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Integrative view of the genvironmental model, with focus on genetic, cytogenetic, and epigenetic factors, which are continuously modified and conditioned by the surrounding environment, ultimately determining the cell fate and tumor progression (see text for details).
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Current (high throughput omics-based) data support the model that human (malignant) germ cell tumors are not initiated by somatic mutations, but, instead through a defined locked epigenetic status, representative of their cell of origin. This elegantly explains the role of both genetic susceptibility as well as environmental factors in the pathogen...
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Context 1
... integrated model (Figure 4) for defining TGCTs as distinct subtypes, concerning both genetic, cytogenetic, and epigenetic biomarkers, is warranted. We have showed that both DNA methylation profiles and miRs expression differ greatly among histological TGCT subtypes, and their detection in liquid biopsies has proved its use, such as miR-371a-3p. ...
Similar publications
Liquid biopsy-based biomarkers, such as microRNAs, represent valuable tools for patient management, but often do not make it to integration in the clinic. We aim to explore issues impeding this transition, in the setting of germ cell tumors, for which novel biomarkers are needed. We describe a model for identifying and validating clinically relevan...
Citations
... Extracranial pediatric germ cell tumors (eGCTs), a model of developmental tumorgenesis, are rare neoplasms occurring in different sites and ages [1]. According to data from the DKKR (Deutsches Kinderkrebsregister) from 1987 to 2011, the incidence rate is 4.8 per million (children aged <15 years). ...
GCTs are developmental tumors and are likely to reflect ontogenetic and teratogenetic determinants. The objective of this study was to identify syndromes with or without congenital anomalies and non-syndromic defects as potential risk factors. Patients with extracranial GCTs (eGCTs) registered in MAKEI 96/MAHO 98 between 1996 and 2017 were included. According to Teilum's holistic concept, malignant and benign teratomas were registered. We used a case-control study design with Orphanet as a reference group for syndromic defects and the Mainz birth registry (EUROCAT) for congenital anomalies at birth. Co-occurring genetic syndromes and/or congenital anomalies were assessed accordingly. Odds ratios and 95% confidence intervals were calculated and p-values for Fisher's exact test with Bonferroni correction if needed. A strong association was confirmed for Swyer (OR 338.6, 95% CI 43.7-2623.6) and Currarino syndrome (OR 34.2, 95% CI 13.2-88.6). We additionally found 16 isolated cases of eGCT with a wide range of syndromes. However, these were not found to be significantly associated following Bonferroni correction. Most of these cases pertained to girls. Regarding non-syndromic defects, no association with eGCTs could be identified. In our study, we confirmed a strong association for Swyer and Currarino syndromes with additional congenital anomalies.
... This differentiation block leads to the formation of testicular germ cell neoplasia in situ (GCNIS), which progresses to overt intratubular seminomas (SEM) and invasive SEM. The origin of non-seminoma tumours is less defined, as they appear to derive from the reprogramming of GCNIS or SEM to undifferentiated pluripotent embryonic carcinomas (EC), which can then differentiate into teratomas (TERA), yolk sac tumours (YST) and choriocarcinomas (CH) [4]. ...
... MiR-NAs are considered promising biomarkers for TCGTs because their expression can be specifically detected in tumour tissue and liquid biopsies, with the MIR-371-373 and MIR-302 clusters highly expressed in TGCTs [17,18] and miR371a-3p currently representing the most promising predictive biomarker [37]. Both the miR302-367 and miR371-373 clusters play critical roles in mouse gonocyte proliferation [41]; therefore, they are considered prominent oncomiRs according to the hypothesis that gonocytes represent the cells of origin of TGCTs [4]. Both clusters are also expressed in human ESCs, and their expression is regulated by pluripotency transcription factors [42]. ...
Background
Testicular germ cell tumours (TGCTs) represent a clinical challenge; they are most prevalent in young individuals and are triggered by molecular mechanisms that are not fully understood. The origin of TGCTs can be traced back to primordial germ cells that fail to mature during embryonic development. These cells express high levels of pluripotency factors, including the transcription factor NANOG which is highly expressed in TGCTs. Gain or amplification of the NANOG locus is common in advanced tumours, suggesting a key role for this master regulator of pluripotency in TGCT stemness and malignancy.
