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Sohel HI, Kiyono T, Zahan UF, Razia S, Ishikawa M, Yamashita H, Kanno K, Sonia SB, Nakayama K, Kyo S. Establishment of a Novel In Vitro and In Vivo Model to Understand Molecular Carcinogenesis of Endometriosis-Related Ovarian Neoplasms. Int J Mol Sci 2025; 26:1995. [PMID: 40076621 PMCID: PMC11901000 DOI: 10.3390/ijms26051995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 02/20/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
The molecular mechanisms through which endometriosis-related ovarian neoplasms (ERONs) develop from benign endometrioma remain unclear. It is especially a long-standing mystery why ovarian endometrioma has the potential to develop into two representative histological subtypes: endometrioid ovarian carcinoma or clear cell ovarian carcinoma. This study aimed to investigate the molecular carcinogenesis of ERONs using newly developed in vitro and in vivo carcinogenesis models. Epithelial cells were isolated and purified from surgically removed benign endometrioma samples, followed by immortalization by overexpressing cyclinD1/CDK4 in combination with the human TERT gene. Immortalized cells were subjected to various molecular manipulations by combining knockout or overexpression of several candidate drivers, including ARID1A, KRAS, PIK3CA, AKT, and MYC, based on previous comprehensive genome-wide studies of ERONs. These cells were then inoculated into immunocompromised mice and evaluated for malignant transformation. Inoculated cells harboring a combination of three genetic alterations successfully developed tumors with malignant features in mice, whereas those with two genetic manipulations failed to do so. Especially, ARID1A gene knockout, combined with overexpressing the KRAS oncogenic mutant allele (or overexpressing AKT) and c-Myc overexpression led to efficient tumor formation. Of note, these three combinations of genetic alterations produced tumors that histologically represented typical clear cell carcinoma in SCID mice, while the same combination led to tumors with endometrioid histology in nude mice. A combination of ARID1A mutation, KRAS mutation or AKT activation, and c-Myc overexpression were confirmed to be the main candidate drivers for the development of ERONs, as suggested by comprehensive genetic analyses of ERONs. A tumor immune microenvironment involving B-cell signaling may contribute to the diverse histological phenotypes. The present model may help to clarify the molecular mechanisms of ERON carcinogenesis and understand their histological diversity and novel molecular targets.
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Affiliation(s)
- Hasibul Islam Sohel
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (H.I.S.); (U.F.Z.); (M.I.); (H.Y.); (K.K.); (S.B.S.)
| | - Tohru Kiyono
- Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Kashiwa 277-8577, Japan;
| | - Umme Farzana Zahan
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (H.I.S.); (U.F.Z.); (M.I.); (H.Y.); (K.K.); (S.B.S.)
| | - Sultana Razia
- Department of Legal Medicine, Shimane University Faculty of Medicine, 89-1 Enya-Cho, Izumo 693-8501, Japan;
| | - Masako Ishikawa
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (H.I.S.); (U.F.Z.); (M.I.); (H.Y.); (K.K.); (S.B.S.)
| | - Hitomi Yamashita
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (H.I.S.); (U.F.Z.); (M.I.); (H.Y.); (K.K.); (S.B.S.)
| | - Kosuke Kanno
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (H.I.S.); (U.F.Z.); (M.I.); (H.Y.); (K.K.); (S.B.S.)
| | - Shahataj Begum Sonia
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (H.I.S.); (U.F.Z.); (M.I.); (H.Y.); (K.K.); (S.B.S.)
| | - Kentaro Nakayama
- Department of Obstetrics and Gynecology, East Medical Center, Nagoya City University, Nagoya 464-8547, Japan
| | - Satoru Kyo
- Department of Obstetrics and Gynecology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; (H.I.S.); (U.F.Z.); (M.I.); (H.Y.); (K.K.); (S.B.S.)
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Giannini A, Massimello F, Caretto M, Cosimi G, Mannella P, Luisi S, Gadducci A, Simoncini T. Factors in malignant transformation of ovarian endometriosis: A narrative review. Gynecol Endocrinol 2024; 40:2409911. [PMID: 39445672 DOI: 10.1080/09513590.2024.2409911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 06/12/2024] [Accepted: 09/19/2024] [Indexed: 10/25/2024] Open
Abstract
Endometriosis is a common estrogen-dependent inflammatory disease with a chronic course and a tendency to recur. The association between endometriosis and cancer has been studied for several years. Numerous reports have demonstrated a strong association between specific ovarian malignancies and endometriotic lesions. Atypical endometriosis has been widely described as a malignant precursor to ovarian epithelial tumors, particularly clear cell carcinomas and endometrioid carcinomas. These histological types associated with endometriosis develop predominantly in the ovary rather than in extragonadal sites. The detailed molecular mechanism of etiology remains unclear. Recent studies have analyzed the genetic and molecular mechanisms involved in endometriosis-associated ovarian cancer. A critical role appears to be played by a carcinogenic model based on iron-induced oxidative stress, which is typical of the endometriosis microenvironment. It has been hypothesized that trans-tubal reflux of blood, endometrial cells and associated iron-induced oxidative stress underlie the development of endometriosis-associated ovarian cancer. However, the multifactorial mechanisms of this malignant transformation are not fully understood. The aim of this review is to summaries the current epidemiological, histopathological, genetic and molecular findings in the progression of endometriosis-associated ovarian cancer.
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Affiliation(s)
- Andrea Giannini
- Department of Clinical and Experimental Medicine, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy
| | - Francesca Massimello
- Department of Clinical and Experimental Medicine, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy
| | - Marta Caretto
- Department of Clinical and Experimental Medicine, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy
| | - Giulia Cosimi
- Department of Clinical and Experimental Medicine, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy
| | - Paolo Mannella
- Department of Clinical and Experimental Medicine, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy
| | - Stefano Luisi
- Department of Clinical and Experimental Medicine, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy
| | - Angiolo Gadducci
- Department of Clinical and Experimental Medicine, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy
| | - Tommaso Simoncini
- Department of Clinical and Experimental Medicine, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy
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Fournier LA, Kalantari F, Wells JP, Lee JS, Trigo-Gonzalez G, Moksa MM, Smith T, White J, Shanks A, Wang SL, Su E, Wang Y, Huntsman DG, Hirst M, Stirling PC. Genome-Wide CRISPR Screen Identifies KEAP1 Perturbation as a Vulnerability of ARID1A-Deficient Cells. Cancers (Basel) 2024; 16:2949. [PMID: 39272807 PMCID: PMC11394604 DOI: 10.3390/cancers16172949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 08/15/2024] [Accepted: 08/16/2024] [Indexed: 09/15/2024] Open
Abstract
ARID1A is the core DNA-binding subunit of the BAF chromatin remodeling complex and is mutated in about 8% of all cancers. The frequency of ARID1A loss varies between cancer subtypes, with clear cell ovarian carcinoma (CCOC) presenting the highest incidence at > 50% of cases. Despite a growing understanding of the consequences of ARID1A loss in cancer, there remains limited targeted therapeutic options for ARID1A-deficient cancers. Using a genome-wide CRISPR screening approach, we identify KEAP1 as a genetic dependency of ARID1A in CCOC. Depletion or chemical perturbation of KEAP1 results in selective growth inhibition of ARID1A-KO cell lines and edited primary endometrial epithelial cells. While we confirm that KEAP1-NRF2 signalling is dysregulated in ARID1A-KO cells, we suggest that this synthetic lethality is not due to aberrant NRF2 signalling. Rather, we find that KEAP1 perturbation exacerbates genome instability phenotypes associated with ARID1A deficiency. Together, our findings identify a potentially novel synthetic lethal interaction of ARID1A-deficient cells.
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Affiliation(s)
- Louis-Alexandre Fournier
- Terry Fox Laboratory, BC Cancer, Vancouver, BC V5L1Z3, Canada
- Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC V5L1Z3, Canada
| | - Forouh Kalantari
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T1Z4, Canada
- Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC V5L1Z3, Canada
| | - James P Wells
- Terry Fox Laboratory, BC Cancer, Vancouver, BC V5L1Z3, Canada
| | - Joon Seon Lee
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T1Z4, Canada
| | - Genny Trigo-Gonzalez
- Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC V5L1Z3, Canada
| | - Michelle M Moksa
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T1Z4, Canada
| | - Theodore Smith
- Terry Fox Laboratory, BC Cancer, Vancouver, BC V5L1Z3, Canada
| | - Justin White
- Terry Fox Laboratory, BC Cancer, Vancouver, BC V5L1Z3, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T1Z4, Canada
| | - Alynn Shanks
- Terry Fox Laboratory, BC Cancer, Vancouver, BC V5L1Z3, Canada
| | - Siyun L Wang
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T1Z4, Canada
| | - Edmund Su
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T1Z4, Canada
| | - Yemin Wang
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T1Z4, Canada
- Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC V5L1Z3, Canada
| | - David G Huntsman
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T1Z4, Canada
- Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC V5L1Z3, Canada
- Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC V6T1Z4, Canada
| | - Martin Hirst
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T1Z4, Canada
| | - Peter C Stirling
- Terry Fox Laboratory, BC Cancer, Vancouver, BC V5L1Z3, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T1Z4, Canada
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Ramachandran R, Nistor S, Gietzmann W, Symons N, Soleymani majd H. Radical total pelvic exenteration with concomitant right nephrectomy in the management of recurrent endometrioid ovarian adenocarcinoma: A case report and literature review. Clin Case Rep 2024; 12:e9148. [PMID: 38962465 PMCID: PMC11220455 DOI: 10.1002/ccr3.9148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 06/05/2024] [Accepted: 06/13/2024] [Indexed: 07/05/2024] Open
Abstract
Endometrioid ovarian adenocarcinoma is a common subtype of epithelial ovarian cancer that can arise on a background of endometriosis. Maximal cytoreductive effort with an aim to remove all macroscopic disease (achieve R0) is the single independent prognostic factor for survival. Complex multidisciplinary surgeries may be required in order to achieve this.
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Affiliation(s)
| | - Sabina Nistor
- Department of Gynaecology OncologyChurchill Hospital, Oxford University Hospitals NHS Foundation TrustOxfordUK
| | - William Gietzmann
- Department of UrologyOxford University Hospitals NHS Foundation TrustOxfordUK
| | - Nicholas Symons
- Department of Colorectal SurgeryOxford University Hospitals NHS Foundation TrustOxfordUK
| | - Hooman Soleymani majd
- Department of Gynaecology OncologyChurchill Hospital, Oxford University Hospitals NHS Foundation TrustOxfordUK
- Nuffield Department of Women's and Reproductive HealthUniversity of OxfordOxfordUK
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5
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Sadlecki P, Walentowicz-Sadlecka M. Molecular landscape of borderline ovarian tumours: A systematic review. Open Med (Wars) 2024; 19:20240976. [PMID: 38859878 PMCID: PMC11163159 DOI: 10.1515/med-2024-0976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/09/2024] [Accepted: 05/05/2024] [Indexed: 06/12/2024] Open
Abstract
Borderline ovarian tumours (BOTs) show intriguing characteristics distinguishing them from other ovarian tumours. The aim of the systematic review was to analyse the spectrum of molecular changes found in BOTs and discuss their significance in the context of the overall therapeutic approach. The systematic review included articles published between 2000 and 2023 in the databases: PubMed, EMBASE, and Cochrane. After a detailed analysis of the available publications, we qualified for the systematic review: 28 publications on proto-oncogenes: BRAF, KRAS, NRAS, ERBB2, and PIK3CA, 20 publications on tumour suppressor genes: BRCA1/2, ARID1A, CHEK2, PTEN, 4 on adhesion molecules: CADM1, 8 on proteins: B-catenin, claudin-1, and 5 on glycoproteins: E-Cadherin. In addition, in the further part of the systematic review, we included eight publications on microsatellite instability and three describing loss of heterozygosity in BOT. Molecular changes found in BOTs can vary on a case-by-case basis, identifying carcinogenic mutations through molecular analysis and developing targeted therapies represent significant advancements in the diagnosis and treatment of ovarian malignancies. Molecular studies have contributed significantly to our understanding of BOT pathogenesis, but substantial research is still required to elucidate the relationship between ovarian neoplasms and extraneous disease, identify accurate prognostic indicators, and develop targeted therapeutic approaches.
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Affiliation(s)
- Pawel Sadlecki
- Medical Department, University of Science and Technology, Bydgoszcz, Poland
- Department of Obstetrics and Gynecology, Regional Polyclinical Hospital, Grudziadz, Poland
| | - Malgorzata Walentowicz-Sadlecka
- Medical Department, University of Science and Technology, Bydgoszcz, Poland
- Department of Obstetrics and Gynecology, Regional Polyclinical Hospital, Grudziadz, Poland
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Hablase R, Kyrou I, Randeva H, Karteris E, Chatterjee J. The "Road" to Malignant Transformation from Endometriosis to Endometriosis-Associated Ovarian Cancers (EAOCs): An mTOR-Centred Review. Cancers (Basel) 2024; 16:2160. [PMID: 38893278 PMCID: PMC11172073 DOI: 10.3390/cancers16112160] [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: 04/19/2024] [Revised: 05/29/2024] [Accepted: 06/01/2024] [Indexed: 06/21/2024] Open
Abstract
Ovarian cancer is an umbrella term covering a number of distinct subtypes. Endometrioid and clear-cell ovarian carcinoma are endometriosis-associated ovarian cancers (EAOCs) frequently arising from ectopic endometrium in the ovary. The mechanistic target of rapamycin (mTOR) is a crucial regulator of cellular homeostasis and is dysregulated in both endometriosis and endometriosis-associated ovarian cancer, potentially favouring carcinogenesis across a spectrum from benign disease with cancer-like characteristics, through an atypical phase, to frank malignancy. In this review, we focus on mTOR dysregulation in endometriosis and EAOCs, investigating cancer driver gene mutations and their potential interaction with the mTOR pathway. Additionally, we explore the complex pathogenesis of transformation, considering environmental, hormonal, and epigenetic factors. We then discuss postmenopausal endometriosis pathogenesis and propensity for malignant transformation. Finally, we summarize the current advancements in mTOR-targeted therapeutics for endometriosis and EAOCs.
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Affiliation(s)
- Radwa Hablase
- College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB83PH, UK; (R.H.); (E.K.)
- Academic Department of Gynaecological Oncology, Royal Surrey NHS Foundation Trust Hospital, Guildford GU2 7XX, UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK (H.R.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry CV1 5FB, UK
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK
- College of Health, Psychology and Social Care, University of Derby, Derby DE22 1GB, UK
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, 11855 Athens, Greece
| | - Harpal Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK (H.R.)
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry CV1 5FB, UK
| | - Emmanouil Karteris
- College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB83PH, UK; (R.H.); (E.K.)
| | - Jayanta Chatterjee
- College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB83PH, UK; (R.H.); (E.K.)
