title: Gonadal maldevelopment as risk factor for germ cell cancer: towards a clinical decision model.
abstract: BACKGROUND
  A disturbed process of gonadal formation and maintenance may result in testicular dysgenesis syndrome or disorders of sex development (DSDs), with an increased germ cell cancer (GCC) risk. Early diagnosis and treatment requires the identification of relevant risk factors and initial pathologic stages.
  
  
  OBJECTIVE
  To evaluate current knowledge and novel insights regarding GCC risk in patients with DSDs, with the aim of providing a model for clinical use.
  
  
  METHODS
  A Medline search was conducted to identify all original and review articles assessing the aetiology of GCC, GCC risk in DSD patients, new predictive markers related to GCC, and possible clinical scenarios related to GCC and DSDs.
  
  
  RESULTS
  Embryonic development is controlled by orchestrated patterns of gene and subsequent protein expression. Knowledge of these networks is essential to understand the mechanisms of disturbed development including GCC formation. GCCs are subdivided into seminomas and nonseminomas, and they all arise from embryonic germ cells that have failed to mature appropriately. The precursor is known as carcinoma in situ (also referred to as testicular intratubular neoplasia and intratubular germ cell neoplasia unclassified) in a testicular microenvironment and gonadoblastoma in a dysgenetic/ovarian microenvironment. GCCs mimic embryonic development, resulting in the identification of diagnostic markers (eg, OCT3/4, SRY [sex determining region Y]-box 2 [SOX2], and [sex determining region Y]-box 17 [SOX17]). Novel insights indicate a subtle interplay of specific single nucleotide polymorphisms, environmental factors, and epigenetic aberrations in the aetiology of GCCs. A genvironmental model combining these factors is presented, proposed as a guideline for clinical management by an experienced multidisciplinary team. The goal is individualised treatment including preservation of gonadal function (if possible) and prevention of malignant transformation.
  
  
  CONCLUSIONS
  A hypothesis is presented in which combined interactions of epigenetic and environmental parameters affect embryonic gonadal development, resulting in delayed/blocked germ cell maturation that determines the risk for GCC formation. Current and future possibilities for early detection of GCCs in risk populations and follow-up in a clinical setting are discussed.
  
  
  RESULTS
  This review analyses current knowledge about the underlying networks that relate to the development of a germ cell cancer in the context of a disorder of sex development. A combined effect of epigenetic and environmental factors is identified in the pathogenesis, and a model is proposed to apply this knowledge to clinical practice.
authors.affiliation: Department of Pathology, Erasmus MC - University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: van der Zwan
authors.affiliation: Department of Pathology, Erasmus MC - University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Katharina
authors.initials: K
authors.lastname: Biermann
authors.affiliation: Department of Urology, Erasmus MC - Sophia, Rotterdam, The Netherlands.
authors.forename: Katja P
authors.initials: KP
authors.lastname: Wolffenbuttel
authors.affiliation: Department of Paediatrics, Ghent University Hospital, Ghent University, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Cools
authors.affiliation: Department of Pathology, Erasmus MC - University Medical Centre Rotterdam, Rotterdam, The Netherlands. Electronic address: l.looijenga@erasmusmc.nl.
authors.forename: Leendert H J
authors.initials: LH
authors.lastname: Looijenga
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood*; D012734:Disorders of Sex Development / Q000097:blood / Q000150:complications*; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D006066:Gonads / Q000002:abnormalities*; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000097:blood* / Q000209:etiology*; D050810:Octamer Transcription Factors / Q000097:blood; D012307:Risk Factors; D051876:Sex-Determining Region Y Protein / Q000097:blood
chemical_list: D014408:Biomarkers, Tumor; D050810:Octamer Transcription Factors; D051876:Sex-Determining Region Y Protein
keywords: Clinical decision guideline; DSDs; Epigenetics; GCC; Microenvironment