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Soto-Heras S, Reinacher L, Wang B, Oh JE, Bunnell M, Park CJ, Hess RA, Ko CJ. Cryptorchidism and testicular cancer in the dog: unresolved questions and challenges in translating insights from human studies†. Biol Reprod 2024; 111:269-291. [PMID: 38738783 DOI: 10.1093/biolre/ioae075] [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: 12/23/2023] [Revised: 05/02/2024] [Accepted: 05/09/2024] [Indexed: 05/14/2024] Open
Abstract
Cryptorchidism, the failure of one or both testes to descend into the scrotum, and testicular cancer show a strong correlation in both dogs and humans. Yet, long-standing medical debates persist about whether the location of undescended testes directly causes testicular cancer in humans or if both conditions stem from a common origin. Although testicular cancer is a prevalent disease in dogs, even less is known about its cause and correlation with testicular descent in this species. This review investigates the relation between these two disorders in dogs, drawing insights from human studies, and examines key biomarkers identified thus far. In addition, it explores potential causal links, including the impact of temperature on maturing testicular cells and a potential shared genetic origin. Notably, this literature review reveals significant differences between men and dogs in reproductive development, histological and molecular features of testicular tumors, and the prevalence of specific tumor types, such as Sertoli cell tumors in cryptorchid dogs and germ cell tumors in humans. These disparities caution against using dogs as models for human testicular cancer research and underscore the limitations when drawing comparisons between species. The paper concludes by suggesting specific research initiatives to enhance our understanding of the complex interplay between cryptorchidism and testicular cancer in dogs.
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Affiliation(s)
- Sandra Soto-Heras
- Epivara, Inc., 2109 S. Oak Street, Suite 100A, Champaign, IL 61820, USA
| | - Lindsey Reinacher
- Epivara, Inc., 2109 S. Oak Street, Suite 100A, Champaign, IL 61820, USA
| | - Bensen Wang
- Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL 61802, USA
| | - Ji Eun Oh
- Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL 61802, USA
| | - Mary Bunnell
- Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL 61802, USA
| | - Chan Jin Park
- Epivara, Inc., 2109 S. Oak Street, Suite 100A, Champaign, IL 61820, USA
- Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL 61802, USA
| | - Rex A Hess
- Epivara, Inc., 2109 S. Oak Street, Suite 100A, Champaign, IL 61820, USA
- Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL 61802, USA
| | - CheMyong Jay Ko
- Epivara, Inc., 2109 S. Oak Street, Suite 100A, Champaign, IL 61820, USA
- Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL 61802, USA
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Jia Y, He P, Ma X, Lv K, Liu Y, Xu Y. PIK3IP1: structure, aberration, function, and regulation in diseases. Eur J Pharmacol 2024; 977:176753. [PMID: 38897445 DOI: 10.1016/j.ejphar.2024.176753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 06/01/2024] [Accepted: 06/16/2024] [Indexed: 06/21/2024]
Abstract
Phosphoinositide 3-kinase (PI3K) pathway, controlling diverse functions in cells, is one of the most frequently dysregulated pathways in cancer. Several negative regulators have been reported to intricately constrain the overactivation of PI3K pathway. Phosphatidylinoinosidine-3-kinase interacting protein 1 (PIK3IP1), as a unique transmembrane protein, is a newly discovered negative regulator of PI3K pathway. PIK3IP1 negatively regulates PI3K activity by directly binding to the p110 catalytic subunit of PI3K. It has been reported that PIK3IP1 is frequently low expressed in tumors and autoimmune diseases. In tumor cells and impaired cardiomyocyte, PIK3IP1 inhibits cell proliferation and survival. Consistently, the expression of PIK3IP1 is related with the condition of cancer. In addition, PIK3IP1 inhibits the inflammatory response and immune function via maintaining the quiescent state of immune cells. Thus, low expression of PIK3IP1 represents the severe condition of autoimmune diseases. PIK3IP1 is regulated by transcription factors, epigenetic factors or micro-RNAs to facilitate its normal function in different cellular contexts. This review integrates the total findings on PIK3IP1 in different disease, and summaries the structure, biological functions and regulatory mechanisms of PIK3IP1.
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Affiliation(s)
- Yingjie Jia
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Pengxing He
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Xubin Ma
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Kaili Lv
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Ying Liu
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Yichao Xu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450001, China.
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Radhakrishnan K, Luu M, Iaria J, Sutherland JM, McLaughlin EA, Zhu HJ, Loveland KL. Activin and BMP Signalling in Human Testicular Cancer Cell Lines, and a Role for the Nucleocytoplasmic Transport Protein Importin-5 in their Crosstalk. Cells 2023; 12:cells12071000. [PMID: 37048077 PMCID: PMC10093041 DOI: 10.3390/cells12071000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/05/2023] [Accepted: 03/09/2023] [Indexed: 03/29/2023] Open
Abstract
Testicular germ cell tumours (TGCTs) are the most common malignancy in young men. Originating from foetal testicular germ cells that fail to differentiate correctly, TGCTs appear after puberty as germ cell neoplasia in situ cells that transform through unknown mechanisms into distinct seminoma and non-seminoma tumour types. A balance between activin and BMP signalling may influence TGCT emergence and progression, and we investigated this using human cell line models of seminoma (TCam-2) and non-seminoma (NT2/D1). Activin A- and BMP4-regulated transcripts measured at 6 h post-treatment by RNA-sequencing revealed fewer altered transcripts in TCam-2 cells but a greater responsiveness to activin A, while BMP4 altered more transcripts in NT2/D1 cells. Activin significantly elevated transcripts linked to pluripotency, cancer, TGF-β, Notch, p53, and Hippo signalling in both lines, whereas BMP4 altered TGF-β, pluripotency, Hippo and Wnt signalling components. Dose-dependent antagonism of BMP4 signalling by activin A in TCam-2 cells demonstrated signalling crosstalk between these two TGF-β superfamily arms. Levels of the nuclear transport protein, IPO5, implicated in BMP4 and WNT signalling, are highly regulated in the foetal mouse germline. IPO5 knockdown in TCam-2 cells using siRNA blunted BMP4-induced transcript changes, indicating that IPO5 levels could determine TGF-β signalling pathway outcomes in TGCTs.