- Academic Department of Gynaecological Oncology, Royal Surrey NHS Foundation Trust Hospital, Guildford GU2 7XX, UK
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Kordowitzki P, Graczyk S, Mechsner S, Sehouli J. Shedding Light on the Interaction Between Rif1 and Telomeres in Ovarian Cancer. Aging Dis 2024; 15:535-545. [PMID: 37548940 PMCID: PMC10917528 DOI: 10.14336/ad.2023.0716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 07/16/2023] [Indexed: 08/08/2023] Open
Abstract
Ovarian cancer, more precisely high-grade serous ovarian cancer, is one of the most lethal age-independent gynecologic malignancies in women worldwide, regardless of age. There is mounting evidence that there is a link between telomeres and the RIF1 protein and the proliferation of cancer cells. Telomeres are hexameric (TTAGGG) tandem repeats at the tip of chromosomes that shorten as somatic cells divide, limiting cell proliferation and serving as an important barrier in preventing cancer. RIF1 (Replication Time Regulation Factor 1) plays, among other factors, an important role in the regulation of telomere length. Interestingly, RIF1 appears to influence the DNA double-strand break (DSB) repair pathway. However, detailed knowledge regarding the interplay between RIF1 and telomeres and their degree of engagement in epithelial ovarian cancer (EOC) is still elusive, despite the fact that such knowledge could be of relevance in clinical practice to find novel biomarkers. In this review, we provide an update of recent literature to elucidate the relation between telomere biology and the RIF1 protein during the development of ovarian cancer in women.
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Affiliation(s)
- Paweł Kordowitzki
- Department of Preclinical and Basic Sciences, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Torun, Poland.
- Department of Gynecology including Center of oncological surgery (CVK) and Department of Gynaecology (CBF), European Competence Center for Ovarian Cancer, Charite, Berlin, Germany.
| | - Szymon Graczyk
- Department of Preclinical and Basic Sciences, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Torun, Poland.
| | - Sylvia Mechsner
- Department of Gynecology including Center of oncological surgery (CVK) and Department of Gynaecology (CBF), European Competence Center for Ovarian Cancer, Charite, Berlin, Germany.
| | - Jalid Sehouli
- Department of Gynecology including Center of oncological surgery (CVK) and Department of Gynaecology (CBF), European Competence Center for Ovarian Cancer, Charite, Berlin, Germany.
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8
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Li JJ, Lee CS. The Role of the AT-Rich Interaction Domain 1A Gene ( ARID1A) in Human Carcinogenesis. Genes (Basel) 2023; 15:5. [PMID: 38275587 PMCID: PMC10815128 DOI: 10.3390/genes15010005] [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: 11/13/2023] [Revised: 12/13/2023] [Accepted: 12/14/2023] [Indexed: 01/27/2024] Open
Abstract
The switch/sucrose non-fermentable (SWI/SNF) (SWI/SNF) complex uses energy from ATP hydrolysis to mobilise nucleosomes on chromatin. Components of SWI/SNF are mutated in 20% of all human cancers, of which mutations in AT-rich binding domain protein 1A (ARID1A) are the most common. ARID1A is mutated in nearly half of ovarian clear cell carcinoma and around one-third of endometrial and ovarian carcinomas of the endometrioid type. This review will examine in detail the molecular functions of ARID1A, including its role in cell cycle control, enhancer regulation, and the prevention of telomerase activity. ARID1A has key roles in the maintenance of genomic integrity, including DNA double-stranded break repair, DNA decatenation, integrity of the cohesin complex, and reduction in replication stress, and is also involved in mismatch repair. The role of ARID1A loss in the pathogenesis of some of the most common human cancers is discussed, with a particular emphasis on gynaecological cancers. Finally, several promising synthetic lethal strategies, which exploit the specific vulnerabilities of ARID1A-deficient cancer cells, are briefly mentioned.
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Affiliation(s)
- Jing Jing Li
- Department of Anatomical Pathology, Liverpool Hospital, Liverpool, NSW 2170, Australia;
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia
| | - Cheok Soon Lee
- Department of Anatomical Pathology, Liverpool Hospital, Liverpool, NSW 2170, Australia;
- Discipline of Pathology, School of Medicine, Western Sydney University, Sydney, NSW 2560, Australia
- South Western Sydney Clinical School, University of New South Wales, Liverpool, NSW 2170, Australia
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW 2010, Australia
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Wagner SK, Moon AS, Howitt BE, Renz M. SMARCA4 loss irrelevant for ARID1A mutated ovarian clear cell carcinoma: A case report. Gynecol Oncol Rep 2023; 50:101305. [PMID: 38033359 PMCID: PMC10685047 DOI: 10.1016/j.gore.2023.101305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/08/2023] [Accepted: 11/12/2023] [Indexed: 12/02/2023] Open
Abstract
Clear cell carcinomas are rare and relatively chemo-insensitive ovarian cancers with a characteristic molecular pathogenesis. Alterations in ARID1A, a component of the multiprotein chromatin remodeling complex SWI/SNF, are likely early events in the development of ovarian clear cancers arising from atypical endometriosis. Insight into additional driver events and particularly mutations in the same chromatin remodeling complex is limited. Isolated loss of SMARCA4, encoding the ATPase of the SWI/SNF complex, characterizes other aggressive gynecologic cancers including small cell carcinomas of the ovary hypercalcemic type (SCCOHT), undifferentiated endometrial carcinomas (UDEC), and uterine sarcomas (SDUS). The ovarian clear cell carcinoma of a 48-year-old showed in the initial surgical specimen a subclonal loss of SMARCA4 in addition to an ARID1A mutation, i.e., two alterations in the SWI/SNF heterochromatin remodeling complex. We anticipated that the SMARCA4 loss would worsen the disease course in analogy to SCCOHT, UDEC, and SDUS. However, the disease did not accelerate. Instead, the recurrent disease showed restored SMARCA4 expression while retaining the ARID1A mutation. Combinatorial redundancy, diversity and sequence in the SWI/SNF complex assembly as well as DNA- and tissue-specificity may explain the observed irrelevance of SMARCA4 loss in the presented ARID1A mutated ovarian clear cell carcinoma.
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Affiliation(s)
- Samantha Kay Wagner
- Department of Obstetrics & Gynecology, Stanford University, Stanford, CA, USA
| | - Ashley S. Moon
- Gynecologic Oncology Division, Department of Obstetrics & Gynecology, Stanford University, Stanford, CA, USA
| | - Brooke E. Howitt
- Department of Clinical Pathology, Stanford University, Stanford, CA, USA
| | - Malte Renz
- Gynecologic Oncology Division, Department of Obstetrics & Gynecology, Stanford University, Stanford, CA, USA
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O'Cearbhaill RE, Miller A, Soslow RA, Lankes HA, DeLair D, Segura S, Chavan S, Zamarin D, DeBernardo R, Moore K, Moroney J, Shahin M, Thaker PH, Wahner-Hendrickson AE, Aghajanian C. A phase 2 study of dasatinib in recurrent clear cell carcinoma of the ovary, fallopian tube, peritoneum or endometrium: NRG oncology/gynecologic oncology group study 0283. Gynecol Oncol 2023; 176:16-24. [PMID: 37418832 PMCID: PMC10529107 DOI: 10.1016/j.ygyno.2023.06.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/22/2023] [Accepted: 06/26/2023] [Indexed: 07/09/2023]
Abstract
OBJECTIVE Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas. High-throughput cell-based drug screening predicted activity of dasatinib, a tyrosine kinase inhibitor, in ARID1A-mutant clear cell carcinoma. METHODS We conducted a phase 2 clinical trial of dasatinib 140 mg once daily by mouth in patients with recurrent or persistent ovarian and endometrial clear cell carcinoma. Patients with measurable disease were enrolled and then assigned to biomarker-defined populations based on BAF250a immunohistochemistry. The translational endpoints included broad next-generation sequencing to assess concordance of protein expression and treatment outcomes. RESULTS Twenty-eight patients, 15 of whom had tumors with retained BAF250a and 13 with loss of BAF250a were evaluable for treatment response and safety. The most common grade 3 adverse events were anemia, fatigue, dyspnea, hyponatremia, pleural effusion, and vomiting. One patient had a partial response, eight (28%) had stable disease, and 15 (53.6%) had disease progression. Twenty-three patients had next-generation sequencing results; 13 had a pathogenic ARID1A alteration. PIK3CA mutations were more prevalent in ARID1A-mutant tumors, while TP53 mutations were more prevalent in ARID1A wild-type tumors. CONCLUSIONS Dasatinib was not an effective single-agent treatment for recurrent or persistent ovarian and endometrial clear cell carcinoma. Studies are urgently needed for this rare gynecologic subtype.
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Affiliation(s)
| | - Austin Miller
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States of America.
| | - Robert A Soslow
- Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.
| | - Heather A Lankes
- NRG Oncology, Operations Center-Philadelphia East, Philadelphia, PA, United States of America; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America.
| | - Deborah DeLair
- Northwell Health, Greenvale, New York, NY, United States of America.
| | - Sheila Segura
- Indiana University School of Medicine, Indianapolis, IN, United States of America.
| | - Shweta Chavan
- Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.
| | - Dmitriy Zamarin
- Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.
| | | | - Kathleen Moore
- University of Oklahoma, Oklahoma City, OK, United States of America.
| | - John Moroney
- University of Chicago, Chicago, IL, United States of America.
| | - Mark Shahin
- Abington Memorial Hospital, Willow Grove, PA, United States of America.
| | - Premal H Thaker
- Washington University, St. Louis, MO, United States of America.
| | | | - Carol Aghajanian
- Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.
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11
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Driva TS, Schatz C, Haybaeck J. Endometriosis-Associated Ovarian Carcinomas: How PI3K/AKT/mTOR Pathway Affects Their Pathogenesis. Biomolecules 2023; 13:1253. [PMID: 37627318 PMCID: PMC10452661 DOI: 10.3390/biom13081253] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 08/05/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
Ovarian clear cell (OCCC) and endometrioid (EnOC) carcinomas are often subsumed under the umbrella term "endometriosis-associated ovarian cancer" (EAOC), since they frequently arise from ectopic endometrium settled in the ovaries. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is known to be aberrantly activated both in endometriosis and EAOC; however, its role in the progression of endometriosis to ovarian cancer remains unclear. In fact, cancer-associated alterations in the mTOR pathway may be found in normal uterine epithelium, likely acting as a first step towards ovarian cancer, through the intermediary stage of endometriosis. This review aims to summarize the current knowledge regarding mTOR signaling dysregulation in the uterine endometrium, endometriosis, and EAOC while focusing on the interconnections between the PI3K/AKT/mTOR pathway and other signaling molecules that give rise to synergistic molecular mechanisms triggering ovarian cancer development in the presence of endometriosis.
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Affiliation(s)
- Tatiana S. Driva
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Christoph Schatz
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Johannes Haybaeck
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
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12
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Saida T, Mori K, Ishiguro T, Saida Y, Satoh T, Nakajima T. Differences in the position of endometriosis-associated and non-associated ovarian cancer relative to the uterus. Insights Imaging 2023; 14:136. [PMID: 37580615 PMCID: PMC10425308 DOI: 10.1186/s13244-023-01468-9] [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: 04/24/2023] [Accepted: 06/17/2023] [Indexed: 08/16/2023] Open
Abstract
BACKGROUND Preoperative assessment of the histological type of ovarian cancer is essential to determine the appropriate treatment strategy. Tumor location may be helpful in this regard. The purpose of this study was to compare the position of endometriosis-associated (EAOCs) and non-associated (non-EAOCs) ovarian cancer relative to the uterus using MRI. METHODS This retrospective study included patients with pathologically confirmed malignant epithelial ovarian tumors who underwent MRI at our hospital between January 2015 and January 2023. T2-weighted images of the sagittal and axial sections of the long axis of the uterine body were used for the analysis. Three blinded experienced radiologists independently interpreted the images and assessed whether the ovarian tumor was attached to the uterus, and the angle between the uterus and the tumor was measured. The presence of attachment and the measured angles were compared for each histology. In addition, the angles between EAOCs, including endometrioid carcinomas (ECs) and clear cell carcinomas (CCCs), were compared with non-EAOCs. RESULTS In total, 184 women (mean age, 56 years; age range, 20-91 years) were evaluated. High-grade serous carcinomas (HGSCs) were significantly smaller than the others and had significantly less uterine attachment than CCCs (p < 0.01 for all readers). According to the mean of the measured angles, CCCs were positioned significantly more posteriorly than HGSCs and mucinous carcinomas (p < 0.02), and EAOCs were positioned significantly more posteriorly to the uterus than non-EAOCs (p < 0.01). CONCLUSION HGSCs are often not attached to the uterus, and EAOCs are positioned more posteriorly to the uterus than non-EAOCs. CRITICAL RELEVANCE STATEMENT High-grade serous carcinomas were often not attached to the uterus, and endometriosis-associated ovarian cancers were positioned more posteriorly to the uterus than non-endometriosis-associated ovarian cancers. KEY POINTS • The position of the ovarian tumor can be determined using MRI. • High-grade serous carcinomas had less attachment to the uterus. • Endometriosis-associated cancers were positioned more posteriorly to the uterus. • The location of ovarian tumors is helpful in estimating histology.
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Affiliation(s)
- Tsukasa Saida
- Department of Radiology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
| | - Kensaku Mori
- Department of Radiology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Toshitaka Ishiguro
- Department of Radiology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Yukihisa Saida
- Department of Radiology, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan
| | - Toyomi Satoh
- Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Takahito Nakajima
- Department of Radiology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
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13
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Collins KE, Wang X, Klymenko Y, Davis NB, Martinez MC, Zhang C, So K, Buechlein A, Rusch DB, Creighton CJ, Hawkins SM. Transcriptomic analyses of ovarian clear-cell carcinoma with concurrent endometriosis. Front Endocrinol (Lausanne) 2023; 14:1162786. [PMID: 37621654 PMCID: PMC10445169 DOI: 10.3389/fendo.2023.1162786] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 07/17/2023] [Indexed: 08/26/2023] Open
Abstract
Introduction Endometriosis, a benign inflammatory disease whereby endometrial-like tissue grows outside the uterus, is a risk factor for endometriosis-associated ovarian cancers. In particular, ovarian endometriomas, cystic lesions of deeply invasive endometriosis, are considered the precursor lesion for ovarian clear-cell carcinoma (OCCC). Methods To explore this transcriptomic landscape, OCCC from women with pathology-proven concurrent endometriosis (n = 4) were compared to benign endometriomas (n = 4) by bulk RNA and small-RNA sequencing. Results Analysis of protein-coding genes identified 2449 upregulated and 3131 downregulated protein-coding genes (DESeq2, P< 0.05, log2 fold-change > |1|) in OCCC with concurrent endometriosis compared to endometriomas. Gene set enrichment analysis showed upregulation of pathways involved in cell cycle regulation and DNA replication and downregulation of pathways involved in cytokine receptor signaling and matrisome. Comparison of pathway activation scores between the clinical samples and publicly-available datasets for OCCC cell lines revealed significant molecular similarities between OCCC with concurrent endometriosis and OVTOKO, OVISE, RMG1, OVMANA, TOV21G, IGROV1, and JHOC5 cell lines. Analysis of miRNAs revealed 64 upregulated and 61 downregulated mature miRNA molecules (DESeq2, P< 0.05, log2 fold-change > |1|). MiR-10a-5p represented over 21% of the miRNA molecules in OCCC with endometriosis and was significantly upregulated (NGS: log2fold change = 4.37, P = 2.43e-18; QPCR: 8.1-fold change, P< 0.05). Correlation between miR-10a expression level in OCCC cell lines and IC50 (50% inhibitory concentration) of carboplatin in vitro revealed a positive correlation (R2 = 0.93). MiR-10a overexpression in vitro resulted in a significant decrease in proliferation (n = 6; P< 0.05) compared to transfection with a non-targeting control miRNA. Similarly, the cell-cycle analysis revealed a significant shift in cells from S and G2 to G1 (n = 6; P< 0.0001). Bioinformatic analysis predicted that miR-10a-5p target genes that were downregulated in OCCC with endometriosis were involved in receptor signaling pathways, proliferation, and cell cycle progression. MiR-10a overexpression in vitro was correlated with decreased expression of predicted miR-10a target genes critical for proliferation, cell-cycle regulation, and cell survival including [SERPINE1 (3-fold downregulated; P< 0.05), CDK6 (2.4-fold downregulated; P< 0.05), and RAP2A (2-3-fold downregulated; P< 0.05)]. Discussion These studies in OCCC suggest that miR-10a-5p is an impactful, potentially oncogenic molecule, which warrants further studies.
