limited interest from fund raisers. However, the study of rare diseases such as unusual cancers has again and again led to breakthroughs in our understanding of more common diseases. It is therefore unsurprising that with the development and accessibility of next-generation sequencing, much has been learnt from studying cancers that are rare and in particular those with uniform biological and clinical behavior. Herein, we describe how shotgun sequencing of cancers such as granulosa cell tumor, endometrial stromal sarcoma, epithelioid hemangioendothelioma, ameloblastoma, small-cell carcinoma of the ovary, clear-cell carcinoma of the ovary, nonepithelial ovarian tumors, chondroblastoma, and giant cell tumor of the bone has led to rapidly translatable discoveries in diagnostics and tumor taxonomies, as well as providing insights into cancer biology.
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22
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Aci�n P, Velasco I, Aci�n M, Capello C, Vela P. Epithelial Ovarian Cancers and Endometriosis. Gynecol Obstet Invest 2015; 79:126-35. [DOI: 10.1159/000367597] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Accepted: 08/14/2014] [Indexed: 11/19/2022]
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23
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Gadducci A, Lanfredini N, Tana R. Novel insights on the malignant transformation of endometriosis into ovarian carcinoma. Gynecol Endocrinol 2014; 30:612-7. [PMID: 24905724 DOI: 10.3109/09513590.2014.926325] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The malignant transformation of endometriosis is an uncommon event, which happens in 0.7-2.5% of the cases, and, when occurs, it usually involves the ovary. A 2 to 3-fold higher risk of ovarian endometrioid and clear cell carcinoma has been reported in women with endometriosis. Pathological studies have detected a morphological continuum of sequential steps from normal endometriotic cyst epithelium to atypical endometriosis and finally to invasive carcinoma. Ovarian endometrioid carcinoma harbors mutations of CTNNB1 in 16-53.3%, of PTEN in 14-20% and of ARID1A in 30-55% of the cases. Ovarian clear cell carcinoma harbors mutations of PIK3CA in 20-40% and of ARID1 in 15-75% of the cases. Whereas estrogen receptors and progesterone receptors are quite always absent, HNF-1b is often over-expressed in this histotype. Atypical endometriosis and endometriosis-related ovarian neoplasms share molecular alterations, such as PTEN mutations, ARID1A mutations and up-regulation of HNF-1b. Moreover, ARID1A mutations have been noted in clear cell tumors and contiguous atypical endometriosis, but not in distant endometriotic lesions. The loss of BAF250a protein expression is suggestive for the presence of ARID1A mutations, and represents an useful marker of malignant transformation of endometriosis.
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Affiliation(s)
- Angiolo Gadducci
- Department of Clinical and Experimental Medicine, Division of Gynecology and Obstetrics, University of Pisa , Pisa , Italy
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Chromosome 20q13.2 ZNF217 locus amplification correlates with decreased E-cadherin expression in ovarian clear cell carcinoma with PI3K-Akt pathway alterations. Hum Pathol 2014; 45:2318-25. [PMID: 25281027 DOI: 10.1016/j.humpath.2014.07.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2014] [Revised: 07/29/2014] [Accepted: 07/30/2014] [Indexed: 11/23/2022]
Abstract
This study aims to evaluate the relationships between chromosome 20q13.2 zinc finger protein 217 (ZNF217) locus amplification, ZNF217 expression, E-cadherin expression, and PI3K-Akt pathway alterations (activating PIK3CA mutations or loss of phosphatase and tensin homolog [PTEN] expression), and whether these molecular alterations can predict the clinical survival data in ovarian clear cell carcinoma (OCCC) patients. Samples and clinical data of 72 OCCC patients were collected. Chromosome 20q13.2 ZNF217 locus amplification was detected by fluorescence in situ hybridization. ZNF217, E-cadherin and PTEN expression were assessed using immunohistochemical stain. PIK3CA mutation was identified by PCR-amplified gene sequencing. Cox proportional hazard regression model was used to estimate the adjusted hazard ratios of survival. Chromosome 20q13.2 ZNF217 locus amplification was detected in 31% (22/72) of cases, and ZNF217 expression was increased in 40% (27/68) of cases. E-cadherin and PTEN expressions were decreased or lost in 44% (32/72) and 14% (10/72) of cases, respectively. Activating PIK3CA mutations were present in 35% (25/72) of cases. Thirty-three OCCC patients (46%) showed activating PI3K-Akt pathway alterations. Chromosome 20q13.2 ZNF217 locus amplification was significantly associated with decreased E-cadherin expression (P = .001). In contrast, ZNF217 expression was not related to ZNF217 amplification or E-cadherin expression. In OCCC patients with activating PI3k-Akt pathway, decreased E-cadherin expression (P = .033) and advanced Federation of Gynecology and Obstetrics stage (P = .014) predicted shorter overall survival. Two conclusions were raised in our study. First, ZNF217 plays a role in down-regulating E-cadherin expression and is a potential therapeutic target for OCCC patients. Second, E-cadherin expression is a prognostic marker for OCCC patients with activating PI3K-Akt pathway.
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Germline BRCA1 and BRCA2 mutations in ovarian cancer: utility of a histology-based referral strategy. Obstet Gynecol 2014; 120:235-40. [PMID: 22776961 DOI: 10.1097/aog.0b013e31825f3576] [Citation(s) in RCA: 112] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To estimate the frequency of BRCA1 and BRCA2 germline mutations in women with nonmucinous epithelial ovarian carcinoma unselected for a family history of breast or ovarian cancer. METHODS From 2004 to 2009, women undergoing surgical staging for nonmucinous epithelial ovarian carcinoma, including fallopian tube and primary peritoneal carcinoma, were invited to participate in tumor banking and genetic counseling for BRCA1 and BRCA2 mutations. Pathology and family history obtained by the gynecologic oncology surgeon and genetic counselors were reviewed. RESULTS Of 131 women fulfilling entry criteria, germline BRCA1 and BRCA2 mutations were found in 20% (26/131) and were exclusively associated with high-grade serous histology (26/103 [25%]). Restricting BRCA1 and BRCA2 testing to women with family histories of hereditary breast and ovarian cancer, as ascertained by the surgeon, missed 14 mutation carriers, lowering detection rates to 9% (12/131) or 11.6% (12/103) if only considering the patients with high-grade serous histology. This improved to 16% (21/131) or 20.4% (21/103) when ascertained by the genetic counselor; however, 5 of 26 (19%) mutation carriers did not have a family history of hereditary breast or ovarian cancer. CONCLUSION Germline BRCA1 and BRCA2 mutations in ovarian (pelvic) cancer are associated with high-grade serous histology. The high incidence (25%) of germline BRCA1 and BRCA2 mutations specific to the high-grade serous subtype suggests that genetic assessment of all women diagnosed with high-grade serous ovarian (pelvic) carcinoma will improve detection rates and capture mutation carriers otherwise missed by referral based on family history alone. LEVEL OF EVIDENCE II.