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Affiliation(s)
- Karthika Radhakrishnan
- Centre for Reproductive Health, Hudson Institute of Medical Research, 27-31 Kanooka Grove, Clayton, VIC 3168, Australia
- Correspondence: (K.R.); (K.L.L.)
| | - Michael Luu
- Centre for Reproductive Health, Hudson Institute of Medical Research, 27-31 Kanooka Grove, Clayton, VIC 3168, Australia
| | - Josie Iaria
- Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC 3050, Australia
| | - Jessie M. Sutherland
- Priority Research Centre for Reproductive Science, Schools of Biomedical Science & Pharmacy and Environmental & Life Sciences, University of Newcastle, Callaghan, NSW 2305, Australia
- Hunter Medical Research Institute (HMRI), New Lambton Heights, NSW 2305, Australia
| | - Eileen A. McLaughlin
- Priority Research Centre for Reproductive Science, Schools of Biomedical Science & Pharmacy and Environmental & Life Sciences, University of Newcastle, Callaghan, NSW 2305, Australia
- Hunter Medical Research Institute (HMRI), New Lambton Heights, NSW 2305, Australia
- Faculty of Science, Medicine and Health, University of Wollongong, Gwynneville, NSW 2500, Australia
| | - Hong-Jian Zhu
- Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC 3050, Australia
| | - Kate L. Loveland
- Centre for Reproductive Health, Hudson Institute of Medical Research, 27-31 Kanooka Grove, Clayton, VIC 3168, Australia
- Department of Molecular and Translational Sciences, Monash University, Clayton, VIC 3800, Australia
- Correspondence: (K.R.); (K.L.L.)
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Hoff AM, Kraggerud SM, Alagaratnam S, Berg KCG, Johannessen B, Høland M, Nilsen G, Lingjærde OC, Andrews PW, Lothe RA, Skotheim RI. Frequent copy number gains of SLC2A3 and ETV1 in testicular embryonal carcinomas. Endocr Relat Cancer 2020; 27:457-468. [PMID: 32580154 PMCID: PMC7424350 DOI: 10.1530/erc-20-0064] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 06/10/2020] [Indexed: 01/03/2023]
Abstract
Testicular germ cell tumours (TGCTs) appear as different histological subtypes or mixtures of these. They show similar, multiple DNA copy number changes, where gain of 12p is pathognomonic. However, few high-resolution analyses have been performed and focal DNA copy number changes with corresponding candidate target genes remain poorly described for individual subtypes. We present the first high-resolution DNA copy number aberration (CNA) analysis on the subtype embryonal carcinomas (ECs), including 13 primary ECs and 5 EC cell lines. We identified recurrent gains and losses and allele-specific CNAs. Within these regions, we nominate 30 genes that may be of interest to the EC subtype. By in silico analysis of data from 150 TGCTs from The Cancer Genome Atlas (TCGA), we further investigated CNAs, RNA expression, somatic mutations and fusion transcripts of these genes. Among primary ECs, ploidy ranged between 2.3 and 5.0, and the most common aberrations were DNA copy number gains at chromosome (arm) 7, 8, 12p, and 17, losses at 4, 10, 11, and 18, replicating known TGCT genome characteristics. Gain of whole or parts of 12p was found in all samples, including a highly amplified 100 kbp segment at 12p13.31, containing SLC2A3. Gain at 7p21, encompassing ETV1, was the second most frequent aberration. In conclusion, we present novel CNAs and the genes located within these regions, where the copy number gain of SLC2A3 and ETV1 are of interest, and which copy number levels also correlate with expression in TGCTs.