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Affiliation(s)
- Kaitlyn E. Collins
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Xiyin Wang
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, United States
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
| | - Yuliya Klymenko
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United States
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Noah B. Davis
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Maria C. Martinez
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Chi Zhang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Kaman So
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Aaron Buechlein
- Center for Genomics and Bioinformatics, Indiana University, Bloomington, IN, United States
| | - Douglas B. Rusch
- Center for Genomics and Bioinformatics, Indiana University, Bloomington, IN, United States
| | - Chad J. Creighton
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Shannon M. Hawkins
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United States
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, United States
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14
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Asaka S, Liu Y, Yu ZC, Rahmanto YS, Ono M, Asaka R, Miyamoto T, Yen TT, Ayhan A, Wang TL, Shih IM. ARID1A Regulates Progesterone Receptor Expression in Early Endometrial Endometrioid Carcinoma Pathogenesis. Mod Pathol 2023; 36:100045. [PMID: 36853791 DOI: 10.1016/j.modpat.2022.100045] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 09/13/2022] [Accepted: 10/18/2022] [Indexed: 01/11/2023]
Abstract
Loss of progesterone receptor (PR) expression is an established risk factor for unresponsiveness to progesterone therapy in patients with endometrial atypical hyperplasia and endometrioid carcinoma. ARID1A is one of the most commonly mutated genes in endometrioid carcinomas, and the loss of its expression is associated with tumor progression. In this study, we investigated the roles of ARID1A deficiency in PR expression in human and murine endometrial epithelial neoplasia. An analysis of genome-wide chromatin immunoprecipitation sequencing in isogenic ARID1A-/- and ARID1A+/+ human endometrial epithelial cells revealed that ARID1A-/- cells showed significantly reduced chromatin immunoprecipitation sequencing signals for ARID1A, BRG1, and H3K27AC in the PgR enhancer region. We then performed immunohistochemistry to correlate the protein expression levels of ARID1A, estrogen receptor, and PR in 50 human samples of endometrial atypical hyperplasia and 75 human samples of endometrial carcinomas. The expression levels of PR but not were significantly lower in ARID1A-deficient low-grade endometrial carcinomas and atypical hyperplasia (P = .0002). When Pten and Pten/Arid1a conditional knockout murine models were used, Pten-/-;Arid1a-/- mice exhibited significantly decreased epithelial PR expression in endometrial carcinomas (P = .003) and atypical hyperplasia (P < .0001) compared with that in the same tissues from Pten-/-;Arid1a+/+ mice. Our data suggest that the loss of ARID1A expression, as occurs in ARID1A-mutated endometrioid carcinomas, decreases PgR transcription by modulating the PgR enhancer region during early tumor development.
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Affiliation(s)
- Shiho Asaka
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Ying Liu
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Zheng-Cheng Yu
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Yohan Suryo Rahmanto
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Motoki Ono
- Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Ryoichi Asaka
- Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tsutomu Miyamoto
- Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Ting-Tai Yen
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ayse Ayhan
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Seirei Mikatahara Hospital, Hamamatsu, Japan; Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tian-Li Wang
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Ie-Ming Shih
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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15
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Ji JX, Cochrane DR, Negri GL, Colborne S, Spencer Miko SE, Hoang LN, Farnell D, Tessier-Cloutier B, Huvila J, Thompson E, Leung S, Chiu D, Chow C, Ta M, Köbel M, Feil L, Anglesio M, Goode EL, Bolton K, Morin GB, Huntsman DG. The proteome of clear cell ovarian carcinoma. J Pathol 2022; 258:325-338. [PMID: 36031730 PMCID: PMC9649886 DOI: 10.1002/path.6006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 08/05/2022] [Accepted: 08/26/2022] [Indexed: 01/19/2023]
Abstract
Clear cell ovarian carcinoma (CCOC) is the second most common subtype of epithelial ovarian carcinoma. Late-stage CCOC is not responsive to gold-standard chemotherapy and results in suboptimal outcomes for patients. In-depth molecular insight is urgently needed to stratify the disease and drive therapeutic development. We conducted global proteomics for 192 cases of CCOC and compared these with other epithelial ovarian carcinoma subtypes. Our results showed distinct proteomic differences in CCOC compared with other epithelial ovarian cancer subtypes including alterations in lipid and purine metabolism pathways. Furthermore, we report potential clinically significant proteomic subgroups within CCOC, suggesting the biologic plausibility of stratified treatment for this cancer. Taken together, our results provide a comprehensive understanding of the CCOC proteomic landscape to facilitate future understanding and research of this disease. © 2022 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Jennifer X Ji
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Dawn R Cochrane
- Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada
| | - Gian Luca Negri
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Shane Colborne
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Sandra E Spencer Miko
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Lynn N Hoang
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - David Farnell
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Basile Tessier-Cloutier
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Jutta Huvila
- Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada
- Department of Biomedicine, University of Turku, Turku, Finland
| | - Emily Thompson
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Samuel Leung
- Genetic Pathology Evaluation Center, Vancouver, BC, Canada
| | - Derek Chiu
- Genetic Pathology Evaluation Center, Vancouver, BC, Canada
| | - Christine Chow
- Genetic Pathology Evaluation Center, Vancouver, BC, Canada
| | - Monica Ta
- Genetic Pathology Evaluation Center, Vancouver, BC, Canada
| | - Martin Köbel
- Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada
| | - Lucas Feil
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
| | - Michael Anglesio
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
| | - Ellen L Goode
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
| | - Kelly Bolton
- Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
| | - Gregg B Morin
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, University of British Columbia, Vancouver, BC, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - David G Huntsman
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
- Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
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16
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Ok Atılgan A, Özen Ö, Haberal Reyhan A, Ayhan A. Clinicopathologic Features and the Loss of ARID1A Expression in Ovarian Seromucinous Borderline Tumors and Seromucinous Carcinomas. Int J Surg Pathol 2022; 31:398-408. [PMID: 36452965 DOI: 10.1177/10668969221134695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
The current study highlighted the ARID1A and SALL4 expression and described histopathologic and immunohistochemical features of ovarian seromucinous tumors (SMTs) including borderline tumors (SMBTs) and seromucinous carcinomas (SMC; namely as endometrioid carcinoma with mucinous differentiation according to WHO 2020 classification). The clinicopathological and immunohistochemical features of 38 SMTs were analyzed, including ARID1A, SALL4, estrogen receptor (ER), progesterone receptor (PR), TP53, keratin 7, keratin 20, CEA, CDX2, WT1, PAX2, and PAX8. SMCs and SMBTs comprised 68.4% (n = 26) and 31.6% (n = 12) of all SMTs, respectively, studied. The mean age of diagnosis was 47.4 years and 41.4 years, and the mean size was 9 cm and 7.45 cm for SMC and SMBT, respectively. There was endometriosis or endometriotic cyst in 61.5% of SMCs and 50% of SMBTs. Immunohistochemically, loss of ARID1A staining was observed in 15 (65.2%) of 26 SMCs, and 3 (33.3%) of the 12 SMBTs. Only one SMC showed focal SALL4 positivity. All SMTs were positive for ER, PR, PAX8, and keratin 7. SMTs were negative for WT1, keratin 20, CDX2, and CEA (negative in 66.7% to 92.3% of the cases). While all SMBTs and 24 (92.3%) of 26 SMCs exhibited “wild-type” TP53 staining, 2 (7.7%) SMCs, both were stage III, showed mutant type TP53 overexpression. We indicate there is a similarity between SMC and SMBT according to the immunohistochemical features. SMBTs are keratin 7, ER, PR positive tumors, and some of them have loss of ARID1A expression and are likely to develop in the background of endometriosis similar to SMC.
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Affiliation(s)
- Alev Ok Atılgan
- Department of Pathology, Baskent University, Faculty of Medicine, Ankara, Turkey
| | - Özlem Özen
- Department of Pathology, Baskent University, Faculty of Medicine, Ankara, Turkey
| | | | - Ali Ayhan
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Baskent University, Faculty of Medicine, Ankara, Turkey
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Mandal J, Mandal P, Wang TL, Shih IM. Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response. J Biomed Sci 2022; 29:71. [PMID: 36123603 PMCID: PMC9484255 DOI: 10.1186/s12929-022-00856-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 09/13/2022] [Indexed: 11/10/2022] Open
Abstract
Chromatin remodeling is an essential cellular process for organizing chromatin structure into either open or close configuration at specific chromatin locations by orchestrating and modifying histone complexes. This task is responsible for fundamental cell physiology including transcription, DNA replication, methylation, and damage repair. Aberrations in this activity have emerged as epigenomic mechanisms in cancer development that increase tumor clonal fitness and adaptability amidst various selection pressures. Inactivating mutations in AT-rich interaction domain 1A (ARID1A), a gene encoding a large nuclear protein member belonging to the SWI/SNF chromatin remodeling complex, result in its loss of expression. ARID1A is the most commonly mutated chromatin remodeler gene, exhibiting the highest mutation frequency in endometrium-related uterine and ovarian carcinomas. As a tumor suppressor gene, ARID1A is essential for regulating cell cycle, facilitating DNA damage repair, and controlling expression of genes that are essential for maintaining cellular differentiation and homeostasis in non-transformed cells. Thus, ARID1A deficiency due to somatic mutations propels tumor progression and dissemination. The recent success of PARP inhibitors in treating homologous recombination DNA repair-deficient tumors has engendered keen interest in developing synthetic lethality-based therapeutic strategies for ARID1A-mutated neoplasms. In this review, we summarize recent advances in understanding the biology of ARID1A in cancer development, with special emphasis on its roles in DNA damage repair. We also discuss strategies to harness synthetic lethal mechanisms for future therapeutics against ARID1A-mutated cancers.
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Affiliation(s)
- Jayaprakash Mandal
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Tian-Li Wang
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Ie-Ming Shih
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, USA.
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18
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Ishizaka A, Taguchi A, Tsuruga T, Maruyama M, Kawata A, Miyamoto Y, Tanikawa M, Ikemura M, Sone K, Mori M, Koga K, Ushiku T, Oda K, Osuga Y. Endometrial cancer with concomitant endometriosis is highly associated with ovarian endometrioid carcinoma: a retrospective cohort study. BMC Womens Health 2022; 22:332. [PMID: 35932070 PMCID: PMC9354371 DOI: 10.1186/s12905-022-01917-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 07/26/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Endometriosis is assumed to be involved in ovarian cancer development, which is called endometriosis-associated ovarian cancer (EAOC). Uterine endometrial cells may be the cell of origin of EAOC. Accumulated carcinogenic changes in the uterine endometrial cells may increase the risk of developing EAOC. To further understand the pathogenesis of EAOCs, we focused on the clinicopathological characteristics of EAOCs in endometrial cancer patients with concomitant endometriosis.
Methods
We retrospectively reviewed 376 patients who were surgically treated for stage I–III endometrial cancer. Clinicopathological characteristics were compared between patients with and without endometriosis. Furthermore, the incidence of simultaneous endometrial and ovarian cancer (SEOC) and the histological characteristics of SEOC were compared between the two groups.
Results
Among 376 patients with endometrial cancer, 51 had concomitant endometriosis. Patients with endometriosis were significantly younger and more frequently had endometrioid G1/G2 tumors than those without endometriosis. The incidence of SEOCs was significantly higher in endometrial cancer patients with endometriosis than those without it (p < 0.0001); notably, 12 of 51 endometrial cancer patients with endometriosis (24%) had SEOCs. All of the ovarian cancers in endometrial cancer patients with endometriosis were endometrioid carcinomas. Moreover, even in those without endometriosis, endometrioid carcinoma was the most common histological type of SEOC.
Conclusion
We revealed that endometrial cancer patients with endometriosis had a high probability of SEOC and that endometrioid carcinoma was the most common histological subtype of SEOC regardless of the presence of endometriosis. For patients with endometrial cancer and endometriosis, careful examination of ovarian endometriotic lesions may be important to detect EAOCs.
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19
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Magnetic resonance imaging findings of cystic ovarian tumors: major differential diagnoses in five types frequently encountered in daily clinical practice. Jpn J Radiol 2022; 40:1213-1234. [PMID: 35916971 DOI: 10.1007/s11604-022-01321-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 07/21/2022] [Indexed: 10/16/2022]
Abstract
There are many types of ovarian tumors, and these different types often form cystic masses with a similar appearance, which can make their differentiation difficult. However, with the exclusion of rare ovarian tumors, the number of ovarian tumors encountered in daily practice is somewhat fixed. It goes without saying that magnetic resonance imaging (MRI) is useful for differentiating ovarian tumors. In this review, we summarize the differential diagnoses for each of the five types of MRI findings commonly encountered in daily practice. First, unilocular cystic masses without mural nodules/solid components include benign lesions such as serous cystadenoma, functional cysts, surface epithelial inclusion cysts, paratubal cysts, and endometriosis. Second, multilocular cystic ovarian lesions include mucinous tumors and ovarian metastases. It should be noted that mucinous tumors may be diagnosed as borderline or carcinoma, even if no solid component is observed. Third, cystic lesions with mural nodules that are unrelated to endometriosis include serous borderline tumor and serous carcinoma. Cystic lesions with solid components are more likely to be malignant, but some may be diagnosed as benign. Fourth, ovarian tumors deriving from endometriosis include seromucinous borderline tumors, endometrioid carcinoma, and clear cell carcinoma. These tumors sometimes need to be differentiated from serous tumors. Finally, cystic lesions with lipid contents include teratoma-related tumors. In mature cystic teratoma, mural nodules (called "Rokitansky protuberance" or "dermoid nipple") are sometimes seen, but they do not suggest malignancy. Some of these lesions can be diagnosed accurately by considering their characteristic imaging findings, their changes over time, MRI findings other than those of the primary lesion, and information from other modalities such as tumor markers. To ensure the optimal treatment for ovarian tumors, it is important to estimate the histological type as well as to diagnose whether a lesion is benign or malignant.
