|
1
|
McGrath IM, Rukins V, Laisk T, Estonian Biobank Research Team, Mortlock S, Montgomery GW. Interaction between genetic risk and comorbid conditions in endometriosis. HGG ADVANCES 2025; 6:100456. [PMID: 40369874 DOI: 10.1016/j.xhgg.2025.100456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 05/09/2025] [Accepted: 05/09/2025] [Indexed: 05/16/2025] Open
Abstract
Endometriosis is a complex disease, and many genetic and environmental risk factors contribute to disease risk. The genetic risk of endometriosis has been well characterized in genome-wide association studies. While few physiological risk factors are known, endometriosis is associated with many comorbid disorders. This study examines the interplay between genetic risk factors, comorbid disorders, and endometriosis. Genetic and health record data from the UK Biobank (5,432 cases; 92,344 controls) and Estonian Biobank (3,824 cases; 15,296 controls) was used to estimate the correlation between comorbidity burden, endometriosis and genetic risk, and to estimate the interactive effects between endometriosis polygenic risk score (PRS) and diagnosis of prevalent comorbidities (uterine fibroids, heavy menstrual bleeding, dysmenorrhea, irritable bowel syndrome, diverticular disease, and asthma) on endometriosis prevalence. The comorbidity burden was significantly higher in endometriosis cases and was positively correlated with endometriosis PRS in women without endometriosis but negatively correlated in women with endometriosis. The absolute increase in endometriosis prevalence conveyed by the presence of several comorbidities (uterine fibroids, heavy menstrual bleeding, dysmenorrhea) was greater in individuals with a high endometriosis PRS compared to a low endometriosis PRS. These findings, consistent across two biobanks, highlight significant interactions between polygenic risk for endometriosis and the diagnosed comorbidities in endometriosis susceptibility that have implications for understanding the underlying mechanisms contributing to disease risk.
Collapse
Affiliation(s)
- Isabelle M McGrath
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia; Department of Psychiatry, University of Oxford, Oxford, UK.
| | - Valentina Rukins
- Estonian Genome Center, Institute of Genomics, University of Tartu, 51010 Tartu linn, Estonia
| | - Triin Laisk
- Estonian Genome Center, Institute of Genomics, University of Tartu, 51010 Tartu linn, Estonia
| | | | - Sally Mortlock
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia; The Australian Women and Girls' Health Research Centre, The University of Queensland, Brisbane, 4072 QLD, Australia
| | - Grant W Montgomery
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia
| |
Collapse
|
|
2
|
Yuan M, Chen S, Liao Z, Wang K. The expression of autophagy-related gene CXCL12 in endometriosis associated ovarian cancer and pan-cancer analysis. Front Endocrinol (Lausanne) 2025; 16:1450892. [PMID: 40166682 PMCID: PMC11955448 DOI: 10.3389/fendo.2025.1450892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 02/24/2025] [Indexed: 04/02/2025] Open
Abstract
Background Endometriosis-associated ovarian cancer (EAOC), an aggressive form of malignant ovarian neoplasm with origins in endometriosis (EM), has risen to prominence recently. Despite extensive investigation, the precise pathophysiology remains elusive.This article explores new autophagy-related DEG genes between EM and EAOC, and investigates CXCL12's expression and prognostic relevance across pan-cancer. Methods From Gene Expression Omnibus (GEO), we retrieved gene sequencing data to uncover DEGs. We carried out enrichment analysis, PPI network construction and explored CXCL12's multi-database expression and prognostic significance employing the analytical tools of ONCOMINE, PrognoScan, GEPIA, and Kaplan-Meier Plotter. Subsequently, assessing the relationship between CXCL12 expression and immune presence in cancer utilizing GEPIA and TIMER. Lastly, CXCL12, IL17, STAT3, and FOXP3 protein expressions were determined through immunohistochemistry analysis in EAOC, EM, and normal endometrial tissues. Results Two DEGs were discovered and enrichment analysis indicated virus-cytokine/receptor interactions, chemokine signaling, and cytokine-cytokine receptor interplay as pivotal in EAOC. Notably, cancerous tissues exhibited reduced CXCL12 levels compared with non-malignant tissues across cancers. CXCL12, IL17, STAT3, Th17/Treg ratio, and FOXP3 expressions were also lower in EAOC than EM and normal tissues. Additionally, CXCL12 expression was related to stage, survival, immune subtype, and molecular classification across cancers. Conclusions In conclusion, our study implicates CXCL12 and altered Th17/Treg balance in progression from EM to EAOC. CXCL12 emerges as a predictive marker for cancer progression across various tumors and is associated with inflammatory response.
Collapse
Affiliation(s)
- Mingwei Yuan
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Sijing Chen
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Zelan Liao
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Kana Wang
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| |
Collapse
|
|
3
|
Linder A, Westbom-Fremer S, Mateoiu C, Olsson Widjaja A, Österlund T, Veerla S, Ståhlberg A, Ulfenborg B, Hedenfalk I, Sundfeldt K. Genomic alterations in ovarian endometriosis and subsequently diagnosed ovarian carcinoma. Hum Reprod 2024; 39:1141-1154. [PMID: 38459814 PMCID: PMC11063555 DOI: 10.1093/humrep/deae043] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 01/25/2024] [Indexed: 03/10/2024] Open
Abstract
STUDY QUESTION Can the alleged association between ovarian endometriosis and ovarian carcinoma be substantiated by genetic analysis of endometriosis diagnosed prior to the onset of the carcinoma? SUMMARY ANSWER The data suggest that ovarian carcinoma does not originate from ovarian endometriosis with a cancer-like genetic profile; however, a common precursor is probable. WHAT IS KNOWN ALREADY Endometriosis has been implicated as a precursor of ovarian carcinoma based on epidemiologic studies and the discovery of common driver mutations in synchronous disease at the time of surgery. Endometrioid ovarian carcinoma and clear cell ovarian carcinoma are the most common endometriosis-associated ovarian carcinomas (EAOCs). STUDY DESIGN, SIZE, DURATION The pathology biobanks of two university hospitals in Sweden were scrutinized to identify women with surgically removed endometrioma who subsequently developed ovarian carcinoma (1998-2016). Only 45 archival cases with EAOC and previous endometriosis were identified and after a careful pathology review, 25 cases were excluded due to reclassification into non-EAOC (n = 9) or because ovarian endometriosis could not be confirmed (n = 16). Further cases were excluded due to insufficient endometriosis tissue or poor DNA quality in either the endometriosis, carcinoma, or normal tissue (n = 9). Finally 11 cases had satisfactory DNA from all three locations and were eligible for further analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS Epithelial cells were collected from formalin-fixed and paraffin-embedded (FFPE) sections by laser capture microdissection (endometrioma n = 11) or macrodissection (carcinoma n = 11) and DNA was extracted. Normal tissue from FFPE sections (n = 5) or blood samples collected at cancer diagnosis (n = 6) were used as the germline controls for each included patient. Whole-exome sequencing was performed (n = 33 samples). Somatic variants (single-nucleotide variants, indels, and copy number alterations) were characterized, and mutational signatures and kataegis were assessed. Microsatellite instability and mismatch repair status were confirmed with PCR and immunohistochemistry, respectively. MAIN RESULTS AND THE ROLE OF CHANCE The median age for endometriosis surgery was 42 years, and 54 years for the subsequent ovarian carcinoma diagnosis. The median time between the endometriosis and ovarian carcinoma was 10 (7-30) years. The data showed that all paired samples harbored one or more shared somatic mutations. Non-silent mutations in cancer-associated genes were frequent in endometriosis; however, the same mutations were never observed in subsequent carcinomas. The degree of clonal dominance, demonstrated by variant allele frequency, showed a positive correlation with the time to cancer diagnosis (Spearman's rho 0.853, P < 0.001). Mutations in genes associated with immune escape were the most conserved between paired samples, and regions harboring these genes were frequently affected by copy number alterations in both sample types. Mutational burdens and mutation signatures suggested faulty DNA repair mechanisms in all cases. LARGE SCALE DATA Datasets are available in the supplementary tables. LIMITATIONS, REASONS FOR CAUTION Even though we located several thousands of surgically removed endometriomas between 1998 and 2016, only 45 paired samples were identified and even fewer, 11 cases, were eligible for sequencing. The observed high level of intra- and inter-heterogeneity in both groups (endometrioma and carcinoma) argues for further studies of the alleged genetic association. WIDER IMPLICATIONS OF THE FINDINGS The observation of shared somatic mutations in all paired samples supports a common cellular origin for ovarian endometriosis and ovarian carcinoma. However, contradicting previous conclusions, our data suggest that cancer-associated mutations in endometriosis years prior to the carcinoma were not directly associated with the malignant transformation. Rather, a resilient ovarian endometriosis may delay tumorigenesis. Furthermore, the data indicate that genetic alterations affecting the immune response are early and significant events. STUDY FUNDING/COMPETING INTEREST(S) The present work has been funded by the Sjöberg Foundation (2021-01145 to K.S.; 2022-01-11:4 to A.S.), Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (965552 to K.S.; 40615 to I.H.; 965065 to A.S.), Swedish Cancer Society (21-1848 to K.S.; 21-1684 to I.H.; 22-2080 to A.S.), BioCARE-A Strategic Research Area at Lund University (I.H. and S.W.-F.), Mrs Berta Kamprad's Cancer Foundation (FBKS-2019-28, I.H.), Cancer and Allergy Foundation (10381, I.H.), Region Västra Götaland (A.S.), Sweden's Innovation Agency (2020-04141, A.S.), Swedish Research Council (2021-01008, A.S.), Roche in collaboration with the Swedish Society of Gynecological Oncology (S.W.-F.), Assar Gabrielsson Foundation (FB19-86, C.M.), and the Lena Wäpplings Foundation (C.M.). A.S. declares stock ownership and is also a board member in Tulebovaasta, SiMSen Diagnostics, and Iscaff Pharma. A.S. has also received travel support from EMBL, Precision Medicine Forum, SLAS, and bioMCC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Collapse
Affiliation(s)
- A Linder
- Department of Obstetrics and Gynecology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - S Westbom-Fremer
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
- Lund University Cancer Centre (LUCC), Lund University, Lund, Sweden
| | - C Mateoiu
- Department of Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - A Olsson Widjaja
- Department of Obstetrics and Gynecology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - T Österlund
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - S Veerla
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
- Lund University Cancer Centre (LUCC), Lund University, Lund, Sweden
| | - A Ståhlberg
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Laboratory Medicine, Sahlgrenska Center for Cancer Research, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - B Ulfenborg
- Department of Biology and Bioinformatics, Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden
| | - I Hedenfalk
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
- Lund University Cancer Centre (LUCC), Lund University, Lund, Sweden
| | - K Sundfeldt
- Department of Obstetrics and Gynecology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| |
Collapse
|
|
4
|
Khan KN, de Ziegler D, Guo SW. Bacterial infection in endometriosis: a silver-lining for the development of new non-hormonal therapy? Hum Reprod 2024; 39:623-631. [PMID: 38300227 DOI: 10.1093/humrep/deae006] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 12/24/2023] [Indexed: 02/02/2024] Open
Abstract
The pathogenesis of endometriosis is a hotly debated topic, yet still cloaked in multiple layers of hypothetical theories. A recent report raises the possibility that bacterial infection, especially those of the genus Fusobacterium, may be the cause of endometriosis, at least in certain women. More importantly, the demonstration that treatment with broad-spectrum antibiotics significantly reduced the size of lesions in a mouse endometriosis model rekindles the hope for new non-hormonal treatments. The development of new therapies has been plagued by strings of unsuccessful clinical trials over the last two decades. Is this antibiotic therapy, a silver lining for the research and development of non-hormonal drugs for endometriosis?
Collapse
Affiliation(s)
- Khaleque N Khan
- Department of Obstetrics and Gynecology, The Clinical and Translational Research Center, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | | | - Sun-Wei Guo
- Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China
- Research Institute, Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
5
|
Takahashi K, Yachida N, Tamura R, Adachi S, Kondo S, Abé T, Umezu H, Nyuzuki H, Okuda S, Nakaoka H, Yoshihara K. Clonal origin and genomic diversity in Lynch syndrome-associated endometrial cancer with multiple synchronous tumors: Identification of the pathogenicity of MLH1 p.L582H. Genes Chromosomes Cancer 2024; 63:e23231. [PMID: 38459936 DOI: 10.1002/gcc.23231] [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: 12/05/2023] [Revised: 02/06/2024] [Accepted: 02/20/2024] [Indexed: 03/11/2024] Open
Abstract
Lynch syndrome-associated endometrial cancer patients often present multiple synchronous tumors and this assessment can affect treatment strategies. We present a case of a 27-year-old woman with tumors in the uterine corpus, cervix, and ovaries who was diagnosed with endometrial cancer and exhibited cervical invasion and ovarian metastasis. Her family history suggested Lynch syndrome, and genetic testing identified a variant of uncertain significance, MLH1 p.L582H. We conducted immunohistochemical staining, microsatellite instability analysis, and Sanger sequencing for Lynch syndrome-associated cancers in three generations of the family and identified consistent MLH1 loss. Whole-exome sequencing for the corpus, cervical, and ovarian tumors of the proband identified a copy-neutral loss of heterozygosity (LOH) occurring at the MLH1 position in all tumors. This indicated that the germline variant and the copy-neutral LOH led to biallelic loss of MLH1 and was the cause of cancer initiation. All tumors shared a portion of somatic mutations with high mutant allele frequencies, suggesting a common clonal origin. There were no mutations shared only between the cervix and ovary samples. The profiles of mutant allele frequencies shared between the corpus and cervix or ovary indicated that two different subclones originating from the corpus independently metastasized to the cervix or ovary. Additionally, all tumors presented unique mutations in endometrial cancer-associated genes such as ARID1A and PIK3CA. In conclusion, we demonstrated clonal origin and genomic diversity in a Lynch syndrome-associated endometrial cancer, suggesting the importance of evaluating multiple sites in Lynch syndrome patients with synchronous tumors.
Collapse
Affiliation(s)
- Kotaro Takahashi
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Department of Cancer Genome Research, Sasaki Institute, Tokyo, Japan
| | - Nozomi Yachida
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Ryo Tamura
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Sosuke Adachi
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Shuhei Kondo
- Division of Pathology, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Tatsuya Abé
- Division of Oral Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hajime Umezu
- Division of Pathology, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Hiromi Nyuzuki
- Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Shujiro Okuda
- Division of bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hirofumi Nakaoka
- Department of Cancer Genome Research, Sasaki Institute, Tokyo, Japan
| | - Kosuke Yoshihara
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| |
Collapse
|
|
6
|
Cai Z, Yang GL, Li Q, Zeng L, Li LX, Song YP, Liu FR. Squamous cell carcinoma associated with endometriosis in the uterus and ovaries: A case report. World J Clin Cases 2023; 11:6240-6245. [PMID: 37731556 PMCID: PMC10507536 DOI: 10.12998/wjcc.v11.i26.6240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/19/2023] [Accepted: 08/23/2023] [Indexed: 09/08/2023] Open
Abstract
BACKGROUND Endometriosis is a common benign gynecological disease that causes dysmenorrhea in women of childbearing age. Malignant tumors derived from endometriosis are rarely reported and are found in only 1% of all patients with endometriosis. Here, we report a well-differentiated squamous cell carcinoma (SCC) caused by squamous metaplasia of endometriosis that co-occurred in the uterus and ovaries. CASE SUMMARY A 57-year-old postmenopausal woman had a 6-month history of irregular uterine bleeding. The uterus and adnexa were examined by computed tomography, and there were two solid cystic masses in the pelvis and right adnexa. Histological findings of surgical specimens showed well-differentiated SCC arising from squamous metaplasia of ectopic endometrial glands in the uterus and ovaries. The patient received chemotherapy after surgery and was followed up for 3 mo without metastasis. CONCLUSION The continuity between ectopic endometrial glands and SCC supports that SCC originates from ectopic endometrial glands with metaplasia towards squamous epithelium.
Collapse
Affiliation(s)
- Zhe Cai
- Department of Pathology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Gao-Liang Yang
- Department of Pathology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Qing Li
- Department of Pathology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Lei Zeng
- Department of Pathology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Li-Xiang Li
- Department of Pathology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Yi-Pei Song
- Medical Imagine Center, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Fan-Rong Liu
- Department of Pathology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| |
Collapse
|
|
7
|
McGrath IM, Montgomery GW, Mortlock S. Insights from Mendelian randomization and genetic correlation analyses into the relationship between endometriosis and its comorbidities. Hum Reprod Update 2023; 29:655-674. [PMID: 37159502 PMCID: PMC10477944 DOI: 10.1093/humupd/dmad009] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 04/10/2023] [Indexed: 05/11/2023] Open
Abstract
BACKGROUND Endometriosis remains a poorly understood disease, despite its high prevalence and debilitating symptoms. The overlap in symptoms and the increased risk of multiple other traits in women with endometriosis is becoming increasingly apparent through epidemiological data. Genetic studies offer a method of investigating these comorbid relationships through the assessment of causal relationships with Mendelian randomization (MR), as well as identification of shared genetic variants and genes involved across traits. This has the capacity to identify risk factors for endometriosis as well as provide insight into the aetiology of disease. OBJECTIVE AND RATIONALE We aim to review the current literature assessing the relationship between endometriosis and other traits using genomic data, primarily through the methods of MR and genetic correlation. We critically examine the limitations of these studies in accordance with the assumptions of the utilized methods. SEARCH METHODS The PubMed database was used to search for peer-reviewed original research articles using the terms 'Mendelian randomization endometriosis' and '"genetic correlation" endometriosis'. Additionally, a Google Scholar search using the terms '"endometriosis" "mendelian randomization" "genetic correlation"' was performed. All relevant publications (n = 21) published up until 7 October 2022 were included in this review. Upon compilation of all traits with published MR and/or genetic correlation with endometriosis, additional epidemiological and genetic information on their comorbidity with endometriosis was sourced by searching for the trait in conjunction with 'endometriosis' on Google Scholar. OUTCOMES The association between endometriosis and multiple pain, gynaecological, cancer, inflammatory, gastrointestinal, psychological, and anthropometric traits has been assessed using MR analysis and genetic correlation analysis. Genetic correlation analyses provide evidence that genetic factors contributing to endometriosis are shared with multiple traits: migraine, uterine fibroids, subtypes of ovarian cancer, melanoma, asthma, gastro-oesophageal reflux disease, gastritis/duodenitis, and depression, suggesting the involvement of multiple biological mechanisms in endometriosis. The assessment of causality with MR has revealed several potential causes (e.g. depression) and outcomes (e.g. ovarian cancer and uterine fibroids) of a genetic predisposition to endometriosis; however, interpretation of these results requires consideration of potential violations of the MR assumptions. WIDER IMPLICATIONS Genomic studies have demonstrated that there is a molecular basis for the co-occurrence of endometriosis with other traits. Dissection of this overlap has identified shared genes and pathways, which provide insight into the biology of endometriosis. Thoughtful MR studies are necessary to ascertain causality of the comorbidities of endometriosis. Given the significant diagnostic delay of endometriosis of 7-11 years, determining risk factors is necessary to aid diagnosis and reduce the disease burden. Identification of traits for which endometriosis is a risk factor is important for holistic treatment and counselling of the patient. The use of genomic data to disentangle the overlap of endometriosis with other traits has provided insights into the aetiology of endometriosis.
Collapse
Affiliation(s)
- Isabelle M McGrath
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Grant W Montgomery
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Sally Mortlock
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| |
Collapse
|
|
8
|
Sun M, Jiang W. Ovarian clear cell carcinoma with or without endometriosis origin in a single institution cohort. Discov Oncol 2023; 14:39. [PMID: 37004660 PMCID: PMC10067778 DOI: 10.1007/s12672-023-00649-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/30/2023] [Indexed: 04/04/2023] Open
Abstract
BACKGROUND As ovarian clear cell carcinoma (OCCC) has distinct clinical features, biology, genetic characteristics and mechanisms of pathogenesis, and whether the origin of endometriosis or not affects the prognosis of OCCC remains controversial. METHODS We retrospectively collected medical records and follow-up data of patients with OCCC treated at the Obstetrics and Gynecology Hospital of Fudan University from January 2009 to December 2019. Further, we divided patients into 2 groups. Group 1: non-endometriosis origin; Group 2: endometriosis origin. Clinicopathological characteristics and survival outcomes were compared between the 2 groups. RESULTS A total of one hundred and twenty-five patients with ovarian clear cell carcinoma were identified and included. In the overall patients' population, the 5 year overall survival was 84.8%, the mean overall survival was 85.9 months. The results of the stratified analysis showed that early stage (FIGO stage I/II) OCCC had a good prognosis. The results of univariate analyses indicated that a statistically significant relationship between overall survival (OS) and FIGO stage, lymph node metastasis, peritoneum metastasis, chemotherapy administration methods, Chinese herbal treatment, molecular target therapy. As for progression-free survival (PFS), a significant relationship between PFS and child-bearing history, largest residual tumor size, FIGO stage, tumor maximum diameter, lymph node metastasis was found, respectively. FIGO stage and lymph node metastasis are common poor prognostic factors affecting OS and PFS. The multivariate regression analysis revealed that FIGO stage (p = 0.028; HR, 1.944; 95% CI 1.073-3.52) and treatment by Chinese herbs (p = 0.018; HR, 0.141; 95% CI 0.028-0.716) were identified as influencing factors with regard to survival. The presence or absence of lymphadenectomy did not affect OS of 125 OCCC patients (p = 0.851; HR, 0.825; 95% CI 0.111-6.153). There was a trend towards a better prognosis for patients with OCCC of endometriosis origin than those with OCCC of non-endometriosis origin (p = 0.062; HR, 0.432; 95% CI 0.179-1.045). The two groups differed with respect to several clinicopathological factors. And the proportion of patients with disease relapse was higher in Group 1 (46.9%) than in Group 2 (25.0%), with a statistically significant difference (p = 0.048). CONCLUSIONS Surgical staging and treatment by Chinese herbs postoperatively are two independent prognostic factors affecting the OS of OCCC, early detection and Chinese herbal medicine combined with chemotherapy postoperatively may be a good choice. Tumor with endometriosis-origin was found less likely to relapse. While the non-necessity of lymphadenectomy in advanced ovarian cancer has been proven, the need for lymphadenectomy in the early stage ovarian cancer, including early stage OCCC, still deserved to be explored.
Collapse
Affiliation(s)
- Mingming Sun
- Department Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 419 Fangxie Road, Shanghai, 200011, People's Republic of China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, People's Republic of China
| | - Wei Jiang
- Department Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 419 Fangxie Road, Shanghai, 200011, People's Republic of China.
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, People's Republic of China.
| |
Collapse
|
|
9
|
Fonseca MAS, Haro M, Wright KN, Lin X, Abbasi F, Sun J, Hernandez L, Orr NL, Hong J, Choi-Kuaea Y, Maluf HM, Balzer BL, Fishburn A, Hickey R, Cass I, Goodridge HS, Truong M, Wang Y, Pisarska MD, Dinh HQ, El-Naggar A, Huntsman DG, Anglesio MS, Goodman MT, Medeiros F, Siedhoff M, Lawrenson K. Single-cell transcriptomic analysis of endometriosis. Nat Genet 2023; 55:255-267. [PMID: 36624343 PMCID: PMC10950360 DOI: 10.1038/s41588-022-01254-1] [Citation(s) in RCA: 73] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 10/28/2022] [Indexed: 01/11/2023]
Abstract
Endometriosis is a common condition in women that causes chronic pain and infertility and is associated with an elevated risk of ovarian cancer. We profiled transcriptomes of >370,000 individual cells from endometriomas (n = 8), endometriosis (n = 28), eutopic endometrium (n = 10), unaffected ovary (n = 4) and endometriosis-free peritoneum (n = 4), generating a cellular atlas of endometrial-type epithelial cells, stromal cells and microenvironmental cell populations across tissue sites. Cellular and molecular signatures of endometrial-type epithelium and stroma differed across tissue types, suggesting a role for cellular restructuring and transcriptional reprogramming in the disease. Epithelium, stroma and proximal mesothelial cells of endometriomas showed dysregulation of pro-inflammatory pathways and upregulation of complement proteins. Somatic ARID1A mutation in epithelial cells was associated with upregulation of pro-angiogenic and pro-lymphangiogenic factors and remodeling of the endothelial cell compartment, with enrichment of lymphatic endothelial cells. Finally, signatures of ciliated epithelial cells were enriched in ovarian cancers, reinforcing epidemiologic associations between these two diseases.
Collapse
Affiliation(s)
- Marcos A S Fonseca
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Marcela Haro
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Kelly N Wright
- Division of Minimally Invasive Gynecologic Surgery, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Xianzhi Lin
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Forough Abbasi
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jennifer Sun
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Lourdes Hernandez
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Natasha L Orr
- Department of Obstetrics and Gynecology, UBC, Vancouver, British Columbia, Canada
| | - Jooyoon Hong
- Department of Obstetrics and Gynecology, UBC, Vancouver, British Columbia, Canada
| | - Yunhee Choi-Kuaea
- Cancer Prevention and Control Program, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Horacio M Maluf
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Bonnie L Balzer
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Aaron Fishburn
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ryan Hickey
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ilana Cass
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Obstetrics and Gynecology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
| | - Helen S Goodridge
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Mireille Truong
- Division of Minimally Invasive Gynecologic Surgery, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yemin Wang
- Department of Obstetrics and Gynecology, UBC, Vancouver, British Columbia, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, and Department of Molecular Oncology, British Columbia Cancer Research Institute, Vancouver, British Columbia, Canada
| | - Margareta D Pisarska
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Huy Q Dinh
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
| | - Amal El-Naggar
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Pathology, Faculty of Medicine, Menoufia University, Menoufia Governorate, Egypt
| | - David G Huntsman
- Department of Obstetrics and Gynecology, UBC, Vancouver, British Columbia, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, and Department of Molecular Oncology, British Columbia Cancer Research Institute, Vancouver, British Columbia, Canada
| | - Michael S Anglesio
- Department of Obstetrics and Gynecology, UBC, Vancouver, British Columbia, Canada
- British Columbia's Gynecological Cancer Research (OVCARE) Program, University of British Columbia, Vancouver General Hospital, and BC Cancer, Vancouver, British Columbia, Canada
| | - Marc T Goodman
- Cancer Prevention and Control Program, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Fabiola Medeiros
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Matthew Siedhoff
- Division of Minimally Invasive Gynecologic Surgery, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Kate Lawrenson
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Cancer Prevention and Control Program, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| |
Collapse
|
|
10
|
Tong A, Di X, Zhao X, Liang X. Review the progression of ovarian clear cell carcinoma from the perspective of genomics and epigenomics. Front Genet 2023; 14:952379. [PMID: 36873929 PMCID: PMC9978161 DOI: 10.3389/fgene.2023.952379] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 02/06/2023] [Indexed: 02/18/2023] Open
Abstract
Ovarian clear cell carcinoma (OCCC) is a rare subtype of epithelial ovarian cancer with unique molecular characteristics, specific biological and clinical behavior, poor prognosis and high resistance to chemotherapy. Pushed by the development of genome-wide technologies, our knowledge about the molecular features of OCCC has been considerably advanced. Numerous studies are emerging as groundbreaking, and many of them are promising treatment strategies. In this article, we reviewed studies about the genomics and epigenetics of OCCC, including gene mutation, copy number variations, DNA methylation and histone modifications.
Collapse
Affiliation(s)
- An Tong
- Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiangjie Di
- Clinical Trial Center, NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Xia Zhao
- Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiao Liang
- Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| |
Collapse
|
|
11
|
Maragliano R, Libera L, Carnevali I, Pensotti V, De Vecchi G, Testa M, Amaglio C, Leoni E, Formenti G, Sessa F, Furlan D, Uccella S. Mixed Neuroendocrine/Non-neuroendocrine Neoplasm (MiNEN) of the Ovary Arising from Endometriosis: Molecular Pathology Analysis in Support of a Pathogenetic Paradigm. Endocr Pathol 2022; 33:400-410. [PMID: 34342838 PMCID: PMC9420090 DOI: 10.1007/s12022-021-09689-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/19/2021] [Indexed: 12/19/2022]
Abstract
Primary ovarian neuroendocrine neoplasms (Ov-NENs) are infrequent and mainly represented by well-differentiated forms (neuroendocrine tumors - NETs - or carcinoids). Poorly differentiated neuroendocrine carcinomas (Ov-NECs) are exceedingly rare and only few cases have been reported in the literature. A subset of Ov-NECs are admixed with non-neuroendocrine carcinomas, as it occurs in other female genital organs, as well (mostly endometrium and uterine cervix), and may be assimilated to mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs) described in digestive and extra-digestive sites. Here, we present a case of large cell Ov-NEC admixed with an endometrioid carcinoma of the ovary, arising in the context of ovarian endometriosis, associated with a uterine endometrial atypical hyperplasia (EAH). We performed targeted next-generation sequencing analysis, along with a comprehensive immunohistochemical study and FISH analysis for TP53 locus, separately on the four morphologically distinct lesions (Ov-NEC, endometrioid carcinoma, endometriosis, and EAH). The results of our study identified molecular alterations of cancer-related genes (PIK3CA, CTNNB1, TP53, RB1, ARID1A, and p16), which were present with an increasing gradient from preneoplastic lesions to malignant proliferations, both neuroendocrine and non-neuroendocrine components. In conclusion, our findings underscored that the two neoplastic components of this Ov-MiNEN share a substantially identical molecular profile and they progress from a preexisting ovarian endometriotic lesion, in a patient with a coexisting preneoplastic proliferation of the endometrium, genotypically and phenotypically related to the ovarian neoplasm. Moreover, this study supports the inclusion of MiNEN in the spectrum ovarian and, possibly, of all gynecological NENs, among which they are currently not classified.
Collapse
Affiliation(s)
- Roberta Maragliano
- Pathology Unit, Dept. of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy
- Dept. of Pathology, ASST Dei Sette Laghi, Varese, Italy
| | - Laura Libera
- Pathology Unit, Dept. of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy
| | | | | | | | - Margherita Testa
- Pathology Unit, Dept. of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy
| | - Cristina Amaglio
- Pathology Unit, Dept. of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy
| | - Eleonora Leoni
- Pathology Unit, Dept. of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy
| | - Giorgio Formenti
- Dept. of Obstetrics and Gynecology, ASST Dei Sette Laghi, Varese, Italy
| | - Fausto Sessa
- Pathology Unit, Dept. of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy
| | - Daniela Furlan
- Pathology Unit, Dept. of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy
| | - Silvia Uccella
- Pathology Unit, Dept. of Medicine and Surgery, University of Insubria, via O. Rossi 9, 21100, Varese, Italy.
| |
Collapse
|
|
12
|
Praetorius TH, Leonova A, Lac V, Senz J, Tessier-Cloutier B, Nazeran TM, Köbel M, Grube M, Kraemer B, Yong PJ, Kommoss S, Anglesio MS. Molecular analysis suggests oligoclonality and metastasis of endometriosis lesions across anatomically defined subtypes. Fertil Steril 2022; 118:524-534. [PMID: 35715244 DOI: 10.1016/j.fertnstert.2022.05.030] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 05/16/2022] [Accepted: 05/17/2022] [Indexed: 01/13/2023]
Abstract
OBJECTIVE To investigate the heterogeneity of somatic cancer-driver mutations within patients and across endometriosis types. DESIGN A single-center cohort, retrospective study. SETTING Tertiary specialist-care center at a university hospital. PATIENT(S) Patients with surgically and histologically confirmed endometriosis of at least 2 anatomically distinct types (ovarian, deep infiltrating, and superficial). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Specimens were analyzed for the presence or absence of somatic cancer-driver mutations using targeted panel sequencing with orthogonal validation using droplet digital polymerase chain reaction and mutation-surrogate immunohistochemistry. RESULT(S) It was found that 13 of 27 patients had informative somatic driver mutations in endometriosis lesions; of these 13 patients, 9 had identical mutations across distinct lesions. Endometriomas showed a higher mutational complexity, with functionally redundant driver mutations in the same gene and within the same lesions. CONCLUSION(S) Our data are consistent with clonality across endometriosis lesions, regardless of subtype. Further, the finding of redundancy in mutations within the same gene and lesions is consistent with endometriosis representing an oligoclonal disease with dissemination likely to consist of multiple epithelial clones traveling together. This suggests that the current anatomically defined classification of endometriosis does not fully recognize the etiology of the disease. A novel classification should consider genomic and other molecular features to promote personalized endometriosis diagnosis and care.
Collapse
Affiliation(s)
- Teresa H Praetorius
- Department of Women's Health, Tübingen University Hospital, Tübingen, Germany; British Columbia's Gynecological Cancer Research Program (OVCARE), University of British Columbia, Vancouver General Hospital, and BC Cancer, Vancouver, Canada
| | - Anna Leonova
- British Columbia's Gynecological Cancer Research Program (OVCARE), University of British Columbia, Vancouver General Hospital, and BC Cancer, Vancouver, Canada; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada
| | - Vivian Lac
- British Columbia's Gynecological Cancer Research Program (OVCARE), University of British Columbia, Vancouver General Hospital, and BC Cancer, Vancouver, Canada
| | - Janine Senz
- British Columbia's Gynecological Cancer Research Program (OVCARE), University of British Columbia, Vancouver General Hospital, and BC Cancer, Vancouver, Canada
| | - Basile Tessier-Cloutier
- British Columbia's Gynecological Cancer Research Program (OVCARE), University of British Columbia, Vancouver General Hospital, and BC Cancer, Vancouver, Canada; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Tayyebeh M Nazeran
- British Columbia's Gynecological Cancer Research Program (OVCARE), University of British Columbia, Vancouver General Hospital, and BC Cancer, Vancouver, Canada
| | - Martin Köbel
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Canada
| | - Marcel Grube
- Department of Women's Health, Tübingen University Hospital, Tübingen, Germany
| | - Bernhard Kraemer
- Department of Women's Health, Tübingen University Hospital, Tübingen, Germany
| | - Paul J Yong
- British Columbia's Gynecological Cancer Research Program (OVCARE), University of British Columbia, Vancouver General Hospital, and BC Cancer, Vancouver, Canada; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada; BC Women's Centre for Pelvic Pain & Endometriosis, BC Women's Hospital and Health Centre, Vancouver, Canada
| | - Stefan Kommoss
- Department of Women's Health, Tübingen University Hospital, Tübingen, Germany
| | - Michael S Anglesio
- British Columbia's Gynecological Cancer Research Program (OVCARE), University of British Columbia, Vancouver General Hospital, and BC Cancer, Vancouver, Canada; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada.
| |
Collapse
|
|
13
|
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: 6] [Impact Index Per Article: 2.0] [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.
Collapse
|
|
14
|
Yoshioka A, Nakaoka H, Fukumoto T, Inoue I, Nishigori C, Kunisada M. The landscape of genetic alterations of UVB-induced skin tumors in DNA repair-deficient mice. Exp Dermatol 2022; 31:1607-1617. [PMID: 35751582 DOI: 10.1111/exd.14634] [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: 04/01/2022] [Revised: 05/25/2022] [Accepted: 06/22/2022] [Indexed: 11/28/2022]
Abstract
Non-melanoma skin cancer (NMSC) is mainly caused by ultraviolet (UV)-induced somatic mutations and is characterized by UV signature modifications. Xeroderma pigmentosum group A (Xpa) knockout mice exhibit extreme UV-induced photo-skin carcinogenesis, along with a photosensitive phenotype. We performed whole-exome sequencing (WES) of squamous cell carcinoma (SCC) samples after repetitive ultraviolet B (UVB) exposure to investigate the differences in the landscape of somatic mutations between Xpa knockout and wild-type mice. Although the tumors that developed in mice harbored UV signature mutations in a similar set of cancer-related genes, the pattern of transcriptional strand asymmetry was largely different; UV signature mutations in Xpa knockout and wild-type mice preferentially occurred in transcribed and non-transcribed strands, respectively, reflecting a deficiency in transcription-coupled nucleotide excision repair in Xpa knockout mice. Serial time point analyses of WES for a tumor induced by only a single UVB exposure showed pathogenic mutations in Kras, Fat1, and Kmt2c, which may be driver genes for the initiation and promotion of SCC in Xpa knockout mice. Furthermore, the inhibitory effects on tumor production in Xpa knockout mice by the anti-inflammatory CXCL1 monoclonal antibody affected the pattern of somatic mutations, wherein the transcriptional strand asymmetry was attenuated and the activated signal transduction was shifted from the RAS/RAF/MAPK to the PIK3CA pathway.
Collapse
Affiliation(s)
- Ai Yoshioka
- Division of Dermatology, Department of Internal Related, Graduate School of Medicine, Kobe University, Kobe, Japan
| | - Hirofumi Nakaoka
- Department of Cancer Genome Research, Sasaki Institute, Tokyo, Japan.,Human Genetics Laboratory, National Institute of Genetics, Mishima, Japan
| | - Takeshi Fukumoto
- Division of Dermatology, Department of Internal Related, Graduate School of Medicine, Kobe University, Kobe, Japan
| | - Ituro Inoue
- Human Genetics Laboratory, National Institute of Genetics, Mishima, Japan
| | - Chikako Nishigori
- Division of Research on Intractable Dermatological Disease, Department of iPS cell Applications, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Makoto Kunisada
- Division of Dermatology, Department of Internal Related, Graduate School of Medicine, Kobe University, Kobe, Japan
| |
Collapse
|
|
15
|
Yamaguchi M, Nakaoka H, Suda K, Yoshihara K, Ishiguro T, Yachida N, Saito K, Ueda H, Sugino K, Mori Y, Yamawaki K, Tamura R, Revathidevi S, Motoyama T, Tainaka K, Verhaak RGW, Inoue I, Enomoto T. Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium. Nat Commun 2022; 13:943. [PMID: 35177608 PMCID: PMC8854701 DOI: 10.1038/s41467-022-28568-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 02/02/2022] [Indexed: 12/15/2022] Open
Abstract
It has become evident that somatic mutations in cancer-associated genes accumulate in the normal endometrium, but spatiotemporal understanding of the evolution and expansion of mutant clones is limited. To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we sequence 1311 endometrial glands from 37 women. By collecting endometrial glands from different parts of the endometrium, we show that multiple glands with the same somatic mutations occupy substantial areas of the endometrium. We demonstrate that “rhizome structures”, in which the basal glands run horizontally along the muscular layer and multiple vertical glands rise from the basal gland, originate from the same ancestral clone. Moreover, mutant clones detected in the vertical glands diversify by acquiring additional mutations. These results suggest that clonal expansions through the rhizome structures are involved in the mechanism by which mutant clones extend their territories. Furthermore, we show clonal expansions and copy neutral loss-of-heterozygosity events occur early in life, suggesting such events can be tolerated many years in the normal endometrium. Our results of the evolutionary dynamics of mutant clones in the human endometrium will lead to a better understanding of the mechanisms of endometrial regeneration during the menstrual cycle and the development of therapies for the prevention and treatment of endometrium-related diseases. Through regeneration, the endometrium accumulates somatic mutations that can lead to diseases like endometriosis and cancer. Here, the authors use genomics to analyse normal endometrial glands from different patient cohorts, detect rhizome structures with common clonal ancestors and infer clonal expansion dynamics.
Collapse
Affiliation(s)
- Manako Yamaguchi
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 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, 101-0062, Japan.
| | - Kazuaki Suda
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan
| | - Kosuke Yoshihara
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan.
| | - Tatsuya Ishiguro
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan
| | - Nozomi Yachida
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan
| | - Kyota Saito
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan
| | - Haruka Ueda
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan
| | - Kentaro Sugino
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan
| | - Yutaro Mori
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan
| | - Kaoru Yamawaki
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan
| | - Ryo Tamura
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 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
| | - Kazuki Tainaka
- Department of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan.,Laboratory for Synthetic Biology, RIKEN Center for Biosystems Dynamics Research, Suita, 565-5241, Japan
| | - Roel G W Verhaak
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.,Department of Neurosurgery, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV, Amsterdam, The Netherlands
| | - 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, Niigata, 951-8510, Japan.
| |
Collapse
|
|
16
|
A Revised Stem Cell Theory for the Pathogenesis of Endometriosis. J Pers Med 2022; 12:jpm12020216. [PMID: 35207704 PMCID: PMC8875896 DOI: 10.3390/jpm12020216] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 01/23/2022] [Accepted: 02/01/2022] [Indexed: 02/04/2023] Open
Abstract
During the past decade, a stem cell-based hypothesis has emerged (among many others) to explain the pathogenesis of endometriosis. The initial hypothesis proposed that endometriosis arose from a single or a few specific cells with stem cell properties, including self-renewal and multi-lineage cell differentiation. The origins of the endometriosis-initiating stem cells were thought to be the bone marrow, uterine endometrium, and other tissues. Based on the implantation or metastatic theory in combination with the initial stem cell theory, one or a few multipotent stem/progenitor cells present in the eutopic endometrium or bone marrow translocate to ectopic sites via fallopian tubes during menstruation, vasculolymphatic routes, or through direct migration and invasion. Subsequently, they give rise to endometriotic lesions followed by differentiation into various cell components of endometriosis, including glandular and stromal cells. Recent somatic mutation analyses of deep infiltrating endometriosis, endometrioma, and eutopic normal endometrium using next-generation sequencing techniques have redefined the stem cell theory. It is now proposed that stem/progenitor cells of at least two different origins—epithelium and stroma—sequentially, differentially, but coordinately contribute to the genesis of endometriosis. The dual stem cell theory on how two (or more) stem/progenitor cells differentially and coordinately participate in the establishment of endometriotic lesions remains to be elucidated. Furthermore, the stem/progenitor cells involved in this theory also remain to be identified. Given that the origin of endometriosis is eutopic endometrium, the candidate cells for endometriotic epithelium-initiating cells are likely to be endometrial epithelial cells positive for either N-cadherin or SSEA-1 or both. The candidate cells for endometriotic stroma-initiating cells may be endometrial mesenchymal stem cells positive for SUSD2. Endometrial side population cells are also a possible candidate because they contain unipotent or multipotent cells capable of behaving as endometrial epithelial and stromal stem/progenitor cells.
Collapse
|
|
17
|
APOBEC mediated mutagenesis drives genomic heterogeneity in endometriosis. J Hum Genet 2022; 67:323-329. [PMID: 35017684 DOI: 10.1038/s10038-021-01003-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 11/11/2021] [Accepted: 11/29/2021] [Indexed: 11/09/2022]
Abstract
Endometriosis is a benign gynecologic condition, acting as a precursor of certain histological subtypes of ovarian cancers. The epithelial cells of endometriotic tissues and normal uterine endometrium accumulated somatic mutations in cancer-associated genes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and Kirsten rat sarcoma (KRAS) proto-oncogene. To determine the genomic characteristic of endometriotic epithelial cells and normal uterine endometrium and to identify the predominant mutational process acting on them, we studied the somatic mutation profiles obtained from whole exome sequencing of 14 endometriotic epithelium and 11 normal uterine endometrium tissues and classified them into mutational signatures. We observed that single base substitutions 2/13 (SBS), attributed to Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit (APOBEC) induced mutagenesis, were significant in endometriotic tissues, but not in the normal uterine endometrium. Additionally, the larger number and wider allele frequency distribution of APOBEC signature mutations, compared to cancer-associated driver mutations in endometriotic epithelium suggested APOBEC mutagenesis as an important source of mutational burden and heterogeneity in endometriosis. Further, the relative risk of enriched APOBEC signature mutations was higher in endometriosis patients who were carriers of APOBEC3A/3B germline deletion, a common polymorphism in East Asians which involves the complete loss of APOBEC3B coding region. Our results illustrate the significance of APOBEC induced mutagenesis in driving the genomic heterogeneity of endometriosis.
Collapse
|
|
18
|
McGregor SM. Pathologic Classification of Ovarian Cancer. Methods Mol Biol 2022; 2424:11-40. [PMID: 34918285 DOI: 10.1007/978-1-0716-1956-8_2] [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: 06/14/2023]
Abstract
Optimal use of human tissue for research requires an understanding of basic pathologic principles. Given that the physical assessment of tissue must occur as part of standard clinical examination, it cannot be handled directly by investigators unless they are also a part of the care team. The purpose of this chapter is to provide an overview of the clinical analytic process, from initial gross handling to histologic examination by light microscopy and the use of ancillary studies, in order to provide context for samples that are used in research and to highlight specific considerations that are relevant for obtaining appropriate tissue for experimental purposes. Given that they comprise >95% of ovarian malignancies, there is an emphasis on epithelial tumors.
Collapse
Affiliation(s)
- Stephanie M McGregor
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA.
| |
Collapse
|
|
19
|
Murakami K, Kanto A, Sakai K, Miyagawa C, Takaya H, Nakai H, Kotani Y, Nishio K, Matsumura N. Frequent PIK3CA mutations in eutopic endometrium of patients with ovarian clear cell carcinoma. Mod Pathol 2021; 34:2071-2079. [PMID: 34172890 PMCID: PMC8514336 DOI: 10.1038/s41379-021-00861-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/11/2021] [Accepted: 06/14/2021] [Indexed: 12/23/2022]
Abstract
Recent studies have reported cancer-associated mutations in normal endometrium. Mutations in eutopic endometrium may lead to endometriosis and endometriosis-associated ovarian cancer. We investigated PIK3CA mutations (PIK3CAm) for three hotspots (E542K, E545K, H1047R) in eutopic endometrium in patients with ovarian cancer and endometriosis from formalin-fixed paraffin-embedded specimens by laser-capture microdissection and droplet digital PCR. The presence of PIK3CAm in eutopic endometrial glands with mutant allele frequency ≥ 15% were as follows: ovarian clear cell carcinoma (OCCC) with PIK3CAm in tumors, 20/300 hotspots in 11/14 cases; OCCC without PIK3CAm, 42/78 hotspots in 11/12 cases; high-grade serous ovarian carcinoma, 8/45 hotspots in 3/5 cases; and endometriotic cysts, 5/63 hotspots in 5/6 cases. These rates were more frequent than in noncancer nonendometriosis controls (7/309 hotspots in 5/17 cases). In OCCC without PIK3CAm, 7/12 (58%) cases showed multiple hotspot mutations in the same eutopic endometrial glands. In 3/54 (5.6%) cases, PIK3CAm was found in eutopic endometrial stroma. Multisampling of the OCCC tumors with PIK3CAm showed intratumor heterogeneity in three of eight cases. In two cases, PIK3CAm was detected in the stromal component of the tumor. Homogenous PIK3CAm in the epithelial component of the tumor matched the mutation in eutopic endometrial glands in only one case. Eutopic endometrial glands in ovarian cancer and endometriosis show high frequency of PIK3CAm that is not consistent with tumors, and multiple hotspot mutations are often found in the same glands. While the mutations identified in eutopic endometrium may not be driver mutations in the patient's cancer, these are still driver mutations but this specific clone has not undergone the requisite steps for the development of cancer.
Collapse
Affiliation(s)
- Kosuke Murakami
- Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Akiko Kanto
- Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuko Sakai
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Chiho Miyagawa
- Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Hisamitsu Takaya
- Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Hidekatsu Nakai
- Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Yasushi Kotani
- Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuto Nishio
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Noriomi Matsumura
- Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan.
| |
Collapse
|
|
20
|
Matsuzaki S, Nagase Y, Ueda Y, Kakuda M, Maeda M, Matsuzaki S, Kamiura S. Placenta Previa Complicated with Endometriosis: Contemporary Clinical Management, Molecular Mechanisms, and Future Research Opportunities. Biomedicines 2021; 9:biomedicines9111536. [PMID: 34829767 PMCID: PMC8614896 DOI: 10.3390/biomedicines9111536] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 10/23/2021] [Accepted: 10/23/2021] [Indexed: 11/16/2022] Open
Abstract
Endometriosis is a common gynecological disease characterized by chronic inflammation, with an estimated prevalence of approximately 5–15% in reproductive-aged women. This study aimed to assess the relationship between placenta previa (PP) and endometriosis. We performed a systematic review of the literature until 30 June 2021, and 24 studies met the inclusion criteria. Using an adjusted pooled analysis, we found that women with endometriosis had a significantly increased rate of PP (adjusted odds ratio (OR) 3.17, 95% confidence interval (CI) 2.58–3.89) compared to those without endometriosis. In an unadjusted analysis, severe endometriosis was associated with an increased prevalence of PP (OR 11.86, 95% CI 4.32–32.57), whereas non-severe endometriosis was not (OR 2.16, 95% CI 0.95–4.89). Notably, one study showed that PP with endometriosis was associated with increased intraoperative bleeding (1.515 mL versus 870 mL, p < 0.01) compared to those without endometriosis. Unfortunately, no studies assessed the molecular mechanisms underlying PP in patients with endometriosis. Our findings suggest that there is a strong association between endometriosis and a higher incidence of PP, as well as poor surgical outcomes during cesarean delivery. Therefore, the development of novel therapeutic agents or methods is warranted to prevent PP in women with endometriosis.
Collapse
Affiliation(s)
- Shinya Matsuzaki
- Department of Gynecology, Osaka International Cancer Institute, Osaka 541-8567, Japan; (M.M.); (S.K.)
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; (Y.N.); (M.K.)
- Correspondence: or (S.M.); (Y.U.); Tel.: +81-6-6945-1181 (S.M.); +81-6-6879-3355 (Y.U.); Fax: +81-6-6945-1929 (S.M.); +81-6-6879-3359 (Y.U.)
| | - Yoshikazu Nagase
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; (Y.N.); (M.K.)
| | - Yutaka Ueda
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; (Y.N.); (M.K.)
- Correspondence: or (S.M.); (Y.U.); Tel.: +81-6-6945-1181 (S.M.); +81-6-6879-3355 (Y.U.); Fax: +81-6-6945-1929 (S.M.); +81-6-6879-3359 (Y.U.)
| | - Mamoru Kakuda
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; (Y.N.); (M.K.)
| | - Michihide Maeda
- Department of Gynecology, Osaka International Cancer Institute, Osaka 541-8567, Japan; (M.M.); (S.K.)
| | - Satoko Matsuzaki
- Osaka General Medical Center, Department of Obstetrics and Gynecology, Osaka 558-8558, Japan;
| | - Shoji Kamiura
- Department of Gynecology, Osaka International Cancer Institute, Osaka 541-8567, Japan; (M.M.); (S.K.)
| |
Collapse
|
|
21
|
Ma J, Zhang L, Zhan H, Mo Y, Ren Z, Shao A, Lin J. Single-cell transcriptomic analysis of endometriosis provides insights into fibroblast fates and immune cell heterogeneity. Cell Biosci 2021; 11:125. [PMID: 34233737 PMCID: PMC8261960 DOI: 10.1186/s13578-021-00637-x] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023] Open
Abstract
Background Endometriosis is an oestrogen-dependent disease with an unclear aetiology and pathogenesis affecting 6–10% of the global female population, predominantly those of reproductive age. Herein, we profile the transcriptomes of approximately 55,000 single cells from three groups including ectopic endometrium, eutopic endometrium from women with endometriosis, and eutopic endometrium from healthy women to create a single-cell transcriptome atlas of endometriosis. Results We have identified 9 cell types and performed single-cell analysis of fibroblasts, and determined a potential developmental trajectory associated with endometriosis. We also identified fibroblast subpopulations related to endometriosis development and found that StAR played an important role in this process. Moreover, T cells in endometriosis were less activated or inflammatory with decreased effector CD8 + T cells, while the composition ratio of natural killer cells decreased and the percentage of monocytes/macrophages increased in endometriosis cysts. In addition, the effectiveness of immune cells in endometriosis lesions, eutopic endometrium from women with endometriosis, and eutopic endometrium from healthy women was distinct. Cell–cell interaction analyses highlighted the imbalanced immune environment in endometriosis lesions and immune cells in endometriosis could promote the development of the disease. Conclusion Our study provided a systematic characterisation of endometriosis and insights into the aetiology and pathology of endometriosis. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-021-00637-x.