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Affiliation(s)
- Andreas M Hoff
- Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Sigrid M Kraggerud
- Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Sharmini Alagaratnam
- Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Kaja C G Berg
- Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Bjarne Johannessen
- Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Maren Høland
- Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Gro Nilsen
- Department of Informatics, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway
| | - Ole C Lingjærde
- Department of Informatics, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway
| | - Peter W Andrews
- The Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Sheffield, UK
| | - Ragnhild A Lothe
- Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Correspondence should be addressed to R A Lothe or R I Skotheim: or
| | - Rolf I Skotheim
- Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- Department of Informatics, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway
- Correspondence should be addressed to R A Lothe or R I Skotheim: or
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Yang Y, Xia C, Zhou Z, Wei D, Xu K, Jia J, Xu W, Zhang H. A multiplex ligation‑dependent probe amplification‑based next‑generation sequencing approach for the detection of copy number variations in the human genome. Mol Med Rep 2018; 18:5823-5833. [PMID: 30365071 DOI: 10.3892/mmr.2018.9581] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 09/28/2018] [Indexed: 11/05/2022] Open
Abstract
The aim of the present study was to describe a multiplex ligation‑dependent probe amplification (MLPA)‑based next‑generation sequencing (NGS) assay that exhibited a significantly higher efficiency in detecting copy number variations (CNVs) and known single‑nucleotide variants, compared with traditional MLPA. MLPA polymerase chain reaction products were used to construct a library with indexed adapters, which was subsequently tested on an NGS platform, and the resulting data were analyzed by a series of analytical software. The reads from each probe reflected genetic variations in the target regions, and fragment differentiation was based on the specific base composition of the sequences, rather than fragment length, which was determined by capillary electrophoresis. The results of this approach were not only consistent with the MLPA results following capillary electrophoresis, but also coincided with the CNV results from the single‑nucleotide polymorphism array chip. This method allowed high‑throughput screening for the number of fragments and samples by integrating additional indices for detection. Furthermore, this technology precisely and accurately performed large‑scale detection and quantification of DNA variations, thereby serving as an effective and sensitive method for diagnosing genetic disorders caused by CNVs and known single‑nucleotide variations. Notably, MLPA‑NGS circumvents the problems associated with the inaccuracies of NGS in CNV detection due to the use of target sequence capture.
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Affiliation(s)
- Yongchen Yang
- Department of Laboratory Medicine, Children's Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai 200040, P.R. China
| | - Chaoran Xia
- Shanghai Institute of Medical Genetics, Children's Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai 200040, P.R. China
| | - Zaiwei Zhou
- Product Department, WuXi Health Net Co., Ltd., Shanghai 200131, P.R. China
| | - Dongkai Wei
- BasePair Biotechnology Co., Ltd., Suzhou, Jiangsu 215028, P.R. China
| | - Kangping Xu
- BasePair Biotechnology Co., Ltd., Suzhou, Jiangsu 215028, P.R. China
| | - Jia Jia
- Shanghai Center for Bioinformation Technology, Shanghai Institutes of Biomedicine, Shanghai Academy of Science and Technology, Shanghai 201203, P.R. China
| | - Wuhen Xu
- Department of Laboratory Medicine, Children's Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai 200040, P.R. China
| | - Hong Zhang
- Department of Laboratory Medicine, Children's Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai 200040, P.R. China
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Selfe J, Goddard NC, McIntyre A, Taylor KR, Renshaw J, Popov SD, Thway K, Summersgill B, Huddart RA, Gilbert DC, Shipley JM. IGF1R signalling in testicular germ cell tumour cells impacts on cell survival and acquired cisplatin resistance. J Pathol 2018; 244:242-253. [PMID: 29160922 PMCID: PMC5817239 DOI: 10.1002/path.5008] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 11/07/2017] [Accepted: 11/14/2017] [Indexed: 12/03/2022]
Abstract
Testicular germ cell tumours (TGCTs) are the most frequent malignancy and cause of death from solid tumours in the 20‐ to 40‐year age group. Although most cases show sensitivity to cis‐platinum‐based chemotherapy, this is associated with long‐term toxicities and chemo‐resistance. Roles for receptor tyrosine kinases other than KIT are largely unknown in TGCT. We therefore conducted a phosphoproteomic screen and identified the insulin growth factor receptor‐1 (IGF1R) as both highly expressed and activated in TGCT cell lines representing the nonseminomatous subtype. IGF1R was also frequently expressed in tumour samples from patients with nonseminomas. Functional analysis of cell line models showed that long‐term shRNA‐mediated IGF1R silencing leads to apoptosis and complete ablation of nonseminoma cells with active IGF1R signalling. Cell lines with high levels of IGF1R activity also showed reduced AKT signalling in response to decreased IGF1R expression as well as sensitivity to the small‐molecule IGF1R inhibitor NVP‐AEW541. These results were in contrast to those in the seminoma cell line TCAM2 that lacked IGF1R signalling via AKT and was one of the two cell lines least sensitive to the IGF1R inhibitor. The dependence on IGF1R activity in the majority of nonseminomas parallels the known role of IGF signalling in the proliferation, migration, and survival of primordial germ cells, the putative cell of origin for TGCT. Upregulation of IGF1R expression and signalling was also found to contribute to acquired cisplatin resistance in an in vitro nonseminoma model, providing a rationale for targeting IGF1R in cisplatin‐resistant disease. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Joanna Selfe
- Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, UK
| | - Neil C Goddard
- Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, UK
| | - Alan McIntyre
- Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, UK
| | - Kathryn R Taylor
- Glioma Team, Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, UK
| | - Jane Renshaw
- Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, UK
| | - Sergey D Popov
- Glioma Team, Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, UK
| | - Khin Thway
- Sarcoma Unit, Department of Histopathology, The Royal Marsden NHS Foundation Trust, London, UK
| | - Brenda Summersgill
- Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, UK
| | - Robert A Huddart
- Department of Clinical Oncology, The Royal Marsden NHS Foundation Trust, Sutton, UK
| | - Duncan C Gilbert
- Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, UK.,Sussex Cancer Centre, Royal Sussex County Hospital, Brighton, UK
| | - Janet M Shipley
- Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, UK
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Chen Y, Qi C, Xia L, Li G. Identification of novel genetic etiology and key molecular pathways for seminoma via network-based studies. Int J Oncol 2017; 51:1280-1290. [DOI: 10.3892/ijo.2017.4092] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 07/19/2017] [Indexed: 11/05/2022] Open
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8
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Gilbert DC, Al-Saadi R, Thway K, Chandler I, Berney D, Gabe R, Stenning SP, Sweet J, Huddart R, Shipley JM. Defining a New Prognostic Index for Stage I Nonseminomatous Germ Cell Tumors Using CXCL12 Expression and Proportion of Embryonal Carcinoma. Clin Cancer Res 2015; 22:1265-73. [PMID: 26453693 DOI: 10.1158/1078-0432.ccr-15-1186] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 09/18/2015] [Indexed: 12/14/2022]
Abstract
PURPOSE Up to 50% of patients diagnosed with stage I nonseminomatous germ cell tumors (NSGCTs) harbor occult metastases. Patients are managed by surveillance with chemotherapy at relapse or adjuvant treatment up front. Late toxicities from chemotherapy are increasingly recognized. Based on a potential biologic role in germ cells/tumors and pilot data, our aim was to evaluate tumor expression of the chemokine CXCL12 alongside previously proposed markers as clinically useful biomarkers of relapse. EXPERIMENTAL DESIGN Immunohistochemistry for tumor expression of CXCL12 was assessed as a biomarker of relapse alongside vascular invasion, histology (percentage embryonal carcinoma), and MIB1 staining for proliferation in formalin-fixed paraffin-embedded orchidectomy samples from patients enrolled in the Medical Research Council's TE08/22 prospective trials of surveillance in stage I NSGCTs. RESULTS TE08/TE22 trial patients had a 76.4% 2-year relapse-free rate, and both CXCL12 expression and percentage embryonal carcinoma provided prognostic value independently of vascular invasion (stratified log rank test P = 0.006 for both). There was no additional prognostic value for MIB1 staining. A model using CXCL12, percentage embryonal carcinoma, and VI defines three prognostic groups that were independently validated. CONCLUSIONS CXCL12 and percentage embryonal carcinoma both stratify patients' relapse risk over and above vascular invasion alone. This is anticipated to improve the stratification of patients and identify high-risk cases to be considered for adjuvant therapy.
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Affiliation(s)
- Duncan C Gilbert
- Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom. MRC Clinical Trials Unit, Aviation House, London, United Kingdom
| | - Reem Al-Saadi
- Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom
| | - Khin Thway
- Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom
| | - Ian Chandler
- Department of Histopathology, Royal Devon and Exeter Hospital, Exeter, United Kingdom
| | - Daniel Berney
- Barts Cancer Institute, Queen Mary, University of London, St Bartholomew's Hospital, London, United Kingdom
| | - Rhian Gabe
- The Hull York Medical School, University of York, Heslington, York, United Kingdom
| | - Sally P Stenning
- MRC Clinical Trials Unit, Aviation House, London, United Kingdom
| | - Joan Sweet
- Toronto General Hospital, Toronto, Ontario, Canada
| | - Robert Huddart
- Department of Academic Radiotherapy and Oncology, Royal Marsden Hospitals NHS Foundation Trust, Sutton, Surrey, United Kingdom
| | - Janet M Shipley
- Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
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Wongtrakoongate P. Epigenetic therapy of cancer stem and progenitor cells by targeting DNA methylation machineries. World J Stem Cells 2015; 7:137-148. [PMID: 25621113 PMCID: PMC4300924 DOI: 10.4252/wjsc.v7.i1.137] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 10/01/2014] [Accepted: 10/29/2014] [Indexed: 02/06/2023] Open
Abstract
Recent advances in stem cell biology have shed light on how normal stem and progenitor cells can evolve to acquire malignant characteristics during tumorigenesis. The cancer counterparts of normal stem and progenitor cells might be occurred through alterations of stem cell fates including an increase in self-renewal capability and a decrease in differentiation and/or apoptosis. This oncogenic evolution of cancer stem and progenitor cells, which often associates with aggressive phenotypes of the tumorigenic cells, is controlled in part by dysregulated epigenetic mechanisms including aberrant DNA methylation leading to abnormal epigenetic memory. Epigenetic therapy by targeting DNA methyltransferases (DNMT) 1, DNMT3A and DNMT3B via 5-Azacytidine (Aza) and 5-Aza-2’-deoxycytidine (Aza-dC) has proved to be successful toward treatment of hematologic neoplasms especially for patients with myelodysplastic syndrome. In this review, I summarize the current knowledge of mechanisms underlying the inhibition of DNA methylation by Aza and Aza-dC, and of their apoptotic- and differentiation-inducing effects on cancer stem and progenitor cells in leukemia, medulloblastoma, glioblastoma, neuroblastoma, prostate cancer, pancreatic cancer and testicular germ cell tumors. Since cancer stem and progenitor cells are implicated in cancer aggressiveness such as tumor formation, progression, metastasis and recurrence, I propose that effective therapeutic strategies might be achieved through eradication of cancer stem and progenitor cells by targeting the DNA methylation machineries to interfere their “malignant memory”.