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20
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Clemente V, Hoshino A, Shetty M, Nelson A, Erickson BK, Baker R, Rubin N, Khalifa M, Weroha SJ, Lou E, Bazzaro M. GLS1 is a protective factor in patients with ovarian clear cell carcinoma and its expression does not correlate with ARID1A-mutated tumors. CANCER RESEARCH COMMUNICATIONS 2022; 2:784-794. [PMID: 36082022 PMCID: PMC9451103 DOI: 10.1158/2767-9764.crc-22-0122] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 05/11/2022] [Accepted: 07/13/2022] [Indexed: 06/15/2023]
Abstract
Targeting glutamine metabolism has emerged as a novel therapeutic strategy for several human cancers, including ovarian cancer. The primary target of this approach is the kidney isoform of glutaminase, glutaminase 1 (GLS1), a key enzyme in glutamine metabolism that is overexpressed in several human cancers. A first-in-class inhibitor of GLS1, called CB839 (Telaglenastat), has been investigated in several clinical trials, with promising results. The first clinical trial of CB839 in platinum-resistant ovarian cancer patients is forthcoming. ARID1A-mutated ovarian clear cell carcinoma (OCCC) is a relatively indolent and chemoresistant ovarian cancer histotype. In OCCC-derived cells ARID1A simultaneously drives GLS1 expression and metabolism reprograming. In ARID1A-mutated OCCC-derived mouse models, loss of ARID1A corresponds to GLS1 upregulation and increases sensitivity to GLS1 inhibition. Thus, targeting of GLS1 with CB839 has been suggested as a targeted approach for OCCC patients with tumors harboring ARID1A-mutations. Here, we investigated whether GLS1 is differentially expressed between OCCC patients whose tumors are ARID1A positive and patients whose tumors are ARID1A negative. In clinical specimens of OCCC, we found that GLS1 overexpression was not correlated with ARID1A loss. In addition, GLS1 overexpression was associated with better clinical outcomes. Our findings have implications for human trials using experimental therapeutics targeting GLS1.
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Affiliation(s)
- Valentino Clemente
- Masonic Cancer Center and Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota
| | - Asumi Hoshino
- Masonic Cancer Center and Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota
| | - Mihir Shetty
- Masonic Cancer Center and Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota
| | - Andrew Nelson
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
| | - Britt K. Erickson
- Masonic Cancer Center and Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota
| | - Ruth Baker
- Masonic Cancer Center and Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota
| | - Nathan Rubin
- Biostatistics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Mahmoud Khalifa
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
| | - S. John Weroha
- Departments of Oncology and Molecular Pharmacology, Mayo Clinic, Rochester, Minnesota
| | - Emil Lou
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Martina Bazzaro
- Masonic Cancer Center and Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota
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21
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Kiyokawa T. Peritoneal Pathology Review: Mullerian, Mucinous and Mesothelial Lesions. Surg Pathol Clin 2022; 15:259-276. [PMID: 35715161 DOI: 10.1016/j.path.2022.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
This review provides an overview of the pathology of selected benign and malignant lesions of the female peritoneum and their often-encountered differential diagnoses. It includes endometriosis and its related lesions, endosalpingiosis, pseudomyxoma peritonei (PMP) and related ovarian/appendiceal pathology, and malignant and benign mesothelial tumors. The current terminology associated with PMP is also discussed.
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Affiliation(s)
- Takako Kiyokawa
- Department of Pathology, The Jikei University School of Medicine, 3-25-8 Nishishimbashi Minato-ku, Tokyo 105-8461, Japan.
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22
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Han L, Zhang B. Malignant transformation of endometriosis in a laparoscopic trocar site a case report. BMC Womens Health 2022; 22:163. [PMID: 35562703 PMCID: PMC9103296 DOI: 10.1186/s12905-022-01749-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 04/29/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Malignant transformation of endometriosis is infrequent at the laparoscopic trocar site. Although malignant transformation is uncommon, it must be acknowledged in order to achieve radical resection. CASE PRESENTATION We report on a 54-year-old woman with trocar site endometriosis 2 years after laparoscopic ovarian endometrial resection. Physical examination revealed a subcutaneous solid tumor with a diameter of 3 cm surrounding the scar of laparoscopic surgery in the right lower abdomen. Transabdominal ultrasonography showed a cystic tumor in the subcutaneous adipose layer of the right lower abdomen. The pathological diagnosis was poorly differentiated endometrioid carcinoma. Hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy were then performed. Histological examination revealed mixed endometrioid carcinoma and clear cell carcinoma. After six cycles of chemotherapy, computed tomography showed no signs of recurrence. CONCLUSIONS Malignant transformation of laparoscopic endometriosis is very uncommon, and the diagnosis and stage are determined by clinical manifestations and imaging examination. The main therapy methods are radical surgery combined with neoadjuvant chemotherapy and adjuvant radiotherapy. At the same time, reducing iatrogenic abdominal incision implantation is an effective prevention method.
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Affiliation(s)
- Ling Han
- Department of Obstetrics and Gynecology, The People's Hospital of China Three Geoges University The People's Hospital of China Three Gorges University. The First People's Hospital of Yichang, Jiefang Road 4, Yichang City, 443003, Hubei Province, People's Republic of China.
| | - Bingyi Zhang
- Department of Ultrasound Imaging, The People's Hospital of China Three Gorges University. The First People's Hospital of Yichang, Yichang City, Hubei Province, People's Republic of China
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23
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Heinze K, Nazeran TM, Lee S, Krämer P, Cairns ES, Chiu DS, Leung SC, Kang EY, Meagher NS, Kennedy CJ, Boros J, Kommoss F, Vollert HW, Heitze F, du Bois A, Harter P, Grube M, Kraemer B, Staebler A, Kommoss FK, Heublein S, Sinn HP, Singh N, Laslavic A, Elishaev E, Olawaiye A, Moysich K, Modugno F, Sharma R, Brand AH, Harnett PR, DeFazio A, Fortner RT, Lubinski J, Lener M, Tołoczko-Grabarek A, Cybulski C, Gronwald H, Gronwald J, Coulson P, El-Bahrawy MA, Jones ME, Schoemaker MJ, Swerdlow AJ, Gorringe KL, Campbell I, Cook L, Gayther SA, Carney ME, Shvetsov YB, Hernandez BY, Wilkens LR, Goodman MT, Mateoiu C, Linder A, Sundfeldt K, Kelemen LE, Gentry-Maharaj A, Widschwendter M, Menon U, Bolton KL, Alsop J, Shah M, Jimenez-Linan M, Pharoah PD, Brenton JD, Cushing-Haugen KL, Harris HR, Doherty JA, Gilks B, Ghatage P, Huntsman DG, Nelson GS, Tinker AV, Lee CH, Goode EL, Nelson BH, Ramus SJ, Kommoss S, Talhouk A, Köbel M, Anglesio MS. Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8 + TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas. J Pathol 2022; 256:388-401. [PMID: 34897700 PMCID: PMC9544180 DOI: 10.1002/path.5849] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 11/12/2021] [Accepted: 12/10/2021] [Indexed: 11/11/2022]
Abstract
ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis-associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumour-infiltrating lymphocytes (CD8+ TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p = 0.012) and was associated with MMRd (p < 0.001) and the presence of CD8+ TILs (p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss-of-function mutation as a result of small indels (p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8+ TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8+ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance. © 2021 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Karolin Heinze
- University of British Columbia, Department of Obstetrics and Gynecology, Vancouver, BC, Canada
- University of British Columbia, Vancouver General Hospital, and BC Cancer. British Columbia’s Gynecological Cancer Research Team (OVCARE), Vancouver, BC, Canada
| | - Tayyebeh M. Nazeran
- University of British Columbia, Vancouver General Hospital, and BC Cancer. British Columbia’s Gynecological Cancer Research Team (OVCARE), Vancouver, BC, Canada
| | - Sandra Lee
- University of Calgary, Department of Pathology and Laboratory Medicine, Calgary, AB, Canada
| | - Pauline Krämer
- University of British Columbia, Department of Obstetrics and Gynecology, Vancouver, BC, Canada
- University Hospital Tübingen, Department of Women’s Health, Tübingen, Germany
| | - Evan S. Cairns
- University of British Columbia, Department of Obstetrics and Gynecology, Vancouver, BC, Canada
| | - Derek S. Chiu
- University of British Columbia, Vancouver General Hospital, and BC Cancer. British Columbia’s Gynecological Cancer Research Team (OVCARE), Vancouver, BC, Canada
| | - Samuel C.Y. Leung
- University of British Columbia, Vancouver General Hospital, and BC Cancer. British Columbia’s Gynecological Cancer Research Team (OVCARE), Vancouver, BC, Canada
| | - Eun Young Kang
- University of Calgary, Department of Pathology and Laboratory Medicine, Calgary, AB, Canada
| | - Nicola S. Meagher
- University of New South Wales, Adult Cancer Program, Lowy Cancer Research Centre, Sydney, New South Wales, Australia
- University of New South Wales, School of Women’s and Children’s Health, Sydney, New South Wales, Australia
| | - Catherine J. Kennedy
- The University of Sydney, Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
- Westmead Hospital, Department of Gynaecological Oncology, Sydney, New South Wales, Australia
| | - Jessica Boros
- The University of Sydney, Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
- Westmead Hospital, Department of Gynaecological Oncology, Sydney, New South Wales, Australia
| | - Friedrich Kommoss
- Medizin Campus Bodensee, Institute of Pathology, Friedrichshafen, Germany
| | - Hans-Walter Vollert
- Medizin Campus Bodensee, Department of Gynecology and Obstetrics, Friedrichshafen, Germany
| | - Florian Heitze
- Kliniken Essen Mitte, Department of Gynecology and Gynecologic Oncology, Essen, Germany
| | - Andreas du Bois
- Kliniken Essen Mitte, Department of Gynecology and Gynecologic Oncology, Essen, Germany
| | - Philipp Harter
- Kliniken Essen Mitte, Department of Gynecology and Gynecologic Oncology, Essen, Germany
| | - Marcel Grube
- University of British Columbia, Department of Obstetrics and Gynecology, Vancouver, BC, Canada
- University Hospital Tübingen, Department of Women’s Health, Tübingen, Germany
| | - Bernhard Kraemer
- University Hospital Tübingen, Department of Women’s Health, Tübingen, Germany
| | - Annette Staebler
- University Hospital Tübingen, Institute of Pathology and Neuropathology, Tübingen, Germany
| | - Felix K.F. Kommoss
- University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany
| | - Sabine Heublein
- University Hospital Heidelberg and National Center for Tumor Diseases, Department of Obstetrics and Gynecology, Heidelberg, Germany
| | - Hans-Peter Sinn
- University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany
| | - Naveena Singh
- Barts Health National Health Service Trust, Department of Pathology, London, UK
| | - Angela Laslavic
- University of Pittsburgh School of Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, PA, USA
| | - Esther Elishaev
- University of Pittsburgh School of Medicine, Department of Pathology, PA, USA
| | - Alex Olawaiye
- University of Pittsburgh School of Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, PA, USA
| | - Kirsten Moysich
- Roswell Park Cancer Institute, Department of Cancer Prevention and Control, Buffalo, NY, USA
| | - Francesmary Modugno
- University of Pittsburgh School of Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, PA, USA
| | - Raghwa Sharma
- Westmead Hospital, Tissue Pathology and Diagnostic Oncology, Sydney, New South Wales, Australia
- University of Sydney, Sydney, New South Wales, Australia
- Western Sydney University, Sydney, New South Wales, Australia
| | - Alison H. Brand
- Westmead Hospital, Department of Gynaecological Oncology, Sydney, New South Wales, Australia
- University of Sydney, Sydney, New South Wales, Australia
| | - Paul R. Harnett
- Westmead Hospital, Department of Gynaecological Oncology, Sydney, New South Wales, Australia
- Westmead Hospital, Crown Princess Mary Cancer Centre, Sydney, New South Wales, Australia
| | - Anna DeFazio
- The University of Sydney, Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
- Westmead Hospital, Department of Gynaecological Oncology, Sydney, New South Wales, Australia
- University of Sydney, Sydney, New South Wales, Australia
- The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, New South Wales, Australia
| | - Renée T. Fortner
- German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany
| | - Jan Lubinski
- Pomeranian Medical University, Department of Genetics and Pathology, International Hereditary Cancer Centre, Szczecin, Poland
| | - Marcin Lener
- Pomeranian Medical University, Department of Genetics and Pathology, International Hereditary Cancer Centre, Szczecin, Poland
| | - Aleksandra Tołoczko-Grabarek
- Pomeranian Medical University, Department of Genetics and Pathology, International Hereditary Cancer Centre, Szczecin, Poland
| | - Cezary Cybulski
- Pomeranian Medical University, Department of Genetics and Pathology, International Hereditary Cancer Centre, Szczecin, Poland
| | - Helena Gronwald
- Pomeranian Medical University, Department of Propaedeutics, Physical Diagnostics and Dental Physiotherapy, Szczecin, Poland
| | - Jacek Gronwald
- Pomeranian Medical University, Department of Genetics and Pathology, International Hereditary Cancer Centre, Szczecin, Poland
| | - Penny Coulson
- The Institute of Cancer Research, Division of Genetics and Epidemiology, London, UK
| | - Mona A El-Bahrawy
- Imperial College London, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, London, UK
| | - Michael E. Jones
- The Institute of Cancer Research, Division of Genetics and Epidemiology, London, UK
| | - Minouk J. Schoemaker
- The Institute of Cancer Research, Division of Genetics and Epidemiology, London, UK
| | - Anthony J. Swerdlow
- The Institute of Cancer Research, Division of Genetics and Epidemiology, London, UK
- The Institute of Cancer Research, Division of Breast Cancer Research, London, UK
| | - Kylie L. Gorringe
- The University of Melbourne, Sir Peter MacCallum Department of Oncology, Melbourne, Australia
- Peter MacCallum Cancer Centre, Women’s Cancer Program, Melbourne, Australia
| | - Ian Campbell
- The University of Melbourne, Sir Peter MacCallum Department of Oncology, Melbourne, Australia
- Peter MacCallum Cancer Centre, Cancer Genetics Laboratory, Research Division, Melbourne, Australia
| | - Linda Cook
- The University of New Mexico, Division of Epidemiology and Biostatistics, Albuquerque, NM, USA
| | - Simon A. Gayther
- Cedars-Sinai Medical Center, Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Los Angeles, CA, USA
| | - Michael E. Carney
- John A. Burns School of Medicine, University of Hawaii, Honolulu, Department of Obstetrics and Gynecology, HI, USA
| | - Yurii B. Shvetsov
- University of Hawaii Cancer Center, Epidemiology Program, Honolulu, HI, USA
| | | | - Lynne R. Wilkens
- University of Hawaii Cancer Center, Epidemiology Program, Honolulu, HI, USA
| | - Marc T. Goodman
- Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Los Angeles, CA, USA
| | - Constantina Mateoiu
- Sahlgrenska Academy at Gothenburg University, Sahlgrenska Center for Cancer Research, Department of Obstetrics and Gynecology, Gothenburg, Sweden
| | - Anna Linder
- Sahlgrenska Academy at Gothenburg University, Sahlgrenska Center for Cancer Research, Department of Obstetrics and Gynecology, Gothenburg, Sweden
| | - Karin Sundfeldt
- Sahlgrenska Academy at Gothenburg University, Sahlgrenska Center for Cancer Research, Department of Obstetrics and Gynecology, Gothenburg, Sweden
| | - Linda E. Kelemen
- Medical University of South Carolina, Hollings Cancer Center and Department of Public Health Sciences, Charleston, SC, USA
| | - Aleksandra Gentry-Maharaj
- University College London, MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, London, UK
- University College London, Department of Women’s Cancer, Institute for Women’s Health, London, UK
| | | | - Usha Menon
- University College London, MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, London, UK
| | - Kelly L. Bolton
- Washington University School of Medicine, Department of Hematology and Oncology, Division of Oncology, St. Louis, MO, USA
| | - Jennifer Alsop
- University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Oncology, Cambridge, UK
| | - Mitul Shah
- Addenbrookes Hospital, Department of Histopathology, Cambridge, UK
| | | | - Paul D.P. Pharoah