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Earp MA, Kelemen LE, Magliocco AM, Swenerton KD, Chenevix-Trench G, Lu Y, Hein A, Ekici AB, Beckmann MW, Fasching PA, Lambrechts D, Despierre E, Vergote I, Lambrechts S, Doherty JA, Rossing MA, Chang-Claude J, Rudolph A, Friel G, Moysich KB, Odunsi K, Sucheston-Campbell L, Lurie G, Goodman MT, Carney ME, Thompson PJ, Runnebaum IB, Dürst M, Hillemanns P, Dörk T, Antonenkova N, Bogdanova N, Leminen A, Nevanlinna H, Pelttari LM, Butzow R, Bunker CH, Modugno F, Edwards RP, Ness RB, du Bois A, Heitz F, Schwaab I, Harter P, Karlan BY, Walsh C, Lester J, Jensen A, Kjær SK, Høgdall CK, Høgdall E, Lundvall L, Sellers TA, Fridley BL, Goode EL, Cunningham JM, Vierkant RA, Giles GG, Baglietto L, Severi G, Southey MC, Liang D, Wu X, Lu K, Hildebrandt MAT, Levine DA, Bisogna M, Schildkraut JM, Iversen ES, Weber RP, Berchuck A, Cramer DW, Terry KL, Poole EM, Tworoger SS, Bandera EV, Chandran U, Orlow I, Olson SH, Wik E, Salvesen HB, Bjorge L, Halle MK, van Altena AM, Aben KKH, Kiemeney LA, Massuger LFAG, Pejovic T, Bean YT, Cybulski C, Gronwald J, Lubinski J, Wentzensen N, Brinton LA, Lissowska J, Garcia-Closas M, Dicks E, Dennis J, Easton DF, Song H, et alEarp MA, Kelemen LE, Magliocco AM, Swenerton KD, Chenevix-Trench G, Lu Y, Hein A, Ekici AB, Beckmann MW, Fasching PA, Lambrechts D, Despierre E, Vergote I, Lambrechts S, Doherty JA, Rossing MA, Chang-Claude J, Rudolph A, Friel G, Moysich KB, Odunsi K, Sucheston-Campbell L, Lurie G, Goodman MT, Carney ME, Thompson PJ, Runnebaum IB, Dürst M, Hillemanns P, Dörk T, Antonenkova N, Bogdanova N, Leminen A, Nevanlinna H, Pelttari LM, Butzow R, Bunker CH, Modugno F, Edwards RP, Ness RB, du Bois A, Heitz F, Schwaab I, Harter P, Karlan BY, Walsh C, Lester J, Jensen A, Kjær SK, Høgdall CK, Høgdall E, Lundvall L, Sellers TA, Fridley BL, Goode EL, Cunningham JM, Vierkant RA, Giles GG, Baglietto L, Severi G, Southey MC, Liang D, Wu X, Lu K, Hildebrandt MAT, Levine DA, Bisogna M, Schildkraut JM, Iversen ES, Weber RP, Berchuck A, Cramer DW, Terry KL, Poole EM, Tworoger SS, Bandera EV, Chandran U, Orlow I, Olson SH, Wik E, Salvesen HB, Bjorge L, Halle MK, van Altena AM, Aben KKH, Kiemeney LA, Massuger LFAG, Pejovic T, Bean YT, Cybulski C, Gronwald J, Lubinski J, Wentzensen N, Brinton LA, Lissowska J, Garcia-Closas M, Dicks E, Dennis J, Easton DF, Song H, Tyrer JP, Pharoah PDP, Eccles D, Campbell IG, Whittemore AS, McGuire V, Sieh W, Rothstein JH, Flanagan JM, Paul J, Brown R, Phelan CM, Risch HA, McLaughlin JR, Narod SA, Ziogas A, Anton-Culver H, Gentry-Maharaj A, Menon U, Gayther SA, Ramus SJ, Wu AH, Pearce CL, Pike MC, Dansonka-Mieszkowska A, Rzepecka IK, Szafron LM, Kupryjanczyk J, Cook LS, Le ND, Brooks-Wilson A. Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA. Hum Genet 2014; 133:481-97. [PMID: 24190013 PMCID: PMC4063682 DOI: 10.1007/s00439-013-1383-3] [Show More Authors] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Accepted: 10/14/2013] [Indexed: 10/26/2022]
Abstract
Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.
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Affiliation(s)
- Madalene A Earp
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada,
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Trabert B, Ness RB, Lo-Ciganic WH, Murphy MA, Goode EL, Poole EM, Brinton LA, Webb PM, Nagle CM, Jordan SJ, Risch HA, Rossing MA, Doherty JA, Goodman MT, Lurie G, Kjær SK, Hogdall E, Jensen A, Cramer DW, Terry KL, Vitonis A, Bandera EV, Olson S, King MG, Chandran U, Anton-Culver H, Ziogas A, Menon U, Gayther SA, Ramus SJ, Gentry-Maharaj A, Wu AH, Pearce CL, Pike MC, Berchuck A, Schildkraut JM, Wentzensen N. Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: a pooled analysis in the Ovarian Cancer Association Consortium. J Natl Cancer Inst 2014; 106:djt431. [PMID: 24503200 DOI: 10.1093/jnci/djt431] [Citation(s) in RCA: 184] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Regular aspirin use is associated with reduced risk of several malignancies. Epidemiologic studies analyzing aspirin, nonaspirin nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen use and ovarian cancer risk have been inconclusive. METHODS We analyzed pooled data from 12 population-based case-control studies of ovarian cancer, including 7776 case patients and 11843 control subjects accrued between 1992 and 2007. Odds ratios (ORs) for associations of medication use with invasive epithelial ovarian cancer were estimated in individual studies using logistic regression and combined using random effects meta-analysis. Associations between frequency, dose, and duration of analgesic use and risk of ovarian cancer were also assessed. All statistical tests were two-sided. RESULTS Aspirin use was associated with a reduced risk of ovarian cancer (OR = 0.91; 95% confidence interval [CI] = 0.84 to 0.99). Results were similar but not statistically significant for nonaspirin NSAIDs, and there was no association with acetaminophen. In seven studies with frequency data, the reduced risk was strongest among daily aspirin users (OR = 0.80; 95% CI = 0.67 to 0.96). In three studies with dose information, the reduced risk was strongest among users of low dose (<100 mg) aspirin (OR = 0.66; 95% CI = 0.53 to 0.83), whereas for nonaspirin NSAIDs, the reduced risk was strongest for high dose (≥500 mg) usage (OR = 0.76; 95% CI = 0.64 to 0.91). CONCLUSIONS Aspirin use was associated with a reduced risk of ovarian cancer, especially among daily users of low-dose aspirin. These findings suggest that the same aspirin regimen proven to protect against cardiovascular events and several cancers could reduce the risk of ovarian cancer 20% to 34% depending on frequency and dose of use.
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Affiliation(s)
- Britton Trabert
- Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (BT, LAB, NW); University of Texas School of Public Health, Houston, TX (RBN); Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA (WL); Channing Division of Network Medicine (MAM, EMP) and Obstetrics and Gynecology Epidemiology Center (DWC, KLT), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Epidemiology, Harvard School of Public Health, Boston, MA (MAM, EMP, DWC, KLT); Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, MN (ELG); Queensland Institute of Medical Research, Brisbane, Australia (PMW, CMN, SJJ, Australian Ovarian Cancer Study Group, the Australian Cancer Study (Ovarian Cancer); Peter MacCallum Cancer Centre, East Melbourne, Australia (Australian Ovarian Cancer Study Group); Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT (HAR); Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA (MAR, JAD); Department of Community and Family Medicine, Section of Biostatistics & Epidemiology, Dartmouth Medical School, Lebanon, NH (JAD); Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA (MTG); Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI (GL); Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark (SKK, EH, AJ); Gynaecologic Clinic, Copenhagen University Hospital, Copenhagen, Denmark (SKK); The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ (EVB, MGK, UC); Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY (SO); Department of Epidemiology, School of Medicine, University of California Irvine, Irvine, CA (HA, AZ); Department of Women's Cancer, University College London, EGA Institute for Wo
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Modi DA, Sunoqrot S, Bugno J, Lantvit DD, Hong S, Burdette JE. Targeting of follicle stimulating hormone peptide-conjugated dendrimers to ovarian cancer cells. NANOSCALE 2014; 6:2812-20. [PMID: 24468839 DOI: 10.1039/c3nr05042d] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Ovarian cancer is the most lethal gynecological malignancy. Current treatment modalities include a combination of surgery and chemotherapy, which often lead to loss of fertility in premenopausal women and a myriad of systemic side effects. To address these issues, we have designed poly(amidoamine) (PAMAM) dendrimers to selectively target the follicle stimulating hormone receptor (FSHR), which is overexpressed by tumorigenic ovarian cancer cells but not by immature primordial follicles and other non-tumorigenic cells. Fluorescein-labeled generation 5 (G5) PAMAM dendrimers were conjugated with the binding peptide domain of FSH (FSH33) that has a high affinity to FSHR. The targeted dendrimers exhibited high receptor selectivity to FSHR-expressing OVCAR-3 cells, resulting in significant uptake and downregulation of an anti-apoptotic protein survivin, while showing minimal interactions with SKOV-3 cells that do not express FSHR. The selectivity of the FSH33-targeted dendrimers was further validated in 3D organ cultures of normal mouse ovaries. Immunostaining of the conjugates revealed their selective binding and uptake by ovarian surface epithelium (OSE) cells that express FSHR, while sparing the immature primordial follicles. In addition, an in vivo study monitoring tissue accumulation following a single intraperitoneal (i.p.) injection of the conjugates showed significantly higher accumulation of FSH33-targeted dendrimers in the ovary and oviduct compared to the non-targeted conjugates. These proof-of-concept findings highlight the potential of these FSH33-targeted dendrimers to serve as a delivery platform for anti-ovarian cancer drugs, while reducing their systemic side effects by preventing nonspecific uptake by the primordial follicles.
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Affiliation(s)
- Dimple A Modi
- Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland Ave. Chicago, IL 60607, USA.
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Terry KL, Karageorgi S, Shvetsov YB, Merritt MA, Lurie G, Thompson PJ, Carney ME, Weber RP, Akushevich L, Lo-Ciganic WH, Cushing-Haugen K, Sieh W, Moysich K, Doherty JA, Nagle CM, Berchuck A, Pearce CL, Pike M, Ness RB, Webb PM, Rossing MA, Schildkraut J, Risch H, Goodman MT. Genital powder use and risk of ovarian cancer: a pooled analysis of 8,525 cases and 9,859 controls. Cancer Prev Res (Phila) 2013; 6:811-21. [PMID: 23761272 PMCID: PMC3766843 DOI: 10.1158/1940-6207.capr-13-0037] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Genital powder use has been associated with risk of epithelial ovarian cancer in some, but not all, epidemiologic investigations, possibly reflecting the carcinogenic effects of talc particles found in most of these products. Whether risk increases with number of genital powder applications and for all histologic types of ovarian cancer also remains uncertain. Therefore, we estimated the association between self-reported genital powder use and epithelial ovarian cancer risk in eight population-based case-control studies. Individual data from each study were collected and harmonized. Lifetime number of genital powder applications was estimated from duration and frequency of use. Pooled ORs were calculated using conditional logistic regression matched on study and age and adjusted for potential confounders. Subtype-specific risks were estimated according to tumor behavior and histology. 8,525 cases and 9,859 controls were included in the analyses. Genital powder use was associated with a modest increased risk of epithelial ovarian cancer [OR, 1.24; 95% confidence interval (CI), 1.15-1.33] relative to women who never used powder. Risk was elevated for invasive serous (OR, 1.20; 95% CI, 1.09-1.32), endometrioid (OR, 1.22; 95% CI, 1.04-1.43), and clear cell (OR, 1.24; 95% CI, 1.01-1.52) tumors, and for borderline serous tumors (OR, 1.46; 95% CI, 1.24-1.72). Among genital powder users, we observed no significant trend (P = 0.17) in risk with increasing number of lifetime applications (assessed in quartiles). We noted no increase in risk among women who only reported nongenital powder use. In summary, genital powder use is a modifiable exposure associated with small-to-moderate increases in risk of most histologic subtypes of epithelial ovarian cancer.
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Affiliation(s)
- Kathryn L Terry
- Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA 02115, USA.
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Shen H, Fridley BL, Song H, Lawrenson K, Cunningham JM, Ramus SJ, Cicek MS, Tyrer J, Stram D, Larson MC, Köbel M, Ziogas A, Zheng W, Yang HP, Wu AH, Wozniak EL, Ling Woo Y, Winterhoff B, Wik E, Whittemore AS, Wentzensen N, Palmieri Weber R, Vitonis AF, Vincent D, Vierkant RA, Vergote I, Van Den Berg D, Van Altena AM, Tworoger SS, Thompson PJ, Tessier DC, Terry KL, Teo SH, Templeman C, Stram DO, Southey MC, Sieh W, Siddiqui N, Shvetsov YB, Shu XO, Shridhar V, Wang-Gohrke S, Severi G, Schwaab I, Salvesen HB, Rzepecka IK, Runnebaum IB, Anne Rossing M, Rodriguez-Rodriguez L, Risch HA, Renner SP, Poole EM, Pike MC, Phelan CM, Pelttari LM, Pejovic T, Paul J, Orlow I, Zawiah Omar S, Olson SH, Odunsi K, Nickels S, Nevanlinna H, Ness RB, Narod SA, Nakanishi T, Moysich KB, Monteiro AN, Moes-Sosnowska J, Modugno F, Menon U, McLaughlin JR, McGuire V, Matsuo K, Mat Adenan NA, Massuger LF, Lurie G, Lundvall L, Lubiński J, Lissowska J, Levine DA, Leminen A, Lee AW, Le ND, Lambrechts S, Lambrechts D, Kupryjanczyk J, Krakstad C, Konecny GE, Krüger Kjaer S, Kiemeney LA, Kelemen LE, Keeney GL, Karlan BY, Karevan R, Kalli KR, Kajiyama H, Ji BT, Jensen A, Jakubowska A, et alShen H, Fridley BL, Song H, Lawrenson K, Cunningham JM, Ramus SJ, Cicek MS, Tyrer J, Stram D, Larson MC, Köbel M, Ziogas A, Zheng W, Yang HP, Wu AH, Wozniak EL, Ling Woo Y, Winterhoff B, Wik E, Whittemore AS, Wentzensen N, Palmieri Weber R, Vitonis AF, Vincent D, Vierkant RA, Vergote I, Van Den Berg D, Van Altena AM, Tworoger SS, Thompson PJ, Tessier DC, Terry KL, Teo SH, Templeman C, Stram DO, Southey MC, Sieh W, Siddiqui N, Shvetsov YB, Shu XO, Shridhar V, Wang-Gohrke S, Severi G, Schwaab I, Salvesen HB, Rzepecka IK, Runnebaum IB, Anne Rossing M, Rodriguez-Rodriguez L, Risch HA, Renner SP, Poole EM, Pike MC, Phelan CM, Pelttari LM, Pejovic T, Paul J, Orlow I, Zawiah Omar S, Olson SH, Odunsi K, Nickels S, Nevanlinna H, Ness RB, Narod SA, Nakanishi T, Moysich KB, Monteiro AN, Moes-Sosnowska J, Modugno F, Menon U, McLaughlin JR, McGuire V, Matsuo K, Mat Adenan NA, Massuger LF, Lurie G, Lundvall L, Lubiński J, Lissowska J, Levine DA, Leminen A, Lee AW, Le ND, Lambrechts S, Lambrechts D, Kupryjanczyk J, Krakstad C, Konecny GE, Krüger Kjaer S, Kiemeney LA, Kelemen LE, Keeney GL, Karlan BY, Karevan R, Kalli KR, Kajiyama H, Ji BT, Jensen A, Jakubowska A, Iversen E, Hosono S, Høgdall CK, Høgdall E, Hoatlin M, Hillemanns P, Heitz F, Hein R, Harter P, Halle MK, Hall P, Gronwald J, Gore M, Goodman MT, Giles GG, Gentry-Maharaj A, Garcia-Closas M, Flanagan JM, Fasching PA, Ekici AB, Edwards R, Eccles D, Easton DF, Dürst M, du Bois A, Dörk T, Doherty JA, Despierre E, Dansonka-Mieszkowska A, Cybulski C, Cramer DW, Cook LS, Chen X, Charbonneau B, Chang-Claude J, Campbell I, Butzow R, Bunker CH, Brueggmann D, Brown R, Brooks-Wilson A, Brinton LA, Bogdanova N, Block MS, Benjamin E, Beesley J, Beckmann MW, Bandera EV, Baglietto L, Bacot F, Armasu SM, Antonenkova N, Anton-Culver H, Aben KK, Liang D, Wu X, Lu K, Hildebrandt MA, Schildkraut JM, Sellers TA, Huntsman D, Berchuck A, Chenevix-Trench G, Gayther SA, Pharoah PD, Laird PW, Goode EL, Leigh Pearce C. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer. Nat Commun 2013; 4:1628. [PMID: 23535649 PMCID: PMC3848248 DOI: 10.1038/ncomms2629] [Show More Authors] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 02/21/2013] [Indexed: 12/19/2022] Open
Abstract
HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
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Affiliation(s)
- Hui Shen
- USC Epigenome Center, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, 90033 California USA
| | - Brooke L. Fridley
- Department of Biostatistics, University of Kansas Medical Center, Kansas City, 66160 Kansas USA
| | - Honglin Song
- Department of Oncology, University of Cambridge, Cambridge, CB1 8RN UK
| | - Kate Lawrenson
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, 90033 California USA
| | - Julie M. Cunningham
- Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, 55905 Minnesota USA
| | - Susan J. Ramus
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, 90033 California USA
| | - Mine S. Cicek
- Division of Epidemiology, Department of Health Science Research, Mayo Clinic, Rochester, 55905 Minnesota USA
| | - Jonathan Tyrer
- Department of Oncology, University of Cambridge, Cambridge, CB1 8RN UK
| | - Douglas Stram
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, 90033 California USA
| | - Melissa C. Larson
- Division of Biomedical Statistics and Informatics, Department of Health Science Research, Mayo Clinic, Rochester, 55905 Minnesota USA
| | - Martin Köbel
- Department of Pathology and Laboratory Medicine, Calgary Laboratory Services, University of Calgary, Calgary, T2N 2T9 Alberta Canada
| | | | - Argyrios Ziogas
- Department of Epidemiology, Center for Cancer Genetics Research and Prevention, School of Medicine, University of California Irvine, Irvine, 92697 California USA
| | - Wei Zheng
- Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Vanderbilt University, Nashville, 37232 Tennessee USA
| | - Hannah P. Yang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 20892 Maryland USA
| | - Anna H. Wu
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, 90033 California USA
| | - Eva L. Wozniak
- Gynaecological Cancer Research Centre, UCL EGA Institute for Women's Health, London, NW1 2BU UK
| | - Yin Ling Woo
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Affiliated to UM Cancer Research Institute, University of Malaya, Kuala Lumpur, 59100 Malaysia
| | - Boris Winterhoff
- Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, 55905 Minnesota USA
| | - Elisabeth Wik
- Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, HB 5006 Norway
- Department of Clinical Science, University of Bergen, Bergen, HB 5006 Norway
| | - Alice S. Whittemore
- Department of Health Research and Policy, Stanford University School of Medicine, Stanford, 94305 California USA
| | - Nicolas Wentzensen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 20892 Maryland USA
| | - Rachel Palmieri Weber
- Department of Community and Family Medicine, Duke University Medical Center, Durham, 27708 North Carolina USA
| | - Allison F. Vitonis
- Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115 Massachusetts USA
| | | | - Robert A. Vierkant
- Division of Biomedical Statistics and Informatics, Department of Health Science Research, Mayo Clinic, Rochester, 55905 Minnesota USA
| | - Ignace Vergote
- Vesalius Research Center, VIB, Leuven, 3000 Belgium
- Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, 3000 Belgium
| | - David Van Den Berg
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, 90033 California USA
| | - Anne M. Van Altena
- Department of Gynaecology, Radboud University Medical Centre, Nijmegen, HB 6500 The Netherlands
| | - Shelley S. Tworoger
- Channing Division of Network Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, 02115 Massachusetts USA
- Department of Epidemiology, Harvard School of Public Health, Boston, 02115 Massachusetts USA
| | - Pamela J. Thompson
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, 96813 USA
| | | | - Kathryn L. Terry
- Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115 Massachusetts USA
- Department of Epidemiology, Harvard School of Public Health, Boston, 02115 Massachusetts USA
| | - Soo-Hwang Teo
- Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, 47500 Malaysia
- University Malaya Cancer Research Institute, University Malaya Medical Centre, University of Malaya, Kuala Lumpur, 59100 Malaysia
| | - Claire Templeman
- Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, 90033 California USA
| | - Daniel O. Stram
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, 90033 California USA
| | - Melissa C. Southey
- Department of Pathology, Genetic Epidemiology Laboratory, University of Melbourne, Melbourne, VIC 3053 Victoria Australia
| | - Weiva Sieh
- Department of Health Research and Policy, Stanford University School of Medicine, Stanford, 94305 California USA
| | - Nadeem Siddiqui
- Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, G4 0SF UK
| | - Yurii B. Shvetsov
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, 96813 USA
| | - Xiao-Ou Shu
- Department of Epidemiology, Center for Cancer Genetics Research and Prevention, School of Medicine, University of California Irvine, Irvine, 92697 California USA
| | - Viji Shridhar
- Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, 55905 Minnesota USA
| | - Shan Wang-Gohrke
- Department of Obstetrics and Gynecology, University of Ulm, Ulm, 89091 Germany
| | - Gianluca Severi
- Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3053 Victoria Australia
- Centre for Molecular, Environmental, Genetic and Analytical Epidemiology, University of Melbourne, Melbourne, VIC 3010 Victoria Australia
| | - Ira Schwaab
- Institut für Humangenetik Wiesbaden, Wiesbaden, 65187 Germany
| | - Helga B. Salvesen
- Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, HB 5006 Norway
- Department of Clinical Science, University of Bergen, Bergen, HB 5006 Norway
| | - Iwona K. Rzepecka
- Department of Molecular Pathology, Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology, Warsaw, 02-781 Poland
| | - Ingo B. Runnebaum
- Department of Gynecology and Obstetrics, Jena University Hospital, Jena, 07743 Germany
| | - Mary Anne Rossing
- Division of Public Health Sciences, Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, 98109 Washington USA
- Department of Epidemiology, University of Washington, Seattle, 98109 Washington USA
| | - Lorna Rodriguez-Rodriguez
- Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, 08901 New Jersey USA
| | - Harvey A. Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, 06520 Connecticut USA
| | - Stefan P. Renner
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center, Erlangen, 91054 Germany
| | - Elizabeth M. Poole
- Channing Division of Network Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, 02115 Massachusetts USA
- Department of Epidemiology, Harvard School of Public Health, Boston, 02115 Massachusetts USA
| | - Malcolm C. Pike
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, 90033 California USA
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York USA
| | - Catherine M. Phelan
- Division of Population Sciences, Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, 33612 Florida USA
| | - Liisa M. Pelttari
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, 00530 Finland
| | - Tanja Pejovic
- Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, 97239 Oregon USA
- Knight Cancer Institute, Oregon Health and Science University, Portland, 97239 Oregon USA
| | - James Paul
- Beatson West of Scotland Cancer Centre, Glasgow, G12 0YN UK
| | - Irene Orlow
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York USA
| | - Siti Zawiah Omar
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Affiliated to UM Cancer Research Institute, University of Malaya, Kuala Lumpur, 59100 Malaysia
| | - Sara H. Olson
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, 10065 New York USA
| | - Kunle Odunsi
- Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, 14263 New York USA
| | - Stefan Nickels
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, 69120 Germany
| | - Heli Nevanlinna
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, 00530 Finland
| | - Roberta B. Ness
- School of Public Health, University of Texas, Houston, 77030 Texas USA
| | - Steven A. Narod
- Women’s College Research Institute, University of Toronto, Toronto, M5G IN8 Ontario Canada
| | - Toru Nakanishi
- Department of Gynecologic Oncology, Aichi Cancer Center Central Hospital, Nagoya, 464-8681 Japan
| | - Kirsten B. Moysich
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, 14263 New York USA
| | - Alvaro N.A. Monteiro
- Division of Population Sciences, Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, 33612 Florida USA
| | - Joanna Moes-Sosnowska
- Department of Molecular Pathology, Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology, Warsaw, 02-781 Poland
| | - Francesmary Modugno
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, 15213 Pennsylvania USA
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, 15213 Pennsylvania USA
- Women’s Cancer Research Program, Magee-Womens Research Institute, University of Pittsburgh Cancer Institute, Pittsburgh, 15213 Pennsylvania USA
| | - Usha Menon
- Gynaecological Cancer Research Centre, UCL EGA Institute for Women's Health, London, NW1 2BU UK
| | - John R. McLaughlin
- Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Toronto, M5T 3M7 Ontario Canada
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, M5G IX5 Ontario Canada
| | - Valerie McGuire
- Department of Health Research and Policy, Stanford University School of Medicine, Stanford, 94305 California USA
| | - Keitaro Matsuo
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, 464-8681 Japan
| | - Noor Azmi Mat Adenan
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Affiliated to UM Cancer Research Institute, University of Malaya, Kuala Lumpur, 59100 Malaysia
| | - Leon F.A.G Massuger
- Department of Gynaecology, Radboud University Medical Centre, Nijmegen, HB 6500 The Netherlands
| | - Galina Lurie
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, 96813 USA
| | - Lene Lundvall
- Gynecologic Clinic, The Juliane Marie Center, Copenhagen University Hospital, Copenhagen, DK-2100 Denmark
| | - Jan Lubiński
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, 70-115 Poland
| | - Jolanta Lissowska
- Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, 02-781 Poland
| | - Douglas A. Levine
- Department of Surgery, Gynecology Service, Memorial Sloan-Kettering Cancer Center, New York, 10021 New York USA
| | - Arto Leminen
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, 00530 Finland
| | - Alice W. Lee
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, 90033 California USA
| | - Nhu D. Le
- Cancer Control Research, BC Cancer Agency, Vancouver, G12 0YN British Columbia Canada
| | - Sandrina Lambrechts
- Vesalius Research Center, VIB, Leuven, 3000 Belgium
- Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, 3000 Belgium
- Department of Oncology, Laboratory for Translational Genetics, University of Leuven, Leuven, 3000 Belgium
| | - Diether Lambrechts
- Vesalius Research Center, VIB, Leuven, 3000 Belgium
- Department of Oncology, Laboratory for Translational Genetics, University of Leuven, Leuven, 3000 Belgium
| | - Jolanta Kupryjanczyk
- Department of Molecular Pathology, Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology, Warsaw, 02-781 Poland
| | - Camilla Krakstad
- Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, HB 5006 Norway
- Department of Clinical Science, University of Bergen, Bergen, HB 5006 Norway
| | - Gottfried E. Konecny
- Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, 90095 California USA
| | - Susanne Krüger Kjaer
- Gynecologic Clinic, The Juliane Marie Center, Copenhagen University Hospital, Copenhagen, DK-2100 Denmark
- Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, DK-2100 Denmark
| | - Lambertus A. Kiemeney
- Department of Epidemiology, Biostatistics and HTA, Radboud University Medical Centre, Nijmegen, HB 6500 Netherlands
- Department of Urology, Radboud University Medical Centre, Nijmegen, HB 6500 The Netherlands
- Comprehensive Cancer Center, Utrecht, 1066CX The Netherlands
| | - Linda E. Kelemen
- Department of Population Health Research, Alberta Health Services-Cancer Care, Calgary, T2N 2T9 Alberta Canada
- Department of Medical Genetics and Oncology, University of Calgary, Calgary, T2N 2T9 Alberta Canada
| | - Gary L. Keeney
- Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, 55905 Minnesota USA
| | - Beth Y. Karlan
- Women’s Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, 90048 California USA
| | - Rod Karevan
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, 90033 California USA
| | - Kimberly R. Kalli
- Department of Medical Oncology, Mayo Clinic, Rochester, 55905 Minnesota USA
| | - Hiroaki Kajiyama
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, 464-8601 Japan
| | - Bu-Tian Ji
- Division of Cancer Etiology and Genetics, National Cancer Institute, Bethesda, 20892 Maryland USA
| | - Allan Jensen
- Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, DK-2100 Denmark
| | - Anna Jakubowska
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, 70-115 Poland
| | - Edwin Iversen
- Department of Statistical Science, Duke University, Durham, 27708 North Carolina USA
| | - Satoyo Hosono
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, 464-8681 Japan
| | - Claus K. Høgdall
- Gynecologic Clinic, The Juliane Marie Center, Copenhagen University Hospital, Copenhagen, DK-2100 Denmark
| | - Estrid Høgdall
- Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, DK-2100 Denmark
- Department of Pathology, Molecular Unit, Herlev Hospital, University of Copenhagen, Copenhagen, 2730 Denmark
| | - Maureen Hoatlin
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, 97239 Oregon USA
| | - Peter Hillemanns
- Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, 30625 Germany
| | - Florian Heitz
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, 45136 Germany
- Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Klinik, Wiesbaden, 65199 Germany
| | - Rebecca Hein
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, 69120 Germany
- Department of Child and Adolescent Psychiatry and Psychotherapy, PMV Research Group, University of Cologne, Cologne, 50923 Germany
| | - Philipp Harter
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, 45136 Germany
- Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Klinik, Wiesbaden, 65199 Germany
| | - Mari K. Halle
- Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, HB 5006 Norway
- Department of Clinical Science, University of Bergen, Bergen, HB 5006 Norway
| | - Per Hall
- Department of Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 171-77 Sweden
| | - Jacek Gronwald
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, 70-115 Poland
| | - Martin Gore
- Gynecological Oncology Unit, Royal Marsden Hospital, London, SW3 6JJ UK
| | - Marc T. Goodman
- Cedars Sinai Medical Center, Samuel Oschin Comprehensive Cancer Center Institute, Los Angeles, 90048 California USA
| | - Graham G. Giles
- Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3053 Victoria Australia
- Centre for Molecular, Environmental, Genetic and Analytical Epidemiology, University of Melbourne, Melbourne, VIC 3010 Victoria Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC 3806 Victoria Australia
| | | | - Montserrat Garcia-Closas
- Division of Genetics and Epidemiology, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW7 3RP UK
| | - James M. Flanagan
- Department of Surgery and Cancer, Imperial College London, London, SW7 2AZ UK
| | - Peter A. Fasching
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center, Erlangen, 91054 Germany
- Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, 90095 California USA
| | - Arif B. Ekici
- Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, 91054 Germany
| | - Robert Edwards
- Maggee Women’s Hospital, Pittsburg, 15213 Pennsylvania USA
| | - Diana Eccles
- Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, S017 1BJ UK
| | - Douglas F. Easton
- Department of Oncology, University of Cambridge, Cambridge, CB1 8RN UK
| | - Matthias Dürst
- Department of Gynecology and Obstetrics, Jena University Hospital, Jena, 07743 Germany
| | - Andreas du Bois
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, 45136 Germany
- Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Klinik, Wiesbaden, 65199 Germany
| | - Thilo Dörk
- Gynaecology Research Unit, Hannover Medical School, Hannover, 30625 Germany
| | - Jennifer A. Doherty
- Section of Biostatistics and Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, 03755 New Hampshire USA
| | - Evelyn Despierre
- Vesalius Research Center, VIB, Leuven, 3000 Belgium
- Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, 3000 Belgium
- Department of Oncology, Laboratory for Translational Genetics, University of Leuven, Leuven, 3000 Belgium
| | - Agnieszka Dansonka-Mieszkowska
- Department of Molecular Pathology, Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology, Warsaw, 02-781 Poland
| | - Cezary Cybulski
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, 70-115 Poland
| | - Daniel W. Cramer
- Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115 Massachusetts USA
- Department of Epidemiology, Harvard School of Public Health, Boston, 02115 Massachusetts USA
| | - Linda S. Cook
- Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, 87131 New Mexico USA
| | - Xiaoqing Chen
- Department of Genetics, Queensland Institute of Medical Research, Herston, QLD 4006 Queensland Australia
| | - Bridget Charbonneau
- Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, 87131 New Mexico USA
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, 69120 Germany
