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      Predicting Gonadal Germ Cell Cancer in People with Disorders of Sex Development; Insights from Developmental Biology

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          Abstract

          The risk of gonadal germ cell cancer (GGCC) is increased in selective subgroups, amongst others, defined patients with disorders of sex development (DSD). The increased risk is due to the presence of part of the Y chromosome, i.e., GonadoBlastoma on Y chromosome GBY region, as well as anatomical localization and degree of testicularization and maturation of the gonad. The latter specifically relates to the germ cells present being at risk when blocked in an embryonic stage of development. GGCC originates from either germ cell neoplasia in situ (testicular environment) or gonadoblastoma (ovarian-like environment). These precursors are characterized by presence of the markers OCT3/4 (POU5F1), SOX17, NANOG, as well as TSPY, and cKIT and its ligand KITLG. One of the aims is to stratify individuals with an increased risk based on other parameters than histological investigation of a gonadal biopsy. These might include evaluation of defined susceptibility alleles, as identified by Genome Wide Association Studies, and detailed evaluation of the molecular mechanism underlying the DSD in the individual patient, combined with DNA, mRNA, and microRNA profiling of liquid biopsies. This review will discuss the current opportunities as well as limitations of available knowledge in the context of predicting the risk of GGCC in individual patients.

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          Testicular germ-cell tumours in a broader perspective.

          J. Wolter Oosterhuis, Leendert H. J. Looijenga (2005)
          The germ-cell tumours are a fascinating group of neoplasms because of their unusual biology and the spectacular therapeutic results that have been obtained in these tumours. Traditionally, this group of neoplasms is presented in an organ-oriented approach. However, recent clinical and experimental data convincingly demonstrate that these neoplasms are one disease with separate entities that can manifest themselves in different anatomical sites. We propose five entities, in which the developmental potential is determined by the maturation stage and imprinting status of the originating germ cell. Recent progress begins to explain the apparent unpredictable development of germ-cell tumours and offers a basis for understanding their exquisite sensitivity to therapy.
          Article 0 comments Cited 225 times – based on 0 reviews     Review now
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            Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care

            Peter A. Lee, Anna Nordenström, Christopher Houk … (2016)
            The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possible outcome improves QoL. The evolution of diagnosis and care continues, while it is still impossible to predict gender development in an individual case with certainty. Such decisions and decisions regarding surgery during infancy that alters external genital anatomy or removes germ cells continue to carry risk.
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              Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers.

              Leendert H. J. Looijenga, Stenvert Drop, Katja Wolffenbuttel … (2006)
              The risk for the development of germ cell tumors is an important factor to deal with in the management of patients with disorders of sex development (DSD). However, this risk is often hard to predict. Recently, major progress has been made in identifying gene-products related to germ cell tumor development (testis-specific protein-Y encoded and octamer binding transcription factor 3/4) and in recognizing early changes of germ cells (maturation delay, preneoplastic lesions, and in situ neoplasia). The newly recognized "undifferentiated gonadal tissue" has been identified as a gonadal differentiation pattern bearing a high risk for the development of gonadoblastoma. It is expected that the combination of these findings will allow for estimation of the risk for tumor development in the individual patient (high risk/intermediate risk/low risk). This article reviews the recent literature regarding the prevalence of germ cell tumors in patients with DSD. Some major limitations regarding this topic, including a confusing terminology referring to the different forms of intersex disorders and unclear criteria for the diagnosis of malignant germ cells at an early age (maturation delay vs. early steps in malignant transformation) are discussed. Thereafter, an overview of the recent advances that have been made in our knowledge of germ cell tumor development and the correct diagnosis of early neoplastic lesions in this patient population is provided. A new classification system for patients with DSD is proposed as a tool to refine our insight in the prevalence of germ cell tumors in specific diagnostic groups.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 10 October 2019
                Publication date Collection: October 2019
                Volume: 20
                Issue: 20
                Electronic Location Identifier: 5017
                Affiliations
                [1 ]Professor Translational Patho-Oncology, Department of Pathology, Lab. for Experimental Patho-Oncology, Erasmus MC-University Medical Center Rotterdam, and Group Looijenga, Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
                [2 ]Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; ckao2@ 123456stanford.edu
                [3 ]Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; midrees@ 123456iupui.edu
                Author notes
                [†]

                Shared last authorship.

                Author information
                https://orcid.org/0000-0002-8146-1911
                Article
                Publisher ID: ijms-20-05017
                DOI: 10.3390/ijms20205017
                PMC ID: 6834166
                PubMed ID: 31658757
                SO-VID: 8603970c-f42a-4814-84cc-96efdbaabc79
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 19 August 2019
                Date accepted : 05 October 2019
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: germ cell cancer,developmental pathogenesis,individual risk assessment,prediction,disorders of sex development
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: germ cell cancer, developmental pathogenesis, individual risk assessment, prediction, disorders of sex development

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