- University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Oncology, Cambridge, UK
- University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Cambridge, UK
| | - James D. Brenton
- University of Cambridge, Cancer Research UK Cambridge Institute, Cambridge, UK
| | - Kara L. Cushing-Haugen
- Fred Hutchinson Cancer Research Center, Program in Epidemiology, Division of Public Health Sciences, Seattle, WA, USA
| | - Holly R. Harris
- Fred Hutchinson Cancer Research Center, Program in Epidemiology, Division of Public Health Sciences, Seattle, WA, USA
| | - Jennifer A. Doherty
- University of Utah, Huntsman Cancer Institute, Department of Population Health Sciences, Salt Lake City, UT, USA
| | - Blake Gilks
- University of British Columbia, Vancouver General Hospital, and BC Cancer. British Columbia’s Gynecological Cancer Research Team (OVCARE), Vancouver, BC, Canada
| | - Prafull Ghatage
- University of Calgary, Department of Oncology, Division of Gynecologic Oncology, Calgary, AB, Canada
| | - David G. Huntsman
- University of British Columbia, Department of Obstetrics and Gynecology, Vancouver, BC, Canada
- University of British Columbia, Vancouver General Hospital, and BC Cancer. British Columbia’s Gynecological Cancer Research Team (OVCARE), Vancouver, BC, Canada
| | - Gregg S. Nelson
- University of Calgary, Department of Oncology, Division of Gynecologic Oncology, Calgary, AB, Canada
| | - Anna V. Tinker
- University of British Columbia, Vancouver General Hospital, and BC Cancer. British Columbia’s Gynecological Cancer Research Team (OVCARE), Vancouver, BC, Canada
- University of British Columbia, Department of Medicine, Vancouver, BC, Canada
| | - Cheng-Han Lee
- University of Alberta, Department of Laboratory Medicine and Pathology, Edmonton, AB, Canada
| | - Ellen L. Goode
- Mayo Clinic, Department of Health Science Research, Division of Epidemiology, Rochester, MN, USA
| | - Brad H. Nelson
- Trev & Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, BC, Canada
| | - Susan J. Ramus
- University of New South Wales, Adult Cancer Program, Lowy Cancer Research Centre, Sydney, New South Wales, Australia
- University of New South Wales, School of Women’s and Children’s Health, Sydney, New South Wales, Australia
| | - Stefan Kommoss
- University Hospital Tübingen, Department of Women’s Health, Tübingen, Germany
| | - Aline Talhouk
- University of British Columbia, Department of Obstetrics and Gynecology, Vancouver, BC, Canada
- University of British Columbia, Vancouver General Hospital, and BC Cancer. British Columbia’s Gynecological Cancer Research Team (OVCARE), Vancouver, BC, Canada
| | - Martin Köbel
- University of Calgary, Department of Pathology and Laboratory Medicine, Calgary, AB, Canada
| | - Michael S. Anglesio
- University of British Columbia, Department of Obstetrics and Gynecology, Vancouver, BC, Canada
- University of British Columbia, Vancouver General Hospital, and BC Cancer. British Columbia’s Gynecological Cancer Research Team (OVCARE), Vancouver, BC, Canada
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24
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Srinivas US, Tay NSC, Jaynes P, Anbuselvan A, Ramachandran GK, Wardyn JD, Hoppe MM, Hoang PM, Peng Y, Lim S, Lee MY, Peethala PC, An O, Shendre A, Tan BWQ, Jemimah S, Lakshmanan M, Hu L, Jakhar R, Sachaphibulkij K, Lim LHK, Pervaiz S, Crasta K, Yang H, Tan P, Liang C, Ho L, Khanchandani V, Kappei D, Yong WP, Tan DSP, Bordi M, Campello S, Tam WL, Frezza C, Jeyasekharan AD. PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production. Oncogene 2022; 41:1986-2002. [PMID: 35236967 DOI: 10.1038/s41388-022-02219-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 01/12/2022] [Accepted: 01/27/2022] [Indexed: 12/26/2022]
Abstract
Inhibitors of the mitotic kinase PLK1 yield objective responses in a subset of refractory cancers. However, PLK1 overexpression in cancer does not correlate with drug sensitivity, and the clinical development of PLK1 inhibitors has been hampered by the lack of patient selection marker. Using a high-throughput chemical screen, we discovered that cells deficient for the tumor suppressor ARID1A are highly sensitive to PLK1 inhibition. Interestingly this sensitivity was unrelated to canonical functions of PLK1 in mediating G2/M cell cycle transition. Instead, a whole-genome CRISPR screen revealed PLK1 inhibitor sensitivity in ARID1A deficient cells to be dependent on the mitochondrial translation machinery. We find that ARID1A knock-out (KO) cells have an unusual mitochondrial phenotype with aberrant biogenesis, increased oxygen consumption/expression of oxidative phosphorylation genes, but without increased ATP production. Using expansion microscopy and biochemical fractionation, we see that a subset of PLK1 localizes to the mitochondria in interphase cells. Inhibition of PLK1 in ARID1A KO cells further uncouples oxygen consumption from ATP production, with subsequent membrane depolarization and apoptosis. Knockdown of specific subunits of the mitochondrial ribosome reverses PLK1-inhibitor induced apoptosis in ARID1A deficient cells, confirming specificity of the phenotype. Together, these findings highlight a novel interphase role for PLK1 in maintaining mitochondrial fitness under metabolic stress, and a strategy for therapeutic use of PLK1 inhibitors. To translate these findings, we describe a quantitative microscopy assay for assessment of ARID1A protein loss, which could offer a novel patient selection strategy for the clinical development of PLK1 inhibitors in cancer.
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Affiliation(s)
- Upadhyayula S Srinivas
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - Norbert S C Tay
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - Patrick Jaynes
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - Akshaya Anbuselvan
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - Gokula K Ramachandran
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - Joanna D Wardyn
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - Michal M Hoppe
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - Phuong Mai Hoang
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - Yanfen Peng
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - Sherlly Lim
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - May Yin Lee
- Genome Institute of Singapore (GIS), Agency for Science Technology and Research (A*STAR), Singapore, Singapore
| | - Praveen C Peethala
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - Omer An
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - Akshay Shendre
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - Bryce W Q Tan
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - Sherlyn Jemimah
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - Manikandan Lakshmanan
- Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Singapore
| | - Longyu Hu
- Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Rekha Jakhar
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore, Singapore
| | - Karishma Sachaphibulkij
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Lina H K Lim
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Shazib Pervaiz
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Karen Crasta
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore, Singapore
| | - Henry Yang
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - Patrick Tan
- Genome Institute of Singapore (GIS), Agency for Science Technology and Research (A*STAR), Singapore, Singapore
- Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Chao Liang
- Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore
| | - Lena Ho
- Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore
| | - Vartika Khanchandani
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
| | - Dennis Kappei
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Wei Peng Yong
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
- National University Cancer Institute, Singapore (NCIS), National University Hospital (NUH), Singapore, Singapore
| | - David S P Tan
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
- National University Cancer Institute, Singapore (NCIS), National University Hospital (NUH), Singapore, Singapore
| | - Matteo Bordi
- Department of Biology, University of Rome 'Tor Vergata', Rome, Italy
| | - Silvia Campello
- Department of Biology, University of Rome 'Tor Vergata', Rome, Italy
| | - Wai Leong Tam
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore
- Genome Institute of Singapore (GIS), Agency for Science Technology and Research (A*STAR), Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | | | - Anand D Jeyasekharan
- Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore.
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore.
- National University Cancer Institute, Singapore (NCIS), National University Hospital (NUH), Singapore, Singapore.
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25
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Evaluation of SWI/SNF Protein Expression by Immunohistochemistry in Ovarian Clear Cell Carcinoma. Int J Gynecol Pathol 2021; 40:156-164. [PMID: 32897960 DOI: 10.1097/pgp.0000000000000687] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Ovarian clear cell carcinomas (OCCC) are known to harbor ARID1A mutations, and several recent studies have described immunohistochemical loss of SMARCA2, SMARCA4, and SMARCB1 in a subset of tumors. We performed ARID1A, SMARCA2, SMARCA4, and SMARCB1 immunohistochemistry on 105 OCCCs to identify possible associations with clinicopathologic features and assess their prognostic value in these tumors. ARID1A, SMARCA4, and SMARCB1 were considered retained if any tumor cell nucleus stained while for SMARCA2, >5% of tumor nuclei were required to be positive. Patients had a mean age of 56 yr and tumors averaged 13 cm in size. Most patients (63%) had stage I tumors with 47% being alive and well, 41% dead from disease, 10% dead from other causes, and 3% alive with disease at last follow-up (mean 72 mo). Tumors showed an admixture of architectural patterns, but papillary was most frequent (49%). Stromal hyalinization was detected in 83% of OCCCs and a background precursor in 78%. High-grade atypia and/or oxyphilic cells were noted in 45% and 29% of tumors, respectively. All OCCCs expressed SMARCA4 and SMARCB1, but the absence of ARID1A was noted in 30% of tumors and SMARCA2 in 8%. ARID1A-retained OCCCs were associated with a dominant tubulocystic or solid pattern, but no other clinicopathologic features reached statistical significance. No switch/sucrose non-fermentable protein expression was predictive of prognosis. Additional studies with known mutational status of these proteins are warranted to better assess their prognostic utility and develop a standardized immunohistochemical scoring system.
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26
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Li H, Liu Y, Wang Y, Zhao X, Qi X. Hormone therapy for ovarian cancer: Emphasis on mechanisms and applications (Review). Oncol Rep 2021; 46:223. [PMID: 34435651 PMCID: PMC8424487 DOI: 10.3892/or.2021.8174] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 08/04/2021] [Indexed: 02/05/2023] Open
Abstract
Ovarian cancer (OC) remains the leading cause of mortality due to gynecological malignancies. Epidemiological studies have demonstrated that steroid hormones released from the hypothalamic-pituitary-ovarian axis can play a role in stimulating or inhibiting OC progression, with gonadotropins, estrogens and androgens promoting OC progression, while gonadotropin-releasing hormone (GnRH) and progesterone may be protective factors in OC. Experimental studies have indicated that hormone receptors are expressed in OC cells and mediate the growth stimulatory or growth inhibitory effects of hormones on these cells. Hormone therapy agents have been evaluated in a number of clinical trials. The majority of these trials were conducted in patients with relapsed or refractory OC with average efficacy and limited side-effects. A better understanding of the mechanisms through which hormones affect cell growth may improve the efficacy of hormone therapy. In the present review article, the role of hormones (GnRH, gonadotropins, androgens, estrogens and progestins) and their receptors in OC tumorigenesis, and hormonal therapy in OC treatment is discussed and summarized.
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Affiliation(s)
- Hongyi Li
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children and Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yu Liu
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children and Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yang Wang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xia Zhao
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children and Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiaorong Qi
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children and Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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27
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Chen S, Li Y, Qian L, Deng S, Liu L, Xiao W, Zhou Y. A Review of the Clinical Characteristics and Novel Molecular Subtypes of Endometrioid Ovarian Cancer. Front Oncol 2021; 11:668151. [PMID: 34150634 PMCID: PMC8210668 DOI: 10.3389/fonc.2021.668151] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 05/17/2021] [Indexed: 12/24/2022] Open
Abstract
Ovarian cancer is one of the most common gynecologic cancers that has the highest mortality rate. Endometrioid ovarian cancer, a distinct subtype of epithelial ovarian cancer, is associated with endometriosis and Lynch syndrome, and is often accompanied by synchronous endometrial carcinoma. In recent years, dysbiosis of the microbiota within the female reproductive tract has been suggested to be involved in the pathogenesis of endometrial cancer and ovarian cancer, with some specific pathogens exhibiting oncogenic having been found to contribute to cancer development. It has been shown that dysregulation of the microenvironment and accumulation of mutations are stimulatory factors in the progression of endometrioid ovarian carcinoma. This would be a potential therapeutic target in the future. Simultaneously, multiple studies have demonstrated the role of four molecular subtypes of endometrioid ovarian cancer, which are of particular importance in the prediction of prognosis. This literature review aims to compile the potential mechanisms of endometrioid ovarian cancer, molecular characteristics, and molecular pathological types that could potentially play a role in the prediction of prognosis, and the novel therapeutic strategies, providing some guidance for the stratified management of ovarian cancer.
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Affiliation(s)
- Shuangfeng Chen
- Department of Obstetrics and Gynecology, Anhui Provincial Hospital, Anhui Medical University, Hefei, China
| | - Yuebo Li
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lili Qian
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Sisi Deng
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Luwen Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Weihua Xiao
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Ying Zhou
- Department of Obstetrics and Gynecology, Anhui Provincial Hospital, Anhui Medical University, Hefei, China.,Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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28
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Yachida N, Yoshihara K, Yamaguchi M, Suda K, Tamura R, Enomoto T. How Does Endometriosis Lead to Ovarian Cancer? The Molecular Mechanism of Endometriosis-Associated Ovarian Cancer Development. Cancers (Basel) 2021; 13:1439. [PMID: 33809880 PMCID: PMC8004227 DOI: 10.3390/cancers13061439] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 12/18/2022] Open
Abstract
Numerous epidemiological and histopathological studies support the notion that clear cell and endometrioid carcinomas derive from ovarian endometriosis. Accordingly, these histologic types are referred to as "endometriosis-associated ovarian cancer" (EAOC). Although the uterine endometrium is also considered an origin of endometriosis, the molecular mechanism involved in transformation of the uterine endometrium to EAOC via ovarian endometriosis has not yet been clarified. Recent studies based on high-throughput sequencing technology have revealed that cancer-associated gene mutations frequently identified in EAOC may exist in the normal uterine endometrial epithelium and ovarian endometriotic epithelium. The continuum of genomic alterations from the uterine endometrium to endometriosis and EAOC has been described, though the significance of cancer-associated gene mutations in the uterine endometrium or endometriosis remains unclear. In this review, we summarize current knowledge regarding the molecular characteristics of the uterine endometrium, endometriosis, and EAOC and discuss the molecular mechanism of cancer development from the normal endometrium through endometriosis in an effort to prevent EAOC.
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Affiliation(s)
| | - Kosuke Yoshihara
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; (N.Y.); (M.Y.); (K.S.); (R.T.); (T.E.)