| | - Ian Campbell
- Research Division, Peter MacCallum Cancer Centre, Cancer Genetics Laboratory, Melbourne, VIC 3002 Victoria Australia
- Department of Pathology, University of Melbourne, Parkville, VIC 3053 Victoria Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3002 Victoria Australia
| | - Ralf Butzow
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, 00530 Finland
- Department of Pathology, Helsinki University Central Hospital, Helsinki, 00530 Finland
| | - Clareann H. Bunker
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, 15213 Pennsylvania USA
| | - Doerthe Brueggmann
- Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, 90033 California USA
| | - Robert Brown
- Department of Surgery and Cancer, Imperial College London, London, SW7 2AZ UK
| | - Angela Brooks-Wilson
- Genome Sciences Centre, BC Cancer Agency, Vancouver, V52 1L3 British Columbia Canada
| | - Louise A. Brinton
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 20892 Maryland USA
| | - Natalia Bogdanova
- Gynaecology Research Unit, Hannover Medical School, Hannover, 30625 Germany
| | - Matthew S. Block
- Department of Medical Oncology, Mayo Clinic, Rochester, 55905 Minnesota USA
| | - Elizabeth Benjamin
- Department of Pathology, Cancer Institute, University College London, London, WC1E 6JJ UK
| | - Jonathan Beesley
- Department of Genetics, Queensland Institute of Medical Research, Herston, QLD 4006 Queensland Australia
| | - Matthias W. Beckmann
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center, Erlangen, 91054 Germany
| | - Elisa V. Bandera
- Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, 08901 New Jersey USA
| | - Laura Baglietto
- Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3053 Victoria Australia
- Centre for Molecular, Environmental, Genetic and Analytical Epidemiology, University of Melbourne, Melbourne, VIC 3010 Victoria Australia
| | | | - Sebastian M. Armasu
- Division of Biomedical Statistics and Informatics, Department of Health Science Research, Mayo Clinic, Rochester, 55905 Minnesota USA
| | - Natalia Antonenkova
- Belarusian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, 223040 Belarus
| | - Hoda Anton-Culver
- Department of Epidemiology, Center for Cancer Genetics Research and Prevention, School of Medicine, University of California Irvine, Irvine, 92697 California USA
| | - Katja K. Aben
- Department of Epidemiology, Biostatistics and HTA, Radboud University Medical Centre, Nijmegen, HB 6500 Netherlands
- Comprehensive Cancer Center, Utrecht, 1066CX The Netherlands
| | - Dong Liang
- College of Pharmacy and Health Sciences, Texas Southern University, Houston, 77044 Texas USA
| | - Xifeng Wu
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, 77030 Texas USA
| | - Karen Lu
- Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, 77030 Texas USA
| | | | | | - Australian Cancer Study
- Department of Genetics, Queensland Institute of Medical Research, Herston, QLD 4006 Queensland Australia
| | - Joellen M. Schildkraut
- Department of Community and Family Medicine, Duke University Medical Center, Durham, 27708 North Carolina USA
- Cancer Prevention, Detection and Control Research Program, Duke Cancer Institute, Durham, 27708 North Carolina USA
| | - Thomas A. Sellers
- Division of Population Sciences, Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, 33612 Florida USA
| | - David Huntsman
- Department of Pathology, Vancouver General Hospital, BC Cancer Agency, Vancouver, V5Z 4E6 British Columbia Canada
| | - Andrew Berchuck
- Gynecologic Cancer Program, Duke Cancer Institute, Durham, 27708 North Carolina USA
| | - Georgia Chenevix-Trench
- Department of Genetics, Queensland Institute of Medical Research, Herston, QLD 4006 Queensland Australia
| | - Simon A. Gayther
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, 90033 California USA
| | - Paul D.P. Pharoah
- Department of Oncology, University of Cambridge, Cambridge, CB1 8RN UK
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN UK
| | - Peter W. Laird
- USC Epigenome Center, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, 90033 California USA
| | - Ellen L. Goode
- Division of Epidemiology, Department of Health Science Research, Mayo Clinic, Rochester, 55905 Minnesota USA
| | - Celeste Leigh Pearce
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, 90033 California USA
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Gurung A, Hung T, Morin J, Gilks CB. Molecular abnormalities in ovarian carcinoma: clinical, morphological and therapeutic correlates. Histopathology 2012; 62:59-70. [DOI: 10.1111/his.12033] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Affiliation(s)
- Ananta Gurung
- Department of Pathology and Laboratory Medicine; Vancouver General Hospital; University of British Columbia; Vancouver; BC; Canada
| | - Tawny Hung
- Department of Pathology and Laboratory Medicine; Vancouver General Hospital; University of British Columbia; Vancouver; BC; Canada
| | - Jason Morin
- Department of Pathology and Laboratory Medicine; Vancouver General Hospital; University of British Columbia; Vancouver; BC; Canada
| | - C Blake Gilks
- Department of Pathology and Laboratory Medicine; Vancouver General Hospital; University of British Columbia; Vancouver; BC; Canada
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Fujiwara S, Terai Y, Kawaguchi H, Takai M, Yoo S, Tanaka Y, Tanaka T, Tsunetoh S, Sasaki H, Kanemura M, Tanabe A, Yamashita Y, Ohmichi M. GPR30 regulates the EGFR-Akt cascade and predicts lower survival in patients with ovarian cancer. J Ovarian Res 2012; 5:35. [PMID: 23163984 PMCID: PMC3543193 DOI: 10.1186/1757-2215-5-35] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2012] [Accepted: 11/09/2012] [Indexed: 01/08/2023] Open
Abstract
UNLABELLED OBJECTIVES G protein-coupled receptor 30 (GPR30) is a 7-transmembrane estrogen receptor that functions alongside traditional estrogen receptors to regulate the cellular responses to estrogen. Recent studies suggest that GPR30 expression is associated with a poor prognosis, and that this is due to the GPR30-mediated transactivation of the EGFR in breast cancer. However, the biological contribution of GPR30 in ovarian cancer remains unclear. The purpose of this study was to elucidate the relationships between GPR30 expression and the clinicopathological findings, and to determine how the signaling cascade influences the prognosis of ovarian cancer. METHODS The expression levels of GPR30, EGFR, ERα, and ERβ were analyzed using an immunohistochemical analysis, and their correlations with the clinicopathological features were examined in 10 patients with borderline malignant tumors and 152 patients with epithelial ovarian cancer. We also examined whether GPR30 signaling activates the EGFR-Akt pathway in an ovarian cancer cell line (Caov-3) by a Western blotting analysis. RESULTS The GPR30 expression in ovarian carcinomas was significantly higher than that in borderline malignancies (p=0.0016), and was not associated with the expression of the EGFR, ERα, or ERβ. The expression of GPR30 in clear cell carcinomas was significantly lower than that in other subtypes of cancer (P <; 0.001). The expression of both GPR30 and EGFR was significantly associated with a poor prognosis in terms of the progression-free survival rate. The phosphorylation of the EGFR and Akt could be significantly enhanced by G1 (p <; 0.05) and inhibited by a Src family kinase inhibitor. CONCLUSION The expression of both GPR30 and EGFR is associated with a poor outcome in ovarian cancer, and GPR30 increases the phosphorylation of Akt via the EGFR in ovarian cancer cells. The regulation of GPR30 might be a potentially useful new therapeutic target in ovarian cancer.
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Affiliation(s)
- Satoe Fujiwara
- Department of Obstetrics and Gynecology, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka, 569-8686, Japan.