Methods
In this study, we analysed the expression of microRNAs (miRNAs) that are regulated by NANOG in TGCTs via integrated bioinformatic analyses of data from The Cancer Genome Atlas and NANOG chromatin immunoprecipitation in human embryonic stem cells. Through gain-of-function experiments, MIR9-2 was further investigated as a novel tumour suppressor regulated by NANOG. After transfection with MIR9-2 mimics, TGCT cells were analysed for cell proliferation, invasion, sensitivity to cisplatin, and gene expression signatures by RNA sequencing.
Results
For the first time, we identified 86 miRNAs regulated by NANOG in TGCTs. Among these, 37 miRNAs were differentially expressed in NANOG-high tumours, and they clustered TGCTs according to their subtypes. Binding of NANOG within 2 kb upstream of the MIR9-2 locus was associated with a negative regulation. Low expression of MIR9-2 was associated with tumour progression and MIR9-2-5p was found to play a role in the control of tumour stemness. A gain of function of MIR9-2-5p was associated with reduced proliferation, invasion, and sensitivity to cisplatin in both embryonal carcinoma and seminoma tumours. MIR9-2-5p expression in TGCT cells significantly reduced the expression of genes regulating pluripotency and cell division, consistent with its functional effect on reducing cancer stemness.
Conclusions
This study provides new molecular insights into the role of NANOG as a key determinant of pluripotency in TGCTs through the regulation of MIR9-2-5p, a novel epigenetic modulator of cancer stemness. Our data also highlight the potential negative feedback mediated by MIR9-2-5p on NANOG expression, which could be exploited as a therapeutic strategy for the treatment of TGCTs.
... Extracranial Pediatric Germ Cell tumors (eGCTs), a model of developmental tumorgenesis, are rare neoplasms, occurring in different sites and ages [1]. According to data from the DKKR (Deutsches Kinderkrebsregister) from 1987 to 2011, the incidence rate is 4.8 per million (children aged < 15 years). ...
GCTs are developmental tumors and likely to reflect ontogenetic and teratogenetic determinants. The objective was to identify syndromes with or without congenital anomalies and non-syndromic defects as potential risk factors. Patients with extracranial GCTs (eGCTs) registered in MAKEI 96/MAHO 98 between 1996 and 2017 were used. According to Teilum's holistic concept malignant and benign teratomas were registered. We used a case control study design with Orphanet as a reference group for syndromic defects and the Mainz birth registry (EUROCAT) for congenital anomalies at birth. Co-occurring genetic syndromes and/or congenital anomalies were assessed accordingly. Odds ratios and 95% confidence intervals were calculated and p-values for Fisher’s exact test with Bonferroni correction if needed. A strong association was confirmed for Swyer (OR 338.6, 95% CI 43.7-2623.6) and Currarino syndrome (OR 34.2, 95% CI 13.2-88.6). We additionally found 17 isolated cases of eGCT with a wide range of syndromes, however not significantly associated following Bonferroni correction. All these cases pertained to girls. Regarding non-syndromic defects, no association with eGCTs could be identified. In our study we confirmed a strong association for Swyer and Currarino syndromes with additional congenital anomalies.
... Interestingly, in the male population, a similar frequency of occurrence was observed for seminoma and mature teratoma, a unique finding of our study. The distribution of GCT by anatomic sites found in our study is comparable to what have been reported from studies conducted in Nigeria (1,32) and other parts of the world (33,34) An earlier study in Zaria recorded the sacrococcygeal region as the most common site ( 4 3 . 6 % ) , f o l l o w e d b y c e r v i c a l r e g i o n a n d retroperitoneal space (35) Edegbe et al also found the most frequent sites to be the sacrococcygeal region (20.5%) and neck (10.3%) in the Ibadan series (8), while Tapper and Lack reported a frequency of 40% and 5.5% for sacrococcygeal and head and neck tumors respectively in the Boston series (36). ...
... Interestingly, an axial distribution has been consistently displayed by GCT reported in the neck (37,38), nose (37,38), sacrococcygeal region (40,41), orbit (42), brain, mediastinum, retroperitoneum and vagina (43). This can be explained by the migration of primordial germ cells along the midline from the yolk sac, via the hindgut and towards the genital ridge in embryonal life (8,33). Remarkably, the Five-year survival has been found to be better for gonadal GCT than for the extragonadal disease (44). ...
... While type V of the tumor consists of a complete cystic drift (a benign form of gestational trophoblastic disease), VI type occurs in people of over 60 years of age and resembles type 1 localized in atypical areas, such as soft tissues of the extremities. 5,6 Mature and immature teratomas are almost always benign, regardless of localization. The prognosis may be unfavorable if they are not completely removed. ...