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29
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Wuyung PE, Rahadiati FB, Tjahjadi H, Salinah S, Kusmardi K, Kodariah R, Wiweko B. Histopathology and ARID1A Expression in Endometriosis- Associated Ovarian Carcinoma (EAOC) Carcinogenesis Model with Endometrial Autoimplantation and DMBA Induction. Asian Pac J Cancer Prev 2021; 22:553-558. [PMID: 33639673 PMCID: PMC8190335 DOI: 10.31557/apjcp.2021.22.2.553] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Ovarian carcinoma is one of the most deadly malignancies in the gynecologic field. The cause is not yet known, and the clinical symptoms are not specific. Endometrioid carcinoma and ovarian clear cell carcinoma can originate from endometriosis and are known as endometriosis-related ovarian carcinoma (EAOC). Development of EAOC experimental animal models is needed for basic research and clinical preparation of human tissue tests. This study aimed to determine the role of the ARID1A gene mutation in the carcinogenetic process of EAOC in experimental animal models induced with DMBA. METHODS In this study, the EAOC experimental model was developed using the autoimplantation technique and DMBA induction. This study involved placebo surgery mice (sham), endometrial autoimplantation, and a combination of endometrial autoimplantation and DMBA induction, which were sacrificed at weeks 5, 10, and 20, respectively. Histopathological assessment and immunohistochemical ARID1A staining with an assessment of positive percentages were carried out on 200 cells. RESULTS This study produced 1 (20%) atypical endometriosis and 1 (20%) clear cell carcinoma at implantation and after 10 weeks of DMBA induction, and 100% endometrioid carcinoma in the DMBA-induced group. ARID1A staining did not show any significant difference (p = 0.313) in all groups. CONCLUSION The combination of endometrial autoimplantation techniques and DMBA induction in the ovary produced atypical endometriosis, clear cell carcinoma, and endometrioid carcinoma, where time is an important factor. There was no significant difference in ARID1A expression between the treatment and control groups.
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Affiliation(s)
- Puspita Eka Wuyung
- Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia.,Animal Research Facilities, Indonesian Medical Education and Research Institute, Faculty of Medicine Universitas Indonesia
| | - Familia Bella Rahadiati
- Specialty Programme in Anatomical Pathology, Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia
| | - Hartono Tjahjadi
- Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia
| | - Salinah Salinah
- Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia
| | - Kusmardi Kusmardi
- Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia
| | - Ria Kodariah
- Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia
| | - Budi Wiweko
- Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Indonesia.,Human Reproduction, Infertility, and Family Planning, Indonesian Medical Education and Research Institute, Faculty of Medicine Universitas Indonesia
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30
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Novikov FV, Luneva IS, Starkova OA. [Molecular genetic profile of seromucinous ovarian tumors]. Arkh Patol 2021; 83:53-57. [PMID: 33512129 DOI: 10.17116/patol20218301153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Seromucinous tumors belong to a group of ovarian epithelial tumors. They were originally described as tumors characterized by Müllerian endocervical differentiation. Molecular genetic studies have indicated these tumors as endometriosis-associated tumors due to the presence of ARID1 gene mutations. However, the histogenesis of these neoplasms is still unstudied.
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Affiliation(s)
- F V Novikov
- Kursk State Medical University of the Ministry of Health of Russia, Kursk, Russia
| | - I S Luneva
- Kursk State Medical University of the Ministry of Health of Russia, Kursk, Russia
| | - O A Starkova
- Kursk State Medical University of the Ministry of Health of Russia, Kursk, Russia
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31
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Ota Y, Ota K, Takahashi T, Suzki S, Sano R, Ota I, Moriya T, Shiota M. Primary endometrioid carcinoma of the uterosacral ligament arising from deep infiltrating endometriosis 6 years after bilateral salpingo-oophorectomy due to atypical proliferative endometrioid tumor of the ovary: a rare case report. World J Surg Oncol 2020; 18:329. [PMID: 33308243 PMCID: PMC7733300 DOI: 10.1186/s12957-020-02105-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 12/02/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Endometriosis can potentially lead to the development of a malignant tumor. Most malignant tumors arising from the endometriosis originate from the ovarian endometrioma, whereas those arising from extragonadal lesions are rare. We report a rare case of endometrioid carcinoma that developed from deep infiltrating endometriosis in the uterosacral ligament 6 years after treatment for atypical proliferative endometrioid tumor of the ovary in a 48-year-old woman. CASE PRESENTATION Six years ago, the patient underwent laparoscopic bilateral salpingo-oophorectomy for her right ovarian tumor with atypical proliferative (borderline) endometrioid tumor accompanied by ovarian endometrioma. The solid tumor in the cul-de-sac was detected during follow-up using magnetic resonance imaging. Positron emission tomography/computed tomography revealed an abnormal accumulation of 18F-fluorodeoxyglucose at the tumor site. Thus, tumor recurrence with borderline malignancy was suspected. The patient underwent diagnostic laparoscopy followed by hysterectomy and partial omentectomy. Retroperitoneal pelvic lymphadenectomy and para-aortic lymphadenectomy were also performed. The cul-de-sac tumor at the left uterosacral ligament was microscopically diagnosed as invasive endometrioid carcinoma arising from deep infiltrating endometriosis. The final diagnosis was primary stage IIB peritoneal carcinoma. The patient received six courses of monthly paclitaxel and carboplatin as adjuvant chemotherapy. The patient showed no evidence of recurrence for 2 years after the treatments. CONCLUSION This study reports a rare case of metachronous endometriosis-related malignancy that developed 6 years after treatment for borderline ovarian tumor. If endometriosis lesions remain after bilateral salpingo-oophorectomy, the physician should keep the malignant nature of endometriosis in mind.
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Affiliation(s)
- Yoshiaki Ota
- Department of Gynecological Oncology, Kawasaki Medical School, Kurashiki, Japan
| | - Kuniaki Ota
- Fukushima Medical Center for Children and Women, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan
| | - Toshifumi Takahashi
- Fukushima Medical Center for Children and Women, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan.
| | - Soichiro Suzki
- Department of Gynecological Oncology, Kawasaki Medical School, Kurashiki, Japan
| | - Rikiya Sano
- Department of Gynecological Oncology, Kawasaki Medical School, Kurashiki, Japan
| | - Ikuko Ota
- Department of Gynecology, Kurashiki Heisei Hospital, Kurashiki, Japan
| | - Takuya Moriya
- Department of Pathology, Kawasaki Medical School, Kurashiki, Japan
| | - Mitsuru Shiota
- Department of Gynecological Oncology, Kawasaki Medical School, Kurashiki, Japan
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32
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Samimi G, Sathyamoorthy N, Tingen CM, Mazloomdoost D, Conroy J, Heckman-Stoddard B, Halvorson LM. Report of the National Cancer Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development-sponsored workshop: gynecology and women's health-benign conditions and cancer. Am J Obstet Gynecol 2020; 223:796-808. [PMID: 32835714 DOI: 10.1016/j.ajog.2020.08.049] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/31/2020] [Accepted: 08/19/2020] [Indexed: 12/14/2022]
Abstract
The Division of Cancer Prevention and the Division of Cancer Biology at the National Cancer Institute and the Gynecologic Health and Disease Branch in the National Institute of Child Health and Human Development organized a workshop in April 2019 to explore current insights into the progression of gynecologic cancers from benign conditions. Working groups were formed based on 3 gynecologic disease types: (1) Endometriosis or Endometrial Cancer and Endometrial-Associated Ovarian Cancer, (2) Uterine Fibroids (Leiomyoma) or Leiomyosarcoma, and (3) Adenomyosis or Adenocarcinoma. In this report, we highlight the key questions and current challenges that emerged from the working group discussions and present potential research opportunities that may advance our understanding of the progression of gynecologic benign conditions to cancer.
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33
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Samartzis EP, Labidi-Galy SI, Moschetta M, Uccello M, Kalaitzopoulos DR, Perez-Fidalgo JA, Boussios S. Endometriosis-associated ovarian carcinomas: insights into pathogenesis, diagnostics, and therapeutic targets-a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1712. [PMID: 33490224 PMCID: PMC7812165 DOI: 10.21037/atm-20-3022a] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Endometriosis is a benign gynecologic condition affecting up to one woman out of ten of reproductive age. It is defined by the presence of endometrial-like tissue in localizations outside of the uterine cavity. It often causes symptoms such as chronic pain, most frequently associated with the menstrual cycle, and infertility, but may also be oligo- or asymptomatic. There is evidence that some ovarian carcinoma (OC) histotypes, mainly the ovarian clear cell (OCCC) and endometrioid (EnOC) carcinoma, may arise from endometriosis. The most frequent genomic alterations in these carcinomas are mutations in the AT-rich interacting domain containing protein 1A (ARID1A) gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which frequently co-occur. In ARID1A deficient cancers preclinical experimental data suggest different targetable mechanisms including epigenetic regulation, cell cycle, genomic instability, the PI3K/AKT/mTOR pathway, inflammatory pathways, immune modulation, or metabolic alterations as potential precision oncology approaches. Most of these strategies are relying on the concept of synthetic lethality in which tumors deficient in ARID1A are more sensitive to the different compounds. Some of these approaches are currently being or have recently been investigated in early clinical trials. The remarkably frequent occurrence of these mutations in endometriosis-associated ovarian cancer, the occurrence in a relatively young population, and the high proportion of platinum-resistant disease certainly warrants further investigation of precision oncology opportunities in this population. Furthermore, advanced knowledge about oncogenic mutations involved in endometriosis-associated ovarian carcinomas may be potentially useful for early cancer detection. However, this approach may be complicated by the frequent occurrence of somatic mutations in benign endometriotic tissue as recent studies suggest. In this narrative review of the current literature, we will discuss the data available on endometriosis-associated ovarian carcinoma, with special emphasis on epidemiology, diagnosis and molecular changes that could have therapeutic implications and clinical applicability in the future.
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Affiliation(s)
- Eleftherios P Samartzis
- Department of Gynecology and Gynecological Cancer Center, University Hospital Zurich, Zurich, Switzerland
| | - S Intidhar Labidi-Galy
- Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland.,Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | | | - Mario Uccello
- Northampton General Hospital NHS Trust, Cliftonville, Northampton, UK
| | - Dimitrios R Kalaitzopoulos
- Department of Gynecology and Gynecological Cancer Center, University Hospital Zurich, Zurich, Switzerland.,Department of Gynecology and Obstetrics, Kantonsspital Schaffhausen, Schaffhausen, Switzerland
| | - J Alejandro Perez-Fidalgo
- Department of Medical Oncology, Hospital Clinico Universitario de Valencia, INCLIVA, CIBERONC, Valencia, Spain
| | - Stergios Boussios
- Department of Medical Oncology, Medway NHS Foundation Trust, Gillingham, Kent, UK.,AELIA Organization, 9th Km Thessaloniki - Thermi, Thessaloniki, Greece
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34
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Zou J, Qin W, Yang L, Wang L, Wang Y, Shen J, Xiong W, Yu S, Song S, Ajani JA, Lin SY, Mills GB, Yuan X, Chen J, Peng G. Genetic alterations and expression characteristics of ARID1A impact tumor immune contexture and survival in early-onset gastric cancer. Am J Cancer Res 2020; 10:3947-3972. [PMID: 33294279 PMCID: PMC7716160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 10/21/2020] [Indexed: 06/12/2023] Open
Abstract
The AT-rich Interactive Domain 1A (ARID1A) is one of the most frequently mutated genes in gastric cancer. Here, we found that genetic variants in noncoding regions of ARID1A associated with altered protein levels by target sequencing. Notably, tumors with ARID1A variants in the 3'untranslated region (3'UTR) exhibited remarkably increased heterogeneity of ARID1A protein. In general, genetic variants and protein deficiency of ARID1A in tumors were associated with a better survival. Strikingly, altered patterns and heterogeneity of ARID1A protein expression were observed in peritumor tissues and carried significant implications in defining tumor immune contexture by multiplex immunohistochemistry. By analyzing the spatial distribution of TILs, we showed that reduced ARID1A protein levels in both tumor and peritumor tissues were significantly correlated with increased density and proximity of TILs to tumor cells. In contrast, high heterogeneity of ARID1A expression was associated with increased TIL density, but reduced proximity of TILs to tumor cells. Collectively, our study characterized ARID1A genetic alterations and its protein expression patterns in EOGC, demonstrating new strategies for clinically assessing its molecular impact on tumor onset and progression, tumor immune response, and patient survival.
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Affiliation(s)
- Jun Zou
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, China
| | - Wan Qin
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, China
| | - Lin Yang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, China
| | - Lulu Wang
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer CenterHouston, TX 77030, USA
| | - Yu Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, China
| | - Jianfeng Shen
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineShanghai 200025, China
| | - Wei Xiong
- Department of Oncology, Second Hospital of Wuhan Iron and Steel (Group) Corp.Wuhan 430080, China
| | - Shiying Yu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, China
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer CenterHouston, TX 77030, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer CenterHouston, TX 77030, USA
| | - Shiaw-Yih Lin
- Department of Systems Biology, The University of Texas MD Anderson Cancer CenterHouston, TX 77030, USA
| | - Gordon B Mills
- Department of Cell, Development & Cancer Biology, Oregon Health and Science University Knight Cancer InstitutePortland, Oregon, USA
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, China
| | - Jianying Chen
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, China
| | - Guang Peng
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer CenterHouston, TX 77030, USA
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35
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Yachida N, Yoshihara K, Suda K, Nakaoka H, Ueda H, Sugino K, Yamaguchi M, Mori Y, Yamawaki K, Tamura R, Ishiguro T, Isobe M, Motoyama T, Inoue I, Enomoto T. ARID1A protein expression is retained in ovarian endometriosis with ARID1A loss-of-function mutations: implication for the two-hit hypothesis. Sci Rep 2020; 10:14260. [PMID: 32868822 PMCID: PMC7459315 DOI: 10.1038/s41598-020-71273-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 08/10/2020] [Indexed: 12/22/2022] Open
Abstract
ARID1A loss-of-function mutation accompanied by a loss of ARID1A protein expression is considered one of the most important driver events in endometriosis-associated ovarian cancer. Although our recent genomic study clarified that ARID1A loss-of-function mutations were detected in 13% of ovarian endometriosis, an association between the ARID1A mutation status and ARID1A protein expression in ovarian endometriosis remains unclear. We performed immunohistochemical staining for ARID1A in 78 ovarian endometriosis samples and 99 clear cell carcinoma samples. We revealed that not only 70 endometriosis samples without ARID1A mutations but also eight endometriosis samples with ARID1A loss-of-function mutations retained ARID1A protein expression. On the other hand, most of clear cell carcinomas with ARID1A loss-of-function mutations showed a loss of ARID1A protein expression. In particular, clear cell carcinoma samples which harbor multiple ARID1A loss-of-function mutations or both a single ARID1A loss-of-function mutation and ARID1A allelic imbalance lost ARID1A protein expression. However, ARID1A protein expression was retained in seven clear cell carcinomas with ARID1A loss-of-function mutations. These results suggest that a single ARID1A loss-of-function mutation is insufficient for ARID1A loss in ovarian endometriosis and some clear cell carcinoma. Further driver events may be needed for the malignant transformation of ovarian endometriosis with ARID1A loss-of-function mutations.