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Quattrocchi L, Sisson M, Green A, Martin SG, Durrant L, Deen S. Expression of angiogenic chemokines in ovarian clear cell carcinoma. J Obstet Gynaecol Res 2012; 39:297-304. [PMID: 22845872 DOI: 10.1111/j.1447-0756.2012.01949.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
AIMS The aim of this study was to assess the expression of angiogenic chemokines (CXCR4/CXCL12) and the vascular endothelial growth factor in ovarian clear cell carcinoma, comparing levels against those in ovarian high-grade serous carcinoma. MATERIAL AND METHODS Tissue microarray samples from 136 cases of epithelial ovarian carcinoma (108 high-grade serous carcinoma and 28 clear cell carcinoma) were reviewed with World Health Organization histological criteria strictly applied to categorize cases according to histological subtype. Only cases without prior exposure to chemotherapy were included. Sections were stained with vascular endothelial growth factor, CXCR4, CXCL12 and assessed using conventional histological scoring (H-scoring). RESULTS Patients with clear cell carcinoma presented at an early stage of the disease (74% stage 1 and 2) and had a significantly better progression-free (P=0.042) survival than those with high-grade serous carcinoma. Low expression profile of the tested markers was seen in cases of clear cell carcinoma contrary to that seen in high-grade serous carcinoma. CONCLUSION The current study reports, for the first time, the difference in expression of a set of angiogeneic prognostic markers between clear cell carcinoma and high-grade serous carcinoma, offering a possible explanation for the apparent chemotherapy resistance. These results are relevant for the design of future clinical studies of first-line treatment for patients with ovarian clear cell carcinoma.
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Affiliation(s)
- Livia Quattrocchi
- Department of Histopathology, Nottingham University Hospitals NHS Trust, Queen's Medical Centre Campus Division of Clinical Pathology Division of Clinical Oncology, School of Molecular Medical Sciences, University of Nottingham, City Hospital Campus, Nottingham, UK
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Pearce CL, Templeman C, Rossing MA, Lee A, Near AM, Webb PM, Nagle CM, Doherty JA, Cushing-Haugen KL, Wicklund KG, Chang-Claude J, Hein R, Lurie G, Wilkens LR, Carney ME, Goodman MT, Moysich K, Kjaer SK, Hogdall E, Jensen A, Goode EL, Fridley BL, Larson MC, Schildkraut JM, Palmieri RT, Cramer DW, Terry KL, Vitonis AF, Titus LJ, Ziogas A, Brewster W, Anton-Culver H, Gentry-Maharaj A, Ramus SJ, Anderson AR, Brueggmann D, Fasching PA, Gayther SA, Huntsman DG, Menon U, Ness RB, Pike MC, Risch H, Wu AH, Berchuck A. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol 2012; 13:385-94. [PMID: 22361336 PMCID: PMC3664011 DOI: 10.1016/s1470-2045(11)70404-1] [Citation(s) in RCA: 671] [Impact Index Per Article: 51.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Endometriosis is a risk factor for epithelial ovarian cancer; however, whether this risk extends to all invasive histological subtypes or borderline tumours is not clear. We undertook an international collaborative study to assess the association between endometriosis and histological subtypes of ovarian cancer. METHODS Data from 13 ovarian cancer case-control studies, which were part of the Ovarian Cancer Association Consortium, were pooled and logistic regression analyses were undertaken to assess the association between self-reported endometriosis and risk of ovarian cancer. Analyses of invasive cases were done with respect to histological subtypes, grade, and stage, and analyses of borderline tumours by histological subtype. Age, ethnic origin, study site, parity, and duration of oral contraceptive use were included in all analytical models. FINDINGS 13 226 controls and 7911 women with invasive ovarian cancer were included in this analysis. 818 and 738, respectively, reported a history of endometriosis. 1907 women with borderline ovarian cancer were also included in the analysis, and 168 of these reported a history of endometriosis. Self-reported endometriosis was associated with a significantly increased risk of clear-cell (136 [20·2%] of 674 cases vs 818 [6·2%] of 13 226 controls, odds ratio 3·05, 95% CI 2·43-3·84, p<0·0001), low-grade serous (31 [9·2%] of 336 cases, 2·11, 1·39-3·20, p<0·0001), and endometrioid invasive ovarian cancers (169 [13·9%] of 1220 cases, 2·04, 1·67-2·48, p<0·0001). No association was noted between endometriosis and risk of mucinous (31 [6·0%] of 516 cases, 1·02, 0·69-1·50, p=0·93) or high-grade serous invasive ovarian cancer (261 [7·1%] of 3659 cases, 1·13, 0·97-1·32, p=0·13), or borderline tumours of either subtype (serous 103 [9·0%] of 1140 cases, 1·20, 0·95-1·52, p=0·12, and mucinous 65 [8·5%] of 767 cases, 1·12, 0·84-1·48, p=0·45). INTERPRETATION Clinicians should be aware of the increased risk of specific subtypes of ovarian cancer in women with endometriosis. Future efforts should focus on understanding the mechanisms that might lead to malignant transformation of endometriosis so as to help identify subsets of women at increased risk of ovarian cancer. FUNDING Ovarian Cancer Research Fund, National Institutes of Health, California Cancer Research Program, California Department of Health Services, Lon V Smith Foundation, European Community's Seventh Framework Programme, German Federal Ministry of Education and Research of Germany, Programme of Clinical Biomedical Research, German Cancer Research Centre, Eve Appeal, Oak Foundation, UK National Institute of Health Research, National Health and Medical Research Council of Australia, US Army Medical Research and Materiel Command, Cancer Council Tasmania, Cancer Foundation of Western Australia, Mermaid 1, Danish Cancer Society, and Roswell Park Alliance Foundation.
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Affiliation(s)
- Celeste Leigh Pearce
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
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KRAS mutations in ovarian low-grade endometrioid adenocarcinoma: association with concurrent endometriosis. Hum Pathol 2012; 43:1177-83. [PMID: 22305241 DOI: 10.1016/j.humpath.2011.10.009] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2011] [Accepted: 10/14/2011] [Indexed: 02/06/2023]
Abstract
The association between ovarian endometrioid adenocarcinoma and endometriosis is well established. However, not all endometrioid adenocarcinomas are directly related to endometriosis, and it has been suggested that there may be clinicopathologic differences between endometriosis-positive and endometriosis-negative tumors. Molecular alterations in endometrioid adenocarcinoma include KRAS and BRAF mutations, but the incidence of these abnormalities in previous reports has been highly variable (0%-36% and 0%-24%, respectively). This may be explained by relatively small sample sizes in earlier studies but could also reflect difficulties in accurately classifying high-grade ovarian malignancies. In the current study, we investigated KRAS and BRAF mutations in 78 low-grade (FIGO grade 1 and 2) endometrioid adenocarcinomas and compared the results with the presence of endometriosis in the tumor-associated ovary and/or in other pelvic sites. KRAS mutations were identified in 12 (29%) of 42 endometriosis-associated endometrioid adenocarcinomas with satisfactory analysis but in only 1 (3%) of 29 tumors in which endometriosis was not identified. BRAF mutation was identified only in a single endometriosis-associated case. These findings support the hypothesis that endometriosis-associated and independent endometrioid adenocarcinoma may develop via different molecular pathways and that KRAS mutations have an important role only in the former tumors. In contrast, BRAF mutations do not appear to have a significant role in either endometrioid adenocarcinoma subgroup. This may be relevant to future targeted therapies in patients with high-stage or recurrent disease and indicate that histopathologists should carefully examine endometrioid adenocarcinoma specimens, including nonneoplastic tissues, for the presence of endometriosis.