The purpose of this study was to analyze the outcomes of extracranial GCT in children in a developing country and to assess prognostic factors. The data on 141 children (<18 years old) with extracranial GCT, confirmed histopathologically, collected over the past 9 years (from February 2013 to June 2022) were retrospectively studied. The patients underwent the same therapy with platinum-containing chemotherapy regimens. In the malignant GCT group, OS and EFS were 81.0 ± 4% and 73 ± 5%, respectively. OS and EFS in the teratoma group were 90 ± 5% and 85 ± 6%. In univariate analysis, parameters like stage of disease, tumor localization, AFP level ≥10,000 ng/mL, serum AFP kinetics and resection status were found to be statistically significant prognostic factors. In the multivariate analysis, the significant adverse factors were the resection status, initial AFP level ≥10,000 ng/mL and serum AFP kinetics slow down (p = .000). Good survival rates can be achieved in developing countries with adequate compliance with treatment protocols. The analysis demonstrates high efficacy of platinum-containing chemotherapy regimens. In our opinion, the protocol used in high-income countries can be implemented in low-income countries with the financial support from the government. The qualification of specialists is also important.
... Testicular germ cell tumors (TGCTs) are the most common cancers among males aged 15 to 45, and are a disease of developmental origin arising from aberrant primordial germ cells/gonocytes in utero [15]. TGCTs have very few mutations [16]. ...
... TGCTs have very few mutations [16]. This suggests that epigenetic mechanisms play an important role in the etiology and biology of TGCTs [15,17]. Epidemiologic studies have indicated that the fetal gonads may be especially sensitive to pro-estrogenic and anti-androgenic insults [18][19][20][21]. ...
... These cisplatin-resistant cells were included as we have previously shown that their cisplatin resistance is driven by epigenetic alterations which is a suspected mechanism of PFAS action [13,31]. Cisplatin is the main treatment for TGCTs and cisplatin resistance is a clinical problem [15]. Cells were maintained in Dulbecco's Modified Eagle Medium with 10% fetal bovine serum (GeminiBio, Sacramento, CA, USA), 1% antibiotic/antimycotic (Corning, Corning, NY, USA), and 1% L-glutamine (Corning, Corning, NY, USA). ...
The potential effects of poly- and perfluoroalkyl substances (PFAS) are a recently emergent human and environmental health concern. There is a consistent link between PFAS exposure and cancer, but the mechanisms are poorly understood. Although epidemiological evidence supporting PFAS exposure and cancer in general is conflicting, there is relatively strong evidence linking PFAS and testicular germ cell tumors (TGCTs). However, no mechanistic studies have been performed to date concerning PFAS and TGCTs. In this report, the effects of the legacy PFAS perfluorooctanesulfonic acid (PFOS) and the newer “clean energy” PFAS lithium bis(trifluoromethylsulfonyl)imide (LiTFSi, called HQ-115), on the tumorigenicity of TGCTs in mice, TGCT cell survival, and metabolite production, as well as gene regulation were investigated. In vitro, the proliferation and survival of both chemo-sensitive and -resistant TGCT cells were minimally affected by a wide range of PFOS and HQ-115 concentrations. However, both chemicals promoted the growth of TGCT cells in mouse xenografts at doses consistent with human exposure but induced minimal acute toxicity, as assessed by total body, kidney, and testis weight. PFOS, but not HQ-115, increased liver weight. Transcriptomic alterations of PFOS-exposed normal mouse testes were dominated by cancer-related pathways and gene expression alterations associated with the H3K27me3 polycomb pathway and DNA methylation, epigenetic pathways that were previously showed to be critical for the survival of TGCT cells after cisplatin-based chemotherapy. Similar patterns of PFOS-mediated gene expression occurred in PFOS-exposed cells in vitro. Metabolomic studies revealed that PFOS also altered metabolites associated with steroid biosynthesis and fatty acid metabolism in TGCT cells, consistent with the proposed ability of PFAS to mimic fatty acid-based ligands controlling lipid metabolism and the proposed role of PFAS as endocrine disrupters. Our data, is the first cell and animal based study on PFAS in TGCTs, support a pro-tumorigenic effect of PFAS on TGCT biology and suggests epigenetic, metabolic, and endocrine disruption as potential mechanