Development of malignant germ cells - the genvironmental hypothesis

Abstract

Human germ cell tumors are of interest because of their epidemiology, clinic and pathobiology. Histologically, they are subdivided into various elements, with similarities to embryogenesis. Recent insight triggered development of a higher order division into five types of human germ cell tumors. In the context of male germ cells, only three are relevant; Type I: teratomas and yolk sac tumors of neonates and infants; Type II: seminomas and nonseminomas of (predominantly) adolescents and adults; and Type III: spermatocytic seminomas of the elderly. Various animal models, both occurring spontaneous or induced, are reported, of which their relevance is still a matter of debate. Recent multidisciplinary studies have led to a significant increase in our understanding of the parameters involved in the earliest pathogenetic steps of human germ cells tumors, particularly the seminomas and nonseminomas (Type II). This paper will discuss a number of interesting insights into the normal and aberrant regulation of germ cell development, resulting in the so-called genvironmental hypothesis. This assumes a subtle interaction between environmental-and (epi)genetic parameters, resulting in clinical/phenotypical characteristics. These influence signaling pathways and thereby developmental processes, including gonadal development, germ cell proliferation, maturation and apoptosis. In the case of a disturbed physiology, either due to the germ cell itself, or the micro-environment, embryonic germ cells, during a specific window of sensitization, might be blocked in their maturation, resulting in carcinoma in situ or gonadoblastoma, the precursors of seminomas and nonseminomas. The level of testicularization of the gonad determines the histological composition of the precursor. These insights will allow a better definition of individuals at risk of developing a germ cell malignancy, and allow a better selection of scientific approaches to elucidate the corresponding pathogenesis.

Histological Assessment of Gonads in DSD: Relevance for Clinical Management

“…Together, these genetic and environmental risk factors are translated into a number of clinical characteristics such as family occurrence, infertility, cryptorchidism, urological anomalies, and DSD with a lifetime risk of 25% (in the presence of GBY [gonadoblastoma region on the Y chromosome], see below) [Rijlaarsdam and Looijenga, 2014]. The combined model of genetic and environmental risk factors is referred to as the genvironmental hypothesis [Looijenga et al, 2013].…”

Diagnostic markers for germ cell neoplasms: from placental-like alkaline phosphatase to micro-RNAs

“…The incidence of TGCT and some other TDS disorders have been increasing around the word, suggesting a strong environmental component in the pathogenesis, but combined with genetic susceptibility [10][11][12]. Discussion on the aetiology of TGCT and TDS exceeds the scope of this review, so the readers are referred to recent comprehensive review articles on this topic [11,13,14].…”

Histopathological pattern of gonads in cases of sex abnormalities in dogs: An attempt of morphological evaluation involving potential for neoplasia

“…A c c e p t e d M a n u s c r i p t 5 consisting of testicular and ovarian elements -the ovotestes with a frequently prevalent ovarian component [11,16]. In several cases of sex disturbances in dogs the demonstrated disturbances involved a sex reversal syndrome, with the presence of 78XX chromosomal set and the absence of SRY and/or ZFY gene [9, 12,14,22] or, less frequently, 78XY set with the presence of SRY gene [6].…”

“…In the cases of sex disturbances in humans an extensive attention is devoted to the tendency of the altered gonads to undergo neoplasia [2][3][4][5]11,17,20]. In veterinary medicine such tendency is not frequently observed.…”

“…A c c e p t e d M a n u s c r i p t 6 The problem of potential neoplasia is discussed in human medicine by several authors since disturbances in sex development are thought to represent one of the main factors of risk for the development of embryonal tumours (seminomas, dysgerminoma) and nonseminomas (embryonal carcinoma, yolk sac tumour, chorionepithelioma, teratoma) [7,11,17,20].…”