Collapse
Affiliation(s)
- Junyan Ma
- Key Laboratory of Women's Reproductive Health Research of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liqi Zhang
- Department of Obstetrics and Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hong Zhan
- Department of Obstetrics and Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yun Mo
- Department of Obstetrics and Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zuanjie Ren
- Department of Obstetrics and Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Anwen Shao
- Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Lin
- Key Laboratory of Women's Reproductive Health Research of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| |
Collapse
|
|
22
|
Hossain MM, Nakayama K, Shanta K, Razia S, Ishikawa M, Ishibashi T, Yamashita H, Sato S, Iida K, Kanno K, Ishikawa N, Kiyono T, Kyo S. Establishment of a Novel In Vitro Model of Endometriosis with Oncogenic KRAS and PIK3CA Mutations for Understanding the Underlying Biology and Molecular Pathogenesis. Cancers (Basel) 2021; 13:cancers13133174. [PMID: 34202354 PMCID: PMC8269352 DOI: 10.3390/cancers13133174] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/17/2021] [Accepted: 06/22/2021] [Indexed: 12/26/2022] Open
Abstract
Simple Summary Endometriosis is a common gynecological condition that causes pelvic pain and infertility. Despite having normal histological features, several cells bear cancer-associated somatic mutations that result in local tissue invasion but rarely metastasize. Several cancer-associated genes, such as KRAS and PIK3CA, are frequently mutated in the endometriotic epithelium. However, the functional behavior and molecular pathogenesis of this disorder remain unclear. In this study, we developed an immortalized endometriotic epithelial cell line with mutations in KRAS and PIK3CA, which are genes associated with aggressive behaviors, such as increased cell migration, invasion, and proliferation. Through microarray analysis, the KRAS- and PIK3CA-specific gene signatures were identified; LOX and PTX3 were found to be responsible for this metastatic behavior. Knockdown of these two genes by siRNA markedly reduced the metastatic ability of the cells. Our findings suggest that inhibition of LOX and PTX3 may be an alternative therapeutic strategy to reduce the incidence of endometriosis. Abstract Endometriosis-harboring cancer-associated somatic mutations of PIK3CA and KRAS provides new opportunities for studying the multistep processes responsible for the functional and molecular changes in this disease. We aimed to establish a novel in vitro endometriosis model to clarify the functional behavior and molecular pathogenesis of this disorder. Immortalized HMOsisEC10 human ovarian endometriotic epithelial cell line was used in which KRAS and PIK3CA mutations were introduced. Migration, invasion, proliferation, and microarray analyses were performed using KRAS and PIK3CA mutant cell lines. In vitro assays showed that migration, invasion, and proliferation were significantly increased in KRAS and PIK3CA mutant cell lines, indicating that these mutations played causative roles in the aggressive behavior of endometriosis. Microarray analysis identified a cluster of gene signatures; among them, two significantly upregulated cancer-related genes, lysyl oxidase (LOX) and pentraxin3 (PTX3), were associated with cell proliferation, invasion, and migration capabilities. Furthermore, siRNA knockdown of the two genes markedly reduced the metastatic ability of the cells. These results suggest that endometriosis with KRAS or PIK3CA mutations can significantly enhance cell migration, invasion, and proliferation by upregulating LOX and PTX3. We propose that LOX and PTX3 silencing using small molecules could be an alternative therapeutic regimen for severe endometriosis.
Collapse
Affiliation(s)
- Mohammad Mahmud Hossain
- Department of Obstetrics and Gynecology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan; (M.M.H.); (K.S.); (S.R.); (M.I.); (T.I.); (H.Y.); (S.S.); (K.I.); (K.K.); (S.K.)
| | - Kentaro Nakayama
- Department of Obstetrics and Gynecology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan; (M.M.H.); (K.S.); (S.R.); (M.I.); (T.I.); (H.Y.); (S.S.); (K.I.); (K.K.); (S.K.)
- Correspondence: (K.N.); (T.K.)
| | - Kamrunnahar Shanta
- Department of Obstetrics and Gynecology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan; (M.M.H.); (K.S.); (S.R.); (M.I.); (T.I.); (H.Y.); (S.S.); (K.I.); (K.K.); (S.K.)
| | - Sultana Razia
- Department of Obstetrics and Gynecology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan; (M.M.H.); (K.S.); (S.R.); (M.I.); (T.I.); (H.Y.); (S.S.); (K.I.); (K.K.); (S.K.)
| | - Masako Ishikawa
- Department of Obstetrics and Gynecology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan; (M.M.H.); (K.S.); (S.R.); (M.I.); (T.I.); (H.Y.); (S.S.); (K.I.); (K.K.); (S.K.)
| | - Tomoka Ishibashi
- Department of Obstetrics and Gynecology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan; (M.M.H.); (K.S.); (S.R.); (M.I.); (T.I.); (H.Y.); (S.S.); (K.I.); (K.K.); (S.K.)
| | - Hitomi Yamashita
- Department of Obstetrics and Gynecology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan; (M.M.H.); (K.S.); (S.R.); (M.I.); (T.I.); (H.Y.); (S.S.); (K.I.); (K.K.); (S.K.)
| | - Seiya Sato
- Department of Obstetrics and Gynecology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan; (M.M.H.); (K.S.); (S.R.); (M.I.); (T.I.); (H.Y.); (S.S.); (K.I.); (K.K.); (S.K.)
| | - Kouji Iida
- Department of Obstetrics and Gynecology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan; (M.M.H.); (K.S.); (S.R.); (M.I.); (T.I.); (H.Y.); (S.S.); (K.I.); (K.K.); (S.K.)
| | - Kosuke Kanno
- Department of Obstetrics and Gynecology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan; (M.M.H.); (K.S.); (S.R.); (M.I.); (T.I.); (H.Y.); (S.S.); (K.I.); (K.K.); (S.K.)
| | - Noriyoshi Ishikawa
- Department of Organ Pathology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan;
| | - Tohru Kiyono
- Project for Prevention of HPV-Related Cancer, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Kashiwa 277-8577, Japan
- Correspondence: (K.N.); (T.K.)
| | - Satoru Kyo
- Department of Obstetrics and Gynecology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan; (M.M.H.); (K.S.); (S.R.); (M.I.); (T.I.); (H.Y.); (S.S.); (K.I.); (K.K.); (S.K.)
| |
Collapse
|
|
23
|
Peng LS, Li ZM, Chen G, Liu FY, Luo Y, Guo JB, Gao GD, Deng YH, Xu LX, Zhou JY, Zou Y. Frequent DYSF rare variants/mutations in 152 Han Chinese samples with ovarian endometriosis. Arch Gynecol Obstet 2021; 304:671-677. [PMID: 33987686 DOI: 10.1007/s00404-021-06094-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 05/06/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE Endometriosis is a common chronic gynecological disease greatly affecting women health. Prior studies have implicated that dysferlin (DYSF) aberration might be involved in the pathogenesis of ovarian endometriosis. In the present study, we explore the potential presence of DYSF mutations in a total of 152 Han Chinese samples with ovarian endometriosis. METHODS We analyze the potential presence of DYSF mutations by direct DNA sequencing. RESULTS A total of seven rare variants/mutations in the DYSF gene in 10 out of 152 samples (6.6%) were identified, including 5 rare variants and 2 novel mutations. For the 5 rare variants, p.R334W and p.G941S existed in 2 samples, p.R865W, p.R1173H and p.G1531S existed in single sample, respectively; for the two novel mutations, p.W352* and p.I1642F, they were identified in three patients. These rare variants/mutations were absent or existed at extremely low frequency either in our 1006 local control women without endometriosis, or in the China Metabolic Analytics Project (ChinaMAP) and Genome Aggregation Database (gnomAD) databases. Evolutionary conservation analysis results suggested that all of these rare variants/mutations were evolutionarily conserved among 11 vertebrate species from Human to Fox. Furthermore, in silico analysis results suggested these rare variants/mutations were disease-causing. Nevertheless, we find no significant association between DYSF rare variants/mutations and the clinical features in our patients. To our knowledge, this is the first report revealing frequent DYSF mutations in ovarian endometriosis. CONCLUSION We identified a high frequency of DYSF rare variants/mutations in ovarian endometriosis for the first time. This study suggests a new correlation between DYSF rare variants/mutations and ovarian endometriosis, implicating DYSF rare variants/mutations might be positively involved in the pathogenesis of ovarian endometriosis.
Collapse
Affiliation(s)
- Li-Sha Peng
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Department of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, No 318 Bayi Avenue, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Zeng-Ming Li
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Department of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, No 318 Bayi Avenue, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Ge Chen
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Department of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, No 318 Bayi Avenue, Nanchang, 330006, Jiangxi, People's Republic of China.,Central Lab, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Fa-Ying Liu
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Department of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, No 318 Bayi Avenue, Nanchang, 330006, Jiangxi, People's Republic of China.,Central Lab, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Yong Luo
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Department of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, No 318 Bayi Avenue, Nanchang, 330006, Jiangxi, People's Republic of China.,Central Lab, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Jiu-Bai Guo
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Department of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, No 318 Bayi Avenue, Nanchang, 330006, Jiangxi, People's Republic of China.,Department of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Guo-Dong Gao
- Department of Clinical Medicine, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Ying-Hui Deng
- Department of Pathology, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Li-Xian Xu
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Department of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, No 318 Bayi Avenue, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Jiang-Yan Zhou
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Department of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, No 318 Bayi Avenue, Nanchang, 330006, Jiangxi, People's Republic of China. .,Department of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, People's Republic of China.
| | - Yang Zou
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Department of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, No 318 Bayi Avenue, Nanchang, 330006, Jiangxi, People's Republic of China. .,Central Lab, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, People's Republic of China.
| |
Collapse
|
|
24
|
Yachida N, Yoshihara K, Suda K, Nakaoka H, Ueda H, Sugino K, Yamaguchi M, Mori Y, Yamawaki K, Tamura R, Ishiguro T, Kase H, Motoyama T, Enomoto T. Biological significance of KRAS mutant allele expression in ovarian endometriosis. Cancer Sci 2021; 112:2020-2032. [PMID: 33675098 PMCID: PMC8088964 DOI: 10.1111/cas.14871] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 12/17/2022] Open
Abstract
KRAS is the most frequently mutated in ovarian endometriosis. However, it is unclear whether the KRAS mutant allele's mRNA is expressed and plays a biological role in ovarian endometriosis. Here, we performed mutation-specific RNA in situ hybridization to evaluate mutant allele expression of KRAS p.G12V, the most frequently detected mutation in ovarian endometriosis in our previous study, in formalin-fixed paraffin-embedded tissue (FFPE) samples of ovarian endometriosis, cancer cell lines, and ovarian cancers. First, we verified that mutant or wild-type allele of KRAS were expressed in all 5 cancer cell lines and 9 ovarian cancer cases corresponding to the mutation status. Next, we applied this assay to 26 ovarian endometriosis cases, and observed mutant allele expression of KRAS p.G12V in 10 cases. Mutant or wild-type allele of KRAS were expressed in line with mutation status in 12 available endometriosis cases for which KRAS gene sequence was determined. Comparison of clinical features between ovarian endometriosis with KRAS p.G12V mutant allele expression and with KRAS wild-type showed that KRAS p.G12V mutant allele expression was significantly associated with inflammation in ovarian endometriosis. Finally, we assessed the spatial distribution of KRAS mutant allele expression in 5 endometriosis cases by performing multiregional sampling. Intratumor heterogeneity of KRAS mutant allele expression was observed in two endometriosis cases, whereas the spatial distribution of KRAS p.G12V mutation signals were diffuse and homogenous in ovarian cancer. In conclusion, evaluation of oncogene mutant expression will be useful for clarifying the biological significance of oncogene mutations in benign tumors.
Collapse
Affiliation(s)
- Nozomi Yachida
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kosuke Yoshihara
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kazuaki Suda
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hirofumi Nakaoka
- Human Genetics Laboratory, National Institute of Genetics, Mishima, Japan.,Department of Cancer Genome Research, Sasaki Institute, Sasaki Foundation, Chiyoda-ku, Japan
| | - Haruka Ueda
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kentaro Sugino
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Manako Yamaguchi
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yutaro Mori
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kaoru Yamawaki
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Ryo Tamura
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Tatsuya Ishiguro
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hiroaki Kase
- Department of Obstetrics and Gynecology, Nagaoka Chuo General Hospital, Nagaoka, Japan
| | - Teiichi Motoyama
- Department of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takayuki Enomoto
- Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| |
Collapse
|
|
25
|
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.
Collapse
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.)
| | | | | | | | | |
Collapse
|
|
26
|
Whole-Exome Sequencing of Rare Site Endometriosis-Associated Cancer. Diseases 2021; 9:diseases9010014. [PMID: 33557369 PMCID: PMC7931088 DOI: 10.3390/diseases9010014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/29/2021] [Accepted: 02/01/2021] [Indexed: 02/06/2023] Open
Abstract
Malignant transformation of extraovarian endometriosis is rare, with the carcinogenesis mechanism unclear. To clarify the actionable variants of rare-site endometriosis-associated cancer (RSEAC), we performed whole-exome sequencing for the tumor, in two patients. The intestine was affected in both cases, although the histology was that of clear cell carcinoma and undifferentiated carcinoma, respectively. Therefore, the cases were referred to as endometriosis-associated intestinal tumors (EIATs). Actionable variants (all frameshift mutations) were identified in tumor suppressor genes ARID1A, PTEN, and p53; however, no oncogenic variants were identified. Both cases were microsatellite stable. The patient with undifferentiated carcinoma exhibited hypermutator and homologous recombination deficiency phenotypes. The dominant mutation signatures were signature 30 (small subset of breast cancers) and 19 (pilocytic astrocytoma) in patient 1, and signature 5 (small subset of breast cancers) and 3 (breast, ovarian, and pancreatic cancers) in patient 2. Immunohistochemistry revealed positive CD8 and PD-1 expression in both patients; patient 1 also showed positive PDL-1 expression. Our results suggest that RSEAC is associated with variants of tumor suppressor genes as epigenetic alterations. Mutation signature-based whole-exome sequencing could be useful to select an adjuvant chemotherapy regimen. High CD8 and PD-1 expression in RSEAC suggests that immune checkpoint inhibitors are useful for treatment.
Collapse
|
|
27
|
Suda K, Cruz Diaz LA, Yoshihara K, Nakaoka H, Yachida N, Motoyama T, Inoue I, Enomoto T. Clonal lineage from normal endometrium to ovarian clear cell carcinoma through ovarian endometriosis. Cancer Sci 2020; 111:3000-3009. [PMID: 32473611 PMCID: PMC7419022 DOI: 10.1111/cas.14507] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 05/14/2020] [Accepted: 05/25/2020] [Indexed: 12/20/2022] Open
Abstract
Clear cell carcinoma of the ovary is thought to arise from endometriosis. In addition, retrograde menstruation of shed endometrium is considered the origin of endometriosis. However, little evidence supports cellular continuity from uterine endometrium to clear cell carcinoma through endometriosis at the genomic level. Here, we performed multiregional whole-exome sequencing to clarify clonal relationships among uterine endometrium, ovarian endometriosis and ovarian clear cell carcinoma in a 56-year-old patient. Many somatic mutations including cancer-associated gene mutations in ARID1A, ATM, CDH4, NRAS and PIK3CA were shared among epithelium samples from uterine endometrium, endometriotic lesions distant from and adjacent to the carcinoma, and the carcinoma. The mutant allele frequencies of shared mutations increased from uterine endometrium to distant endometriosis, adjacent endometriosis, and carcinoma. Although a splice site mutation of ARID1A was shared among the four epithelium samples, a frameshift insertion in ARID1A was shared by adjacent endometriosis and carcinoma samples, suggesting that the biallelic mutations triggered malignant transformation. Somatic copy number alterations, including loss of heterozygosity events at PIK3CA and ATM, were identified only in adjacent endometriosis and carcinoma, suggesting that mutant allele-specific imbalance is another key factor driving malignant transformation. By reconstructing a clonal evolution tree based on the somatic mutations, we showed that the epithelium samples were derived from a single ancestral clone. Although the study was limited to a single patient, the results from this illustrative case could suggest the possibility that epithelial cells of ovarian endometriosis and clear cell carcinoma were descendants of uterine endometrial epithelium.
Collapse
Affiliation(s)
- Kazuaki Suda
- Department of Obstetrics and GynecologyNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
| | - Luis Antonio Cruz Diaz
- Department of GeneticsSchool of Life SciencesSOKENDAI (Graduate University for Advanced Studies)MishimaJapan
- Human Genetics LaboratoryNational Institute of GeneticsMishimaJapan
| | - Kosuke Yoshihara
- Department of Obstetrics and GynecologyNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
| | - Hirofumi Nakaoka
- Department of GeneticsSchool of Life SciencesSOKENDAI (Graduate University for Advanced Studies)MishimaJapan
- Human Genetics LaboratoryNational Institute of GeneticsMishimaJapan
- Department of Cancer Genome ResearchSasaki InstituteSasaki FoundationChiyoda‐kuJapan
| | - Nozomi Yachida
- Department of Obstetrics and GynecologyNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
| | - Teiichi Motoyama
- Department of Molecular and Diagnostic PathologyNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
| | - Ituro Inoue
- Department of GeneticsSchool of Life SciencesSOKENDAI (Graduate University for Advanced Studies)MishimaJapan
- Human Genetics LaboratoryNational Institute of GeneticsMishimaJapan
| | - Takayuki Enomoto
- Department of Obstetrics and GynecologyNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
| |
Collapse
|