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Litchfield K, Summersgill B, Yost S, Sultana R, Labreche K, Dudakia D, Renwick A, Seal S, Al-Saadi R, Broderick P, Turner NC, Houlston RS, Huddart R, Shipley J, Turnbull C. Whole-exome sequencing reveals the mutational spectrum of testicular germ cell tumours. Nat Commun 2015; 6:5973. [PMID: 25609015 PMCID: PMC4338546 DOI: 10.1038/ncomms6973] [Citation(s) in RCA: 145] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Accepted: 11/25/2014] [Indexed: 01/01/2023] Open
Abstract
Testicular germ cell tumours (TGCTs) are the most common cancer in young men. Here we perform whole-exome sequencing (WES) of 42 TGCTs to comprehensively study the cancer's mutational profile. The mutation rate is uniformly low in all of the tumours (mean 0.5 mutations per Mb) as compared with common cancers, consistent with the embryological origin of TGCT. In addition to expected copy number gain of chromosome 12p and mutation of KIT, we identify recurrent mutations in the tumour suppressor gene CDC27 (11.9%). Copy number analysis reveals recurring amplification of the spermatocyte development gene FSIP2 (15.3%) and a 0.4 Mb region at Xq28 (15.3%). Two treatment-refractory patients are shown to harbour XRCC2 mutations, a gene strongly implicated in defining cisplatin resistance. Our findings provide further insights into genes involved in the development and progression of TGCT.
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Affiliation(s)
- Kevin Litchfield
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
| | - Brenda Summersgill
- Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
| | - Shawn Yost
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
| | - Razvan Sultana
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
| | - Karim Labreche
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
- Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75019, Paris, France
| | - Darshna Dudakia
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
| | - Anthony Renwick
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
| | - Sheila Seal
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
| | - Reem Al-Saadi
- Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
| | - Peter Broderick
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
| | - Nicholas C. Turner
- The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
| | - Richard S. Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
| | - Robert Huddart
- Academic Radiotherapy Unit, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
| | - Janet Shipley
- Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
| | - Clare Turnbull
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
- William Harvey Research Institute, Queen Mary University London, Charterhouse Square, London EC1M 6BQ, UK
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Rijlaarsdam MA, Looijenga LHJ. An oncofetal and developmental perspective on testicular germ cell cancer. Semin Cancer Biol 2014; 29:59-74. [PMID: 25066859 DOI: 10.1016/j.semcancer.2014.07.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Accepted: 07/17/2014] [Indexed: 12/19/2022]
Abstract
Germ cell tumors (GCTs) represent a diverse group of tumors presumably originating from (early fetal) developing germ cells. Most frequent are the testicular germ cell cancers (TGCC). Overall, TGCC is the most frequent malignancy in Caucasian males (20-40 years) and remains an important cause of (treatment related) mortality in these young men. The strong association between the phenotype of TGCC stem cell components and their totipotent ancestor (fetal primordial germ cell or gonocyte) makes these tumors highly relevant from an onco-fetal point of view. This review subsequently discusses the evidence for the early embryonic origin of TGCCs, followed by an overview of the crucial association between TGCC pathogenesis, genetics, environmental exposure and the (fetal) testicular micro-environment (genvironment). This culminates in an evaluation of three genvironmentally modulated hallmarks of TGCC directly related to the oncofetal pathogenesis of TGCC: (1) maintenance of pluripotency, (2) cell cycle control/cisplatin sensitivity and (3) regulation of proliferation/migration/apoptosis by KIT-KITL mediated receptor tyrosine kinase signaling. Briefly, TGCC exhibit identifiable stem cell components (seminoma and embryonal carcinoma) and progenitors that show large and consistent similarities to primordial/embryonic germ cells, their presumed totipotent cells of origin. TGCC pathogenesis depends crucially on a complex interaction of genetic and (micro-)environmental, i.e. genvironmental risk factors that have only been partly elucidated despite significant effort. TGCC stem cell components also show a high degree of similarity with embryonic stem/germ cells (ES) in the regulation of pluripotency and cell cycle control, directly related to their exquisite sensitivity to DNA damaging agents (e.g. cisplatin). Of note, (ES specific) micro-RNAs play a pivotal role in the crossover between cell cycle control, pluripotency and chemosensitivity. Moreover, multiple consistent observations reported TGCC to be associated with KIT-KITL mediated receptor tyrosine kinase signaling, a pathway crucially implicated in proliferation, migration and survival during embryogenesis including germ cell development. In conclusion, TGCCs are a fascinating model for onco-fetal developmental processes especially with regard to studying cell cycle control, pluripotency maintenance and KIT-KITL signaling. The knowledge presented here contributes to better understanding of the molecular characteristics of TGCC pathogenesis, translating to identification of at risk individuals and enhanced quality of care for TGCC patients (diagnosis, treatment and follow-up).
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Affiliation(s)
- Martin A Rijlaarsdam
- Department of Pathology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Leendert H J Looijenga
- Department of Pathology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands.