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King SM, Burdette JE. Evaluating the progenitor cells of ovarian cancer: analysis of current animal models. BMB Rep 2011; 44:435-45. [PMID: 21777513 DOI: 10.5483/bmbrep.2011.44.7.435] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Serous ovarian cancer is one of the most lethal gynecological malignancies. Progress on effective diagnostics and therapeutics for this disease are hampered by ambiguity as to the cellular origins of this histotype of ovarian cancer, as well as limited suitable animal models to analyze early stages of disease. In this report, we will review current animal models with respect to the two proposed progenitor cells for serous ovarian cancer, the ovarian surface epithelium and the fallopian tube epithelium.
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Affiliation(s)
- Shelby M King
- Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 60607, USA
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Kuhn E, Meeker AK, Visvanathan K, Gross AL, Wang TL, Kurman RJ, Shih IM. Telomere length in different histologic types of ovarian carcinoma with emphasis on clear cell carcinoma. Mod Pathol 2011; 24:1139-45. [PMID: 21499239 PMCID: PMC4763925 DOI: 10.1038/modpathol.2011.67] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Ovarian carcinoma is composed of a heterogeneous group of tumors with distinct clinico-pathological and molecular features. Alteration of telomerase activity has been reported in ovarian tumors but the pattern of telomere length in their specific histological subtypes has not been reported. In this study, we performed quantitative telomere fluorescence in situ hybridization on a total of 219 ovarian carcinomas including 106 high-grade serous carcinomas, 26 low-grade serous carcinomas, 56 clear cell carcinomas and 31 low-grade endometrioid carcinomas. The mean relative telomere length of carcinoma to stromal cells was calculated as a telomere index. This index was significantly higher in clear cell carcinoma compared with the other histologic types (P=0.007). Overall there was no association between the telomere index and mortality, but when stratified by histologic types, the hazard ratio for death among women with clear cell carcinoma with a telomere index >1 was significantly increased at 4.93 (95% CI 1.64-14.86, P=0.005) when compared with those with a telomere index ≤1. In conclusion, our results provide new evidence that telomere length significantly differs by histologic type in ovarian carcinoma. Specifically, clear cell carcinomas have longer mean relative telomere lengths compared with the other histologic types and longer telomeres in clear cell carcinoma are associated with increased mortality suggesting that aberrations in telomere length may have an important role in the development and progression of this neoplasm.
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Affiliation(s)
- Elisabetta Kuhn
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MA, USA
| | - Alan K Meeker
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MA, USA,Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MA, USA
| | - Kala Visvanathan
- Department of Medical Oncology, Johns Hopkins School of Medicine, Baltimore, MA, USA,Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MA, USA
| | - Amy L Gross
- Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MA, USA
| | - Tian-Li Wang
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MA, USA,Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MA, USA
| | - Robert J Kurman
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MA, USA,Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MA, USA,Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MA, USA
| | - Ie-Ming Shih
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MA, USA,Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MA, USA,Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MA, USA
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[The new insights of ovarian carcinogenesis... and their possible impacts on our current practice]. ACTA ACUST UNITED AC 2010; 38:645-7. [PMID: 21030281 DOI: 10.1016/j.gyobfe.2010.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, Senz J, McConechy MK, Anglesio MS, Kalloger SE, Yang W, Heravi-Moussavi A, Giuliany R, Chow C, Fee J, Zayed A, Prentice L, Melnyk N, Turashvili G, Delaney AD, Madore J, Yip S, McPherson AW, Ha G, Bell L, Fereday S, Tam A, Galletta L, Tonin PN, Provencher D, Miller D, Jones SJM, Moore RA, Morin GB, Oloumi A, Boyd N, Aparicio SA, Shih IM, Mes-Masson AM, Bowtell DD, Hirst M, Gilks B, Marra MA, Huntsman DG. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med 2010; 363:1532-43. [PMID: 20942669 PMCID: PMC2976679 DOI: 10.1056/nejmoa1008433] [Citation(s) in RCA: 1294] [Impact Index Per Article: 86.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Ovarian clear-cell and endometrioid carcinomas may arise from endometriosis, but the molecular events involved in this transformation have not been described. METHODS We sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodes BAF250a, a key component of the SWI–SNF chromatin remodeling complex. We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas. RESULTS ARID1A mutations were seen in 55 of 119 ovarian clear-cell carcinomas (46%), 10 of 33 endometrioid carcinomas (30%), and none of the 76 high-grade serous ovarian carcinomas. Seventeen carcinomas had two somatic mutations each. Loss of the BAF250a protein correlated strongly with the ovarian clear-cell carcinoma and endometrioid carcinoma subtypes and the presence of ARID1A mutations. In two patients, ARID1A mutations and loss of BAF250a expression were evident in the tumor and contiguous atypical endometriosis but not in distant endometriotic lesions. CONCLUSIONS These data implicate ARID1A as a tumor-suppressor gene frequently disrupted in ovarian clear-cell and endometrioid carcinomas. Since ARID1A mutation and loss of BAF250a can be seen in the preneoplastic lesions, we speculate that this is an early event in the transformation of endometriosis into cancer. (Funded by the British Columbia Cancer Foundation and the Vancouver General Hospital–University of British Columbia Hospital Foundation.).
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Taniguchi S, Fujimori M, Sasaki T, Tsutsui H, Shimatani Y, Seki K, Amano J. Targeting solid tumors with non-pathogenic obligate anaerobic bacteria. Cancer Sci 2010; 101:1925-32. [PMID: 20579076 PMCID: PMC11158574 DOI: 10.1111/j.1349-7006.2010.01628.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Molecular-targeting drugs with fewer severe adverse effects are attracting great attention as the next wave of cancer treatment. There exist, however, populations of cancer cells resistant to these drugs that stem from the instability of tumor cells and/or the existence of cancer stem cells, and thus specific toxicity is required to destroy them. If such selectivity is not available, these targets may be sought out not by the cancer cell types themselves, but rather in their adjacent cancer microenvironments by means of hypoxia, low pH, and so on. The anaerobic conditions present in malignant tumor tissues have previously been regarded as a source of resistance in cancer cells against conventional therapy. However, there now appears to be a way to make use of these limiting factors as a selective target. In this review, we will refer to several trials, including our own, to direct attention to the utilizable anaerobic conditions present in malignant tumor tissues and the use of bacteria as carriers to target them. Specifically, we have been developing a method to attack solid cancers using the non-pathogenic obligate anaerobic bacterium Bifidobacterium longum as a vehicle to selectively recognize and target the anaerobic conditions in solid cancer tissues. We will also discuss the existence of low oxygen pressure in tumor masses in spite of generally enhanced angiogenesis, overview current cancer therapies, especially the history and present situation of bacterial utility to treat solid tumors, and discuss the rationality and future possibilities of this novel mode of cancer treatment.
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Affiliation(s)
- Shun'ichiro Taniguchi
- Department of Molecular Oncology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Tokyo, Japan.
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MacKenzie F, Bullock DG, Ratcliffe JG. UK external quality assessment scheme for immunoassays in endocrinology. DER PATHOLOGE 1992; 32 Suppl 2:265-70. [PMID: 1809064 DOI: 10.1007/s00292-011-1488-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
UK EQAS provide the UK with a comprehensive system for EQA in endocrinology, as well as in other aspects of clinical chemistry and laboratory medicine. UK EQAS in endocrinology are scientifically designed to yield an objective assessment of participants' performance and stimulate improvements in between-laboratory agreement. The design uses appropriate specimens, based on liquid human serum and prepared with minimal processing and additives in the organising centres to enable detailed study of recovery and other important factors. Target values are validated by reproducibility on repeated distribution and by recovery and parallelism studies. Reports are presented informatively, and emphasise the cumulative scoring system (bias and variance) for performance assessment. Computerised data processing and data presentation form an integral part of these schemes, and a common core computing system is in use throughout these UK EQAS. Participants receive advice and assistance in the interpretation of performance data and, when appropriate, in the resolution of problems.
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Affiliation(s)
- F MacKenzie
- UK EQAS for Thyroid-related Hormones, Wolfson Research Laboratories, Queen Elizabeth Hospital, Birmingham, UK
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