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Affiliation(s)
- Nozomi Yachida
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ward, Niigata, 951-8510, Japan
| | - Kosuke Yoshihara
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ward, Niigata, 951-8510, Japan.
| | - Kazuaki Suda
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ward, Niigata, 951-8510, Japan
| | - Hirofumi Nakaoka
- Human Genetics Laboratory, National Institute of Genetics, Mishima, 411-8540, Japan.,Department of Cancer Genome Research, Sasaki Institute, Sasaki Foundation, Chiyoda-ku, Tokyo, 101-0062, Japan
| | - Haruka Ueda
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ward, Niigata, 951-8510, Japan
| | - Kentaro Sugino
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ward, Niigata, 951-8510, Japan
| | - Manako Yamaguchi
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ward, Niigata, 951-8510, Japan
| | - Yutaro Mori
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ward, Niigata, 951-8510, Japan
| | - Kaoru Yamawaki
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ward, Niigata, 951-8510, Japan
| | - Ryo Tamura
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ward, Niigata, 951-8510, Japan
| | - Tatsuya Ishiguro
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ward, Niigata, 951-8510, Japan
| | - Masanori Isobe
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ward, Niigata, 951-8510, Japan
| | - Teiichi Motoyama
- Department of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan
| | - Ituro Inoue
- Human Genetics Laboratory, National Institute of Genetics, Mishima, 411-8540, Japan
| | - Takayuki Enomoto
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ward, Niigata, 951-8510, Japan
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Wu CW, Chen MH, Huang KH, Chang SC, Fang WL, Lin CH, Chao Y, Lo SS, Li AFY, Shyr YM. The clinicopathological characteristics and genetic alterations between younger and older gastric cancer patients with curative surgery. Aging (Albany NY) 2020; 12:18137-18150. [PMID: 32961530 PMCID: PMC7585087 DOI: 10.18632/aging.103627] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 06/22/2020] [Indexed: 01/24/2023]
Abstract
Few reports have investigated different genetic alterations according to age in various cancers. In total, 1749 GC patients receiving curative surgery were enrolled. The clinicopathological features, and prognoses were compared between younger (<65 years) and older (≥65 years) patients. Genetic mutations were analyzed using mass spectrometric single nucleotide polymorphism genotyping technology, including 68 validated mutations within eight genes (TP53, ARID1A, BRAF, and the PI3K/AKT pathway) previously reported in relation to age. Younger patients were more likely to be female and have poor cell differentiation, diffuse-type tumors, less lymphovascular invasion, fewer liver metastases, and better 5-year overall survival (OS) (68.0% vs. 54.6%, P<0.001) and disease-free survival (DFS) (65.4% vs. 53.0%, P<0.001) rates than older patients. Regarding the genetic alterations, older patients had more microsatellite instability-high (MSI-H) tumors and more ARID1A mutations than younger patients. Younger patients had significantly better OS and DFS rates than older patients for each pathological Tumor, Node, Metastasis (TNM) stage. Older patients had a significantly higher non-cancer related death rate than younger patients (36.2% vs. 12.3%, P<0.001). Age was an independent prognostic factor in GC. In conclusion, age was associated with different clinicopathological features and genetic alterations in GC with curative surgery.
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Affiliation(s)
- Chew-Wun Wu
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ming-Huang Chen
- School of Medicine, National Yang-Ming University, Taipei, Taiwan,Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Kuo-Hung Huang
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Shih-Ching Chang
- School of Medicine, National Yang-Ming University, Taipei, Taiwan,Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Wen-Liang Fang
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chien-Hsing Lin
- Genome Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Yee Chao
- School of Medicine, National Yang-Ming University, Taipei, Taiwan,Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Su-Shun Lo
- School of Medicine, National Yang-Ming University, Taipei, Taiwan,National Yang-Ming University Hospital, Yilan, Taiwan
| | - Anna Fen-Yau Li
- School of Medicine, National Yang-Ming University, Taipei, Taiwan,Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Ming Shyr
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan,School of Medicine, National Yang-Ming University, Taipei, Taiwan
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Murakami K, Kotani Y, Nakai H, Matsumura N. Endometriosis-Associated Ovarian Cancer: The Origin and Targeted Therapy. Cancers (Basel) 2020; 12:cancers12061676. [PMID: 32599890 PMCID: PMC7352633 DOI: 10.3390/cancers12061676] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/18/2020] [Accepted: 06/22/2020] [Indexed: 12/11/2022] Open
Abstract
Endometrial cysts (ECs) are thought to be the origin of endometriosis-associated ovarian cancer (EAOC). A hypothesis that the oxidative stress of iron in cysts causes “malignant transformation of ECs” has been proposed, but this has not been verified. Several population-based studies showed that endometriosis was a risk factor but did not reflect the “malignant transformation of ECs”. A review showed that most patients were diagnosed with EAOC early in monitoring following detection of ECs, and that these cases might have been cancer from the start. Epidemiologically, EAOC was reduced by hysterectomy rather than by cystectomy of ECs. Gene mutation analyses identified oncogenic mutations in endometriosis and normal endometrium and revealed that the same mutations were present at different endometriotic lesions. It was also shown that most of the gene mutations found in endometriosis occurred in normal endometrium. Taking together, EAOC might be caused by eutopic endometrial glandular epithelial cells with oncogenic mutations that have undergone menstrual blood reflux and engrafted in the ovary, rather than by low-risk ECs acquiring oncogenic mutations and becoming malignant. This review discusses the mechanisms of EAOC development and targeted therapy based on genetic variation in EAOC with a focus on eutopic endometrium.
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Shinmura H, Yoneyama K, Harigane E, Tsunoda Y, Fukami T, Matsushima T, Takeshita T. Use of tumor markers to distinguish endometriosis-related ovarian neoplasms from ovarian endometrioma. Int J Gynecol Cancer 2020; 30:831-836. [PMID: 32354795 PMCID: PMC7362875 DOI: 10.1136/ijgc-2020-001210] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 04/10/2020] [Accepted: 04/13/2020] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Only few studies have focused on tumor markers used in the preoperative diagnosis of endometriosis-related ovarian neoplasms, and previous studies have only assessed serum CA125 levels. This study investigated the significance of preoperative tumor markers and clinical characteristics in distinguishing endometriosis-related ovarian neoplasms from ovarian endometrioma. METHODS A case-control study was conducted on 283 women who were diagnosed with confirmed pathology with endometriosis-related ovarian neoplasms (n=21) and ovarian endometrioma (n=262) at a single institution from April 2008 to April 2018. The serum CA125, CA19-9, carcinoembryogenic antigen (CEA), sialyl Lewis-x antigen (SLX), and lactate dehydrogenase (LDH) levels, age, tumor size, and the presence of mural nodule of the patients were analyzed. RESULTS Patients with endometriosis-related ovarian neoplasms were more likely to be older (48 (range, 26-81) vs 39 (range, 22-68) years, P<0.001), have higher levels of CA19-9 (42 vs 19 U/mL, P=0.013), CEA (1.3 vs 0.84 ng/mL, P=0.007), SLX (41 vs 33 U/mL, P=0.050), and LDH (189 vs 166 U/mL, P<0.001) and larger tumor size (79 vs 55 mm, P=0.001), and present with mural nodule (85.7 vs 4.5 %, P<0.001) than those with ovarian endometrioma. The CA125 levels did not significantly differ between the two groups. The area under the curve for each factor was as follows: CA19-9 level, 0.672 (95% CI 0.52 to 0.83; P=0.013); CEA level, 0.725 (95% CI 0.58 to 0.87; P=0.007); SLX level, 0.670 (95% CI 0.53 to 0.84; P=0.050); LDH level, 0.800 (95% CI 0.70 to 0.90; P<0.001); age, 0.775 (95% CI 0.65 to 0.90; P<0.001); and tumor size, 0.709 (95% CI 0.56 to 0.86; P=0.001). Age was a better marker than CA19-9, CEA, and SLX levels according to the receiver operating characteristic curve analysis. The optimal cut-off values for age and tumor size were 47 years and 80 mm, respectively. CONCLUSIONS The assessment of serum CA19-9, CEA, SLX, and LDH levels may be a useful tool in the preoperative evaluation to differentiate between endometriosis-related ovarian neoplasms and ovarian endometrioma.
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Affiliation(s)
- Hiroki Shinmura
- Obstetrics and Gynecology, Nippon Medical School Musashikosugi Hospital, Kawasaki-shi, Japan
| | - Koichi Yoneyama
- Obstetrics and Gynecology, Nippon Medical School Musashikosugi Hospital, Kawasaki-shi, Japan
| | - Eika Harigane
- Obstetrics and Gynecology, Nippon Medical School Musashikosugi Hospital, Kawasaki-shi, Japan
| | - Yohei Tsunoda
- Obstetrics and Gynecology, Nippon Medical School Musashikosugi Hospital, Kawasaki-shi, Japan
| | - Takehiko Fukami
- Obstetrics and Gynecology, Nippon Medical School Musashikosugi Hospital, Kawasaki-shi, Japan
| | - Takashi Matsushima
- Obstetrics and Gynecology, Nippon Medical School Musashikosugi Hospital, Kawasaki-shi, Japan
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Wang Y, Hoang L, Ji JX, Huntsman DG. SWI/SNF Complex Mutations in Gynecologic Cancers: Molecular Mechanisms and Models. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2020; 15:467-492. [PMID: 31977292 DOI: 10.1146/annurev-pathmechdis-012418-012917] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The SWI/SNF (mating type SWItch/Sucrose NonFermentable) chromatin remodeling complexes interact with histones and transcription factors to modulate chromatin structure and control gene expression. These evolutionarily conserved multisubunit protein complexes are involved in regulating many biological functions, such as differentiation and cell proliferation. Genomic studies have revealed frequent mutations of genes encoding multiple subunits of the SWI/SNF complexes in a wide spectrum of cancer types, including gynecologic cancers. These SWI/SNF mutations occur at different stages of tumor development and are restricted to unique histologic types of gynecologic cancers. Thus, SWI/SNF mutations have to function in the appropriate tissue and cell context to promote gynecologic cancer initiation and progression. In this review, we summarize the current knowledge of SWI/SNF mutations in the development of gynecologic cancers to provide insights into both molecular pathogenesis and possible treatment implications for these diseases.
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Affiliation(s)
- Yemin Wang
- Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada; , , .,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada; .,Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, British Columbia V6Z 2K8, Canada
| | - Lien Hoang
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada;
| | - Jennifer X Ji
- Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada; , , .,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada;
| | - David G Huntsman
- Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada; , , .,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada; .,Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, British Columbia V6Z 2K8, Canada
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Ovarian Seromucinous Tumors: Pathogenesis, Morphologic Spectrum, and Clinical Issues. Diagnostics (Basel) 2020; 10:diagnostics10020077. [PMID: 32023964 PMCID: PMC7168900 DOI: 10.3390/diagnostics10020077] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 01/28/2020] [Accepted: 01/29/2020] [Indexed: 02/07/2023] Open
Abstract
Ovarian seromucinous tumors were introduced in the 2014 World Health Organization (WHO) classification as one of the seven types of ovarian epithelial tumors. They are characterized by frequent association with endometriosis and bilaterality, microscopic appearance of papillary architecture, and admixture of a variety of müllerian-type epithelium. They are considered to be endometriosis-related ovarian neoplasms, along with endometrioid and clear cell tumors; recent molecular studies suggest this particular tumor is a variant of endometrioid tumor. Discrepancies in nomenclature, definition, and morphology of seromucinous tumors appear to be a source of confusion, for both clinicians and general surgicalpathologists. This review summarizes the clinicopathological features of benign, borderline, and malignant seromucinous tumors, as well as controversies regarding these tumors.
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Cao Q, Wang C, Ding Y, Xu D, Qian S, Shen H, Qi J. ARID1A upregulation predicts better survival in patients with urothelial bladder carcinoma. J Int Med Res 2020; 48:300060519895687. [PMID: 31891283 PMCID: PMC7783253 DOI: 10.1177/0300060519895687] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Objective AT-rich interactive domain-containing protein 1A (ARID1A) is frequently
mutated or deficient in various types of tumors. However, the role of ARID1A
in bladder cancer remains unclear. We aimed to evaluate ARID1A expression
and its biological role and correlation with prognosis in patients with
urothelial bladder carcinoma (BUC). Methods ARID1A expression levels in BUC and normal tissues were assessed by
immunohistochemistry and correlated with clinicopathological characteristics
and patient outcomes. Downregulation of ARID1A was mimicked by transfection
with small interfering RNA in T24 bladder cancer cells, and the effects on
cell proliferation and migration were evaluated. Results ARID1A expression was significantly reduced in BUC tissues and was
significantly associated with T stage and AJCC stage. Upregulation of ARID1A
predicted a better prognosis in BUC patients. ARID1A expression and lymph
node status were identified as independent prognostic factors for overall
survival. Silencing of ARID1A promoted the proliferation of
BUC cells. Conclusions ARID1A may represent a novel diagnostic and prognostic biomarker in patients
with BUC.
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Affiliation(s)
- Qifeng Cao
- Department of Urology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen Wang
- Department of Urology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Ding
- Department of Urology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ding Xu
- Department of Urology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Subo Qian
- Department of Urology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haibo Shen
- Department of Urology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Qi
- Department of Urology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Lee HY, Hong JH, Byun JH, Kim HJ, Baek SK, Kim JY, Kim KH, Yun J, Kim JA, Park K, Lee HJ, Lee JL, Won YW, Kim IH, Bae WK, Park KH, Sun DS, Lee S, Lee MY, Lee GJ, Hong SH, Jung YH, An HJ. Clinical Characteristics of Clear Cell Ovarian Cancer: A Retrospective Multicenter Experience of 308 Patients in South Korea. Cancer Res Treat 2020; 52:277-283. [PMID: 31319640 PMCID: PMC6962489 DOI: 10.4143/crt.2019.292] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 07/12/2019] [Indexed: 01/22/2023] Open
Abstract
PURPOSE The purpose of this study was to evaluate clinical characteristics and treatment pattern of ovarian clear cell carcinoma (OCCC) in Korea and the role of adjuvant chemotherapy in early stage. MATERIALS AND METHODS Medical records of 308 cases of from 21 institutions were reviewed and data including age, performance status, endometriosis, thromboembolism, stage, cancer antigen 125, treatment, recurrence, and death were collected. RESULTS Regarding stage of OCCC, it was stage I in 194 (63.6%), stage II in 34 (11.1%), stage III in 66 (21.6%), and stage IV in 11 (3.6%) patients. All patients underwent surgery. Optimal surgery (residual disease ≤ 1 cm) was achieved in 89.3%. Majority of patients (80.5%) received postoperative chemotherapy. The most common regimen was taxane-platinum combination (96%). Median relapse-free survival (RFS) was 138.5 months for stage I, 33.4 for stage II, 19.3 for stage III, and 9.7 for stage IV. Median overall survival (OS) were not reached, 112.4, 48.7, and 18.3 months for stage I, II, III, and IV, respectively. Early-stage (stage I), endometriosis, and optimal debulking were identified as favorable prognostic factors for RFS. Early-stage and optimal debulking were also favorable prognostic factors for OS. Majority of patients with early-stage received adjuvant chemotherapy. However, additional survival benefit was not found in terms of recurrence. CONCLUSION Majority of patients had early-stage and received postoperative chemotherapy regardless of stage. Early-stage and optimal debulking were identified as favorable prognostic factors. In stage IA or IB, adding adjuvant chemotherapy did not show difference in survival. Further study focusing on OCCC is required.
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Affiliation(s)
- Hee Yeon Lee
- Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ji Hyung Hong
- Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae Ho Byun
- Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea
| | - Hee-Jun Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Sun Kyung Baek
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea
| | - Jin Young Kim
- Department of Hemato-Oncology, Keimyung University Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Korea
| | - Ki Hyang Kim
- Department of Internal Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Jina Yun
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Jung A Kim
- Department of Internal Medicine, Kyung Hee University Gangdong Hospital, Seoul, Korea
| | - Kwonoh Park
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Hyo Jin Lee
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| | - Jung Lim Lee
- Department of Hemato-oncology, Daegu Fatima Hospital, Daegu, Korea
| | - Young-Woong Won
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Il Hwan Kim
- Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Woo Kyun Bae
- Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Chonnam National University College of Medicine, Hwasun, Korea
| | - Kyong Hwa Park
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Der-Sheng Sun
- Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea
| | - Suee Lee
- Department of Internal Medicine, Dong-A University Hospital, Busan, Korea
| | - Min-Young Lee
- Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Guk Jin Lee
- Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Korea
| | - Sook Hee Hong
- Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | | | - Ho Jung An
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
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Trizzino M, Barbieri E, Petracovici A, Wu S, Welsh SA, Owens TA, Licciulli S, Zhang R, Gardini A. The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II. Cell Rep 2019; 23:3933-3945. [PMID: 29949775 DOI: 10.1016/j.celrep.2018.05.097] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 03/20/2018] [Accepted: 05/30/2018] [Indexed: 12/17/2022] Open
Abstract
AT-rich interactive domain-containing proteins 1A and 1B (ARID1A and ARID1B) are mutually exclusive subunits of the chromatin remodeler SWI/SNF. ARID1A is the most frequently mutated chromatin regulator across all cancers, and ovarian clear cell carcinoma (OCCC) carries the highest prevalence of ARID1A mutations (∼57%). Despite evidence implicating ARID1A in tumorigenesis, the mechanism remains elusive. Here, we demonstrate that ARID1A binds active regulatory elements in OCCC. Depletion of ARID1A represses RNA polymerase II (RNAPII) transcription but results in modest changes to accessibility. Specifically, pausing of RNAPII is severely impaired after loss of ARID1A. Compromised pausing results in transcriptional dysregulation of active genes, which is compensated by upregulation of ARID1B. However, a subset of ARID1A-dependent genes is not rescued by ARID1B, including many p53 and estrogen receptor (ESR1) targets. Our results provide insight into ARID1A-mediated tumorigenesis and unveil functions of SWI/SNF in modulating RNAPII dynamics.
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Affiliation(s)
- Marco Trizzino
- The Wistar Institute, Gene Expression and Regulation Program, 3601 Spruce Street, Philadelphia, PA 19104, USA
| | - Elisa Barbieri
- The Wistar Institute, Gene Expression and Regulation Program, 3601 Spruce Street, Philadelphia, PA 19104, USA
| | - Ana Petracovici
- Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Shuai Wu
- The Wistar Institute, Gene Expression and Regulation Program, 3601 Spruce Street, Philadelphia, PA 19104, USA
| | - Sarah A Welsh
- The Wistar Institute, Gene Expression and Regulation Program, 3601 Spruce Street, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Tori A Owens
- The Wistar Institute, Gene Expression and Regulation Program, 3601 Spruce Street, Philadelphia, PA 19104, USA
| | - Silvia Licciulli
- The Wistar Institute, Gene Expression and Regulation Program, 3601 Spruce Street, Philadelphia, PA 19104, USA
| | - Rugang Zhang
- The Wistar Institute, Gene Expression and Regulation Program, 3601 Spruce Street, Philadelphia, PA 19104, USA
| | - Alessandro Gardini
- The Wistar Institute, Gene Expression and Regulation Program, 3601 Spruce Street, Philadelphia, PA 19104, USA.
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Buza N. Frozen Section Diagnosis of Ovarian Epithelial Tumors: Diagnostic Pearls and Pitfalls. Arch Pathol Lab Med 2019; 143:47-64. [PMID: 30785337 DOI: 10.5858/arpa.2018-0289-ra] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Epithelial tumors of the ovary are one of the most frequently encountered gynecologic specimens in the frozen section laboratory. The preoperative diagnostic workup of an ovarian mass is typically limited to imaging studies and serum markers, both of which suffer from low sensitivity and specificity. Therefore, intraoperative frozen section evaluation is crucial for determining the required extent of surgery, that is, cystectomy for benign tumors, oophorectomy or limited surgical staging for borderline tumors in younger patients to preserve fertility, or extensive staging procedure for ovarian carcinomas. Ovarian epithelial tumors may exhibit a wide range of morphologic patterns, which often overlap with each other and can mimic a variety of other ovarian nonepithelial neoplasms as well. A combination of careful gross examination, appropriate sampling and interpretation of morphologic findings, and familiarity with the clinical context is the key to the accurate frozen section diagnosis and successful intraoperative consultation. OBJECTIVE.— To review the salient frozen section diagnostic features of ovarian epithelial tumors, with special emphasis on useful clinicopathologic and morphologic clues and potential diagnostic pitfalls. DATA SOURCES.— Review of the literature and personal experience of the author. CONCLUSIONS.— Frozen section evaluation of ovarian tumors continues to pose a significant diagnostic challenge for practicing pathologists. This review article presents detailed discussions of the most common clinical scenarios and diagnostic problems encountered during intraoperative frozen section evaluation of mucinous, serous, endometrioid, and clear cell ovarian tumors.
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Affiliation(s)
- Natalia Buza
- From the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
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Králíčková M, Laganà AS, Ghezzi F, Vetvicka V. Endometriosis and risk of ovarian cancer: what do we know? Arch Gynecol Obstet 2019; 301:1-10. [DOI: 10.1007/s00404-019-05358-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 10/25/2019] [Indexed: 12/15/2022]
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De P, Dey N. Mutation-Driven Signals of ARID1A and PI3K Pathways in Ovarian Carcinomas: Alteration Is An Opportunity. Int J Mol Sci 2019; 20:ijms20225732. [PMID: 31731647 PMCID: PMC6888220 DOI: 10.3390/ijms20225732] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/08/2019] [Accepted: 11/13/2019] [Indexed: 12/24/2022] Open
Abstract
The chromosome is a functionally dynamic structure. The dynamic nature of chromosome functionally connects it to almost every event within a cell, in health and sickness. Chromatin remodeling system acts in unison with the cell survival pathway in mediating a variety of cellular functions, including mitosis, differentiation, DNA damage repair, and apoptosis. In humans, the 16 SWI/SNF complexes are a class of nucleosome remodelers, and ARID1A, an epigenetic tumor suppressor, is a member of mammalian 17 chromatin remodeling complex, SWI/SNF. Alterations of chromatin remodeling system contribute to tumorigenic events in various cancers, including ovarian cancers. Oncogenic changes of genes of the PI3K pathway are one of the potential genetic determinants of ovarian carcinomas. In this review, we present the data demonstrating the co-occurrence of mutations of ARID1A and the PI3K pathway in our cohort of ovarian cancers from the Avera Cancer Institute (SD, USA). Taking into account data from our cohort and the cBioPortal, we interrogate the opportunity provided by this co-occurrence in the context of mutation-driven signals in the life cycle of a tumor cell and its response to the targeted anti-tumor drugs.
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Affiliation(s)
- Pradip De
- Translational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD 57105, USA;
- Department of Internal Medicine, SSOM, University of South Dakota, Sioux Falls, SD 57105, USA
- VieCure, Greenwood Village, CO 80112, USA
| | - Nandini Dey
- Translational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD 57105, USA;
- Department of Internal Medicine, SSOM, University of South Dakota, Sioux Falls, SD 57105, USA
- Correspondence:
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Laganà AS, Garzon S, Götte M, Viganò P, Franchi M, Ghezzi F, Martin DC. The Pathogenesis of Endometriosis: Molecular and Cell Biology Insights. Int J Mol Sci 2019; 20:E5615. [PMID: 31717614 PMCID: PMC6888544 DOI: 10.3390/ijms20225615] [Citation(s) in RCA: 269] [Impact Index Per Article: 44.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 11/01/2019] [Accepted: 11/07/2019] [Indexed: 12/15/2022] Open
Abstract
The etiopathogenesis of endometriosis is a multifactorial process resulting in a heterogeneous disease. Considering that endometriosis etiology and pathogenesis are still far from being fully elucidated, the current review aims to offer a comprehensive summary of the available evidence. We performed a narrative review synthesizing the findings of the English literature retrieved from computerized databases from inception to June 2019, using the Medical Subject Headings (MeSH) unique ID term "Endometriosis" (ID:D004715) with "Etiology" (ID:Q000209), "Immunology" (ID:Q000276), "Genetics" (ID:D005823) and "Epigenesis, Genetic" (ID:D044127). Endometriosis may origin from Müllerian or non-Müllerian stem cells including those from the endometrial basal layer, Müllerian remnants, bone marrow, or the peritoneum. The innate ability of endometrial stem cells to regenerate cyclically seems to play a key role, as well as the dysregulated hormonal pathways. The presence of such cells in the peritoneal cavity and what leads to the development of endometriosis is a complex process with a large number of interconnected factors, potentially both inherited and acquired. Genetic predisposition is complex and related to the combined action of several genes with limited influence. The epigenetic mechanisms control many of the processes involved in the immunologic, immunohistochemical, histological, and biological aberrations that characterize the eutopic and ectopic endometrium in affected patients. However, what triggers such alterations is not clear and may be both genetically and epigenetically inherited, or it may be acquired by the particular combination of several elements such as the persistent peritoneal menstrual reflux as well as exogenous factors. The heterogeneity of endometriosis and the different contexts in which it develops suggest that a single etiopathogenetic model is not sufficient to explain its complex pathobiology.
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Affiliation(s)
- Antonio Simone Laganà
- Department of Obstetrics and Gynecology, “Filippo Del Ponte” Hospital, University of Insubria, Piazza Biroldi 1, 21100 Varese, Italy; (S.G.); (F.G.)
| | - Simone Garzon
- Department of Obstetrics and Gynecology, “Filippo Del Ponte” Hospital, University of Insubria, Piazza Biroldi 1, 21100 Varese, Italy; (S.G.); (F.G.)
| | - Martin Götte
- Department of Gynecology and Obstetrics, Münster University Hospital, D-48149 Münster, Germany;
| | - Paola Viganò
- Reproductive Sciences Laboratory, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Via Olgettina 60, 20136 Milan, Italy;
| | - Massimo Franchi
- Department of Obstetrics and Gynecology, AOUI Verona, University of Verona, Piazzale Aristide Stefani 1, 37126 Verona, Italy;
| | - Fabio Ghezzi
- Department of Obstetrics and Gynecology, “Filippo Del Ponte” Hospital, University of Insubria, Piazza Biroldi 1, 21100 Varese, Italy; (S.G.); (F.G.)
| | - Dan C. Martin
- School of Medicine, University of Tennessee Health Science Center, 910 Madison Ave, Memphis, TN 38163, USA;
- Virginia Commonwealth University, 907 Floyd Ave, Richmond, VA 23284, USA
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Gladbach YS, Wiegele L, Hamed M, Merkenschläger AM, Fuellen G, Junghanss C, Maletzki C. Unraveling the Heterogeneous Mutational Signature of Spontaneously Developing Tumors in MLH1 -/- Mice. Cancers (Basel) 2019; 11:cancers11101485. [PMID: 31581674 PMCID: PMC6827043 DOI: 10.3390/cancers11101485] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 09/18/2019] [Accepted: 09/26/2019] [Indexed: 02/07/2023] Open
Abstract
Mismatch repair deficient (MMR-D) tumors exemplify the prototypic hypermutator phenotype. Owing to the high mutation rates, plenty of neo-antigens are present on the tumor cells' surface, ideally shared among different cancer types. The MLH1 knock out mouse represents a preclinical model that resembles features of the human MMR-D counterpart. While these mice develop neoplasias in a sequential twin-peaked manner (lymphomas > gastrointestinal tumors (GIT)) we aimed at identification of underlying molecular mechanisms. Using whole-genome sequencing, we focused on (I) shared and (II) mutually exclusive mutations and describe the process of ongoing mutational events in tumor-derived cell cultures. The landscape of MLH1-/- tumors is heterogeneous with only a few shared mutations being detectable among different tumor entities (ARID1A and IDH2). With respect to coding microsatellite analysis of MMR-D-related target genes, partial overlap was detectable, yet recognizing shared antigens. The present study is the first reporting results of a comparison between spontaneously developing tumors in MMR-D driven tumorigenesis. Additionally to identifying ARID1A as potential causative mutation hotspot, this comprehensive characterization of the mutational landscape may be a good starting point to refine therapeutic concepts.
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Affiliation(s)
- Yvonne Saara Gladbach
- Institute for Biostatistics and Informatics in Medicine and Ageing Research (IBIMA), Rostock University Medical Center, University of Rostock, 18057 Rostock, Germany.
- Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany.
- Division of Applied Bioinformatics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany.
| | - Leonie Wiegele
- Department of Internal Medicine, Medical Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, University of Rostock, 18057 Rostock, Germany.
| | - Mohamed Hamed
- Institute for Biostatistics and Informatics in Medicine and Ageing Research (IBIMA), Rostock University Medical Center, University of Rostock, 18057 Rostock, Germany.
| | - Anna-Marie Merkenschläger
- Institute for Biostatistics and Informatics in Medicine and Ageing Research (IBIMA), Rostock University Medical Center, University of Rostock, 18057 Rostock, Germany.
| | - Georg Fuellen
- Institute for Biostatistics and Informatics in Medicine and Ageing Research (IBIMA), Rostock University Medical Center, University of Rostock, 18057 Rostock, Germany.
| | - Christian Junghanss
- Department of Internal Medicine, Medical Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, University of Rostock, 18057 Rostock, Germany.
| | - Claudia Maletzki
- Department of Internal Medicine, Medical Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, University of Rostock, 18057 Rostock, Germany.
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Wang Y, Nicholes K, Shih IM. The Origin and Pathogenesis of Endometriosis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2019; 15:71-95. [PMID: 31479615 DOI: 10.1146/annurev-pathmechdis-012419-032654] [Citation(s) in RCA: 247] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Recent molecular genetic findings on endometriosis and normal endometrium suggest a modified model in which circulating epithelial progenitor or stem cells intended to regenerate uterine endometrium after menstruation may become overreactive and trapped outside the uterus. These trapped epithelium-committed progenitor cells form nascent glands through clonal expansion and recruit polyclonal stromal cells, leading to the establishment of deep infiltrating endometriosis. Once formed, the ectopic tissue becomes subject to immune surveillance, resulting in chronic inflammation. The inflammatory response orchestrated by nuclear factor-κB signaling is exacerbated by aberrations in the estrogen receptor-β and progesterone receptor pathways, which are also affected by local inflammation, forming a dysregulated inflammation-hormonal loop. Glandular epithelium within endometriotic tissue harbors cancer-associated mutations that are frequently detected in endometriosis-related ovarian cancers. In this review, we summarize recent advances that have illuminated the origin and pathogenesis of endometriosis and have provided new avenues for research that promise to improve the early diagnosis and management of endometriosis.
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Affiliation(s)
- Yeh Wang
- Pathobiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA; , ,
| | - Kristen Nicholes
- Pathobiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA; , ,
| | - Ie-Ming Shih
- Pathobiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA; , , .,Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
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