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McIver SC, Roman SD, Nixon B, Loveland KL, McLaughlin EA. The rise of testicular germ cell tumours: the search for causes, risk factors and novel therapeutic targets. F1000Res 2013; 2:55. [PMID: 24555040 PMCID: PMC3901536 DOI: 10.12688/f1000research.2-55.v1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/15/2013] [Indexed: 12/11/2022] Open
Abstract
Since the beginning of the 20th century there has been a decline in the reproductive vitality of men within the Western world. The declining sperm quantity and quality has been associated with increased overt disorders of sexual development including hypospadias, undescended testes and type II testicular germ cell tumours (TGCTs). The increase in TGCTs cannot be accounted for by genetic changes in the population. Therefore exposure to environmental toxicants appears to be a major contributor to the aetiology of TGCTs and men with a genetic predisposition are particularly vulnerable. In particular, Type II TGCTs have been identified to arise from a precursor lesion Carcinoma
in situ (CIS), identified as a dysfunctional gonocyte; however, the exact triggers for CIS development are currently unknown. Therefore the transition from gonocytes into spermatogonia is key to those studying TGCTs. Recently we have identified seven miRNA molecules (including members of the miR-290 family and miR-136, 463* and 743a) to be significantly changed over this transition period. These miRNA molecules are predicted to have targets within the CXCR4, PTEN, DHH, RAC and PDGF pathways, all of which have important roles in germ cell migration, proliferation and homing to the spermatogonial stem cell niche. Given the plethora of potential targets affected by each miRNA molecule, subtle changes in miRNA expression could have significant consequences e.g. tumourigenesis. The role of non-traditional oncogenes and tumour suppressors such as miRNA in TGCT is highlighted by the fact that the majority of these tumours express wild type p53, a pivotal tumour suppressor usually inactivated in cancer. While treatment of TGCTs is highly successful, the impact of these treatments on fertility means that identification of exact triggers, earlier diagnosis and alternate treatments are essential. This review examines the genetic factors and possible triggers of type II TGCT to highlight target areas for potential new treatments.
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Affiliation(s)
- Skye C McIver
- ARC Centre of Excellence in Biotechnology & Development, School of Environmental & Life Sciences, University of Newcastle, Callaghan, 2308, Australia
| | - Shaun D Roman
- ARC Centre of Excellence in Biotechnology & Development, School of Environmental & Life Sciences, University of Newcastle, Callaghan, 2308, Australia
| | - Brett Nixon
- ARC Centre of Excellence in Biotechnology & Development, School of Environmental & Life Sciences, University of Newcastle, Callaghan, 2308, Australia
| | - Kate L Loveland
- Department of Biochemistry & Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, 3800, Australia ; Department of Anatomy & Developmental Biology, School of Biomedical Sciences, Monash University, Clayton, 3800, Australia
| | - Eileen A McLaughlin
- ARC Centre of Excellence in Biotechnology & Development, School of Environmental & Life Sciences, University of Newcastle, Callaghan, 2308, Australia
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13
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Abstract
The failure of testicular descent or cryptorchidism is the most common defect in newborn boys. The descent of the testes during development is controlled by insulin-like 3 peptide and steroid hormones produced in testicular Leydig cells, as well as by various genetic and developmental factors. While in some cases the association with genetic abnormalities and environmental causes has been shown, the etiology of cryptorchidism remains uncertain. Cryptorchidism is an established risk factor for infertility and testicular germ cell tumors (TGCT). Experimental animal models suggest a causative role for an abnormal testicular position on the disruption of spermatogenesis however the link between cryptorchidism and TGCT is less clear. The most common type of TGCT in cryptorchid testes is seminoma, believed to be derived from pluripotent prenatal germ cells. Recent studies have shown that seminoma cells and their precursor carcinoma in situ cells express a number of spermatogonial stem cell (SSC) markers suggesting that TGCTs might originate from adult stem cells. We review here the data on changes in the SSC somatic cell niche observed in cryptorchid testes of mouse models and in human patients. We propose that the misregulation of growth factors' expression may alter the balance between SSC self-renewal and differentiation and shift stem cells toward neoplastic transformation.
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Affiliation(s)
- Lydia Ferguson
- Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International UniversityMiami, FL, USA
| | - Alexander I. Agoulnik
- Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International UniversityMiami, FL, USA
- *Correspondence: Alexander I. Agoulnik, Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, HLSI 419B, Miami, FL 33199, USA. e-mail:
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14
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Singhera M, Lees K, Huddart R, Horwich A. Minimizing toxicity in early-stage testicular cancer treatment. Expert Rev Anticancer Ther 2012; 12:185-93. [PMID: 22316366 DOI: 10.1586/era.11.212] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Testicular cancer is the paradigm of a curable malignancy, with 10-year survival rates exceeding 95%. Cisplatin-based regimes offer a survival gain of several decades of life; however, measures of outcomes in testicular cancer are evolving. Survivorship issues are becoming increasingly important in this young adult population. Long-term risks of second malignancy and cardiovascular disease secondary to chemotherapy and radiotherapy have been extensively documented, leading to an increased uptake of surveillance. However, the optimal surveillance schedule is not universally agreed upon. Research into modalities to detect relapse and frequency is ongoing. Reducing the treatment burden with fewer cycles of chemotherapy (one cycle of bleomycin, cisplatin and etoposide instead of two for stage I high-risk nonseminomatous tumors) or less toxic alternatives (carboplatin instead of radiotherapy for stage I seminomas) is currently being explored. This article details the toxicities associated with the diagnosis and treatments of early-stage testicular cancer and current strategies used to minimize toxicity while retaining the excellent cure rates.
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Affiliation(s)
- Mausam Singhera
- Institute of Cancer Research and Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, UK
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DeFrances MC, Debelius DR, Cheng J, Kane LP. Inhibition of T-cell activation by PIK3IP1. Eur J Immunol 2012; 42:2754-9. [PMID: 22706993 DOI: 10.1002/eji.201141653] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2011] [Revised: 06/04/2012] [Accepted: 06/06/2012] [Indexed: 11/07/2022]
Abstract
The PI-3 kinase (PI3K) pathway is critical for T-cell development and activation. Several negative regulators of this pathway have already been described and characterized: the lipid phosphatases SHIP, inositol polyphosphate-4-phosphatase, type II (INPP4B), and phosphatase and tensin homolog (PTEN), the latter of which are tumor suppressors. PIK3IP1 (PI3K interacting protein 1) is a recently described transmembrane protein that has the ability to bind the catalytic protein p110 and prevent its activation by the p85 family adaptor proteins. Thus far, nothing is known about the possible role of PIK3IP1 in the regulation of lymphocyte development or activation. Here, we show for the first time that PIK3IP1 is expressed in T cells. Ectopic expression of PIK3IP1 in Jurkat or D10 T-cell lines inhibited activation of an NFAT/AP-1 transcriptional reporter. Conversely, siRNA-mediated silencing of PIK3IP1 in the same cell lines modestly augmented Akt phosphorylation, T-cell activation, and production of IL-2. These results suggest that the novel PI3K regulator PIK3IP1 plays an inhibitory role in T-cell activation.
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Affiliation(s)
- Marie C DeFrances
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Abstract
PURPOSE OF REVIEW This overview discusses several important developments in testicular germ cell tumors in the past year. RECENT FINDINGS Genomic studies continue to investigate gene expression as possible markers for disease relapse and chemotherapy resistance. Optimal treatment strategies for early-stage seminomas are evolving toward surveillance versus chemotherapy and away from radiation, and the role of retroperitoneal lymph node dissection in disseminated nonseminomatous cancers in complete remission is becoming less certain. SUMMARY Treatment and surveillance paradigms continue to be defined and refined for both early and late-stage disease as research in these areas continues and the data from multiple large studies mature.
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McIver SC, Stanger SJ, Santarelli DM, Roman SD, Nixon B, McLaughlin EA. A unique combination of male germ cell miRNAs coordinates gonocyte differentiation. PLoS One 2012; 7:e35553. [PMID: 22536405 PMCID: PMC3334999 DOI: 10.1371/journal.pone.0035553] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Accepted: 03/21/2012] [Indexed: 12/16/2022] Open
Abstract
The last 100 years have seen a concerning decline in male reproductive health associated with decreased sperm production, sperm function and male fertility. Concomitantly, the incidence of defects in reproductive development, such as undescended testes, hypospadias and testicular cancer has increased. Indeed testicular cancer is now recognised as the most common malignancy in young men. Such cancers develop from the pre-invasive lesion Carcinoma in Situ (CIS), a dysfunctional precursor germ cell or gonocyte which has failed to successfully differentiate into a spermatogonium. It is therefore essential to understand the cellular transition from gonocytes to spermatogonia, in order to gain a better understanding of the aetiology of testicular germ cell tumours. MicroRNA (miRNA) are important regulators of gene expression in differentiation and development and thus highly likely to play a role in the differentiation of gonocytes. In this study we have examined the miRNA profiles of highly enriched populations of gonocytes and spermatogonia, using microarray technology. We identified seven differentially expressed miRNAs between gonocytes and spermatogonia (down-regulated: miR-293, 291a-5p, 290-5p and 294*, up-regulated: miR-136, 743a and 463*). Target prediction software identified many potential targets of several differentially expressed miRNA implicated in germ cell development, including members of the PTEN, and Wnt signalling pathways. These targets converge on the key downstream cell cycle regulator Cyclin D1, indicating that a unique combination of male germ cell miRNAs coordinate the differentiation and maintenance of pluripotency in germ cells.
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Affiliation(s)
- Skye C. McIver
- ARC Centre of Excellence in Biotechnology and Development, Discipline of Biological Sciences, School of Environmental and Life Sciences, University of Newcastle, Callaghan, New South Wales, Australia
| | - Simone J. Stanger
- ARC Centre of Excellence in Biotechnology and Development, Discipline of Biological Sciences, School of Environmental and Life Sciences, University of Newcastle, Callaghan, New South Wales, Australia
| | - Danielle M. Santarelli
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia
| | - Shaun D. Roman
- ARC Centre of Excellence in Biotechnology and Development, Discipline of Biological Sciences, School of Environmental and Life Sciences, University of Newcastle, Callaghan, New South Wales, Australia
| | - Brett Nixon
- ARC Centre of Excellence in Biotechnology and Development, Discipline of Biological Sciences, School of Environmental and Life Sciences, University of Newcastle, Callaghan, New South Wales, Australia
| | - Eileen A. McLaughlin
- ARC Centre of Excellence in Biotechnology and Development, Discipline of Biological Sciences, School of Environmental and Life Sciences, University of Newcastle, Callaghan, New South Wales, Australia
- * E-mail:
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Mohamed GH, Gelfond JAL, Nicolas MM, Brand TC, Sarvis JA, Leach RJ, Johnson-Pais TL. Genomic characterization of testis cancer: association of alterations with outcome of clinical stage 1 mixed germ cell nonseminomatous germ cell tumor of the testis. Urology 2012; 80:485.e1-5. [PMID: 22503760 DOI: 10.1016/j.urology.2012.02.026] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Revised: 01/27/2012] [Accepted: 02/14/2012] [Indexed: 11/27/2022]
Abstract
OBJECTIVE To identify genomic markers that are reliable in predicting lymph node metastases in clinical stage 1 non-seminomatous germ cell tumors (NSGCTs). METHODS Comparative genomic array technology was used to identify regions of genomic amplification or deletion in clinical stage 1 NSGCTs. Twelve stage 1 mixed germ cell testicular tumors were analyzed, which were obtained from 8 patients who had no evidence of nodal metastasis when retroperitoneal lymph node dissection (RPLND) had been performed (ie, were RPLND negative) and 4 patients who had nodal metastases (ie, were RPLND positive). RESULTS Differences between the genomic alterations associated with the two classes of tumors were identified. Genomic alterations previously reported in other subtypes of testicular tumors were observed in both metastatic and nonmetastatic cases. Statistically suggestive differences in mean copy number of the Y chromosome were found between metastatic and nonmetastatic cases (P = .0142). CONCLUSION This finding suggests the presence of chromosome Y deletions to be a potential genetic marker for prediction of mixed germ cell tumor progression. This is a first step toward identifying chromosomal markers of progression in testicular cancer in clinical stage 1 mixed germ cell NSGCT.
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Affiliation(s)
- Gihan H Mohamed
- Department of Pathology, University of Texas Health Science Center, San Antonio, TX 78229, USA
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Gilbert DC, Chandler I, Summersgill B, McIntyre A, Missiaglia E, Goddard NC, Huddart RA, Shipley J. Genomic gain and over expression of CCL2 correlate with vascular invasion in stage I non-seminomatous testicular germ-cell tumours. ACTA ACUST UNITED AC 2011; 34:e114-21; discussion e121. [DOI: 10.1111/j.1365-2605.2011.01161.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Looijenga LHJ, Gillis AJM, Stoop H, Biermann K, Oosterhuis JW. Dissecting the molecular pathways of (testicular) germ cell tumour pathogenesis; from initiation to treatment-resistance. ACTA ACUST UNITED AC 2011; 34:e234-51. [PMID: 21564133 DOI: 10.1111/j.1365-2605.2011.01157.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Human type II germ cell tumours (GCTs) originate from an embryonic germ cell, either as a primordial germ cell or gonocyte. This start determines the biological as well as clinical characteristics of this type of cancer, amongst others their totipotency as well as their overall (exceptional) sensitivity to DNA damaging agents. The histology of the precursor lesion, either carcinoma in situ or gonadoblastoma, depends on the level of testicularization (i.e. testis formation) of the gonad. The impact of either intrinsic (genetic) - and environmental factors involved in the pathogenesis is demonstrated by disorders of sex development as well as testicular dysgenesis syndrome as risk factors, including cryptorchidism, hypospadias and disturbed fertility as parameters. This knowledge allows identification of individuals at risk for development of this type of cancer, being a population of interest for screening. Factors known to regulate pluripotency during embryogenesis are proven to be of diagnostic value for type II GCTs, including OCT3/4, even applicable for non-invasive screening. In addition, presence of stem cell factor, also known as KITLG, allows distinction between delayed matured germ cells and the earliest stages of malignant transformation. This is of special interest because of the identified association between development of type II GCTs of the testis and a limited number of single nucleotide polymorphisms, including some likely related to KITL. Transition from the precursor lesion to an invasive cancer is associated with gain of the short arm of chromosome 12, in which multiple genes might be involved, including KRAS2 and possibly NANOG (pseudogenes). While most precursor lesions will progress to an invasive cancer, only a limited number of cancers will develop treatment resistance. Putative explanatory mechanisms are identified, including presence of microsatellite instability, BRAF mutations, apoptosis suppression and p21 sub-cellular localization. It remains to be investigated how these different pathways integrate to each other and how informative they are at the patient-individual level. Further understanding will allow development of more targeted treatment, which will benefit quality of life of these young cancer patients.
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Affiliation(s)
- L H J Looijenga
- Department of Pathology, Erasmus MC-University Medical Center Rotterdam, Josephine Nefkens Institute, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
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Gilbert D, Rapley E, Shipley J. Testicular germ cell tumours: predisposition genes and the male germ cell niche. Nat Rev Cancer 2011; 11:278-88. [PMID: 21412254 DOI: 10.1038/nrc3021] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Testicular germ cell tumours (TGCTs) of adults and adolescents are putatively derived from primordial germ cells or gonocytes. Recently reported genome-wide association studies implicate six gene loci that predispose to TGCT development. Remarkably, the functions of proteins encoded by genes within these regions bridge our understanding between the pathways involved in primordial germ cell physiology, male germ cell development and the molecular pathology of TGCTs. Furthermore, this improved understanding of the mechanisms underlying TGCT development and dissemination has clinical relevance for the management of patients with these tumours.
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Affiliation(s)
- Duncan Gilbert
- Sussex Cancer Centre, Royal Sussex County Hospital, Eastern Road, Brighton BN2 5BE, East Sussex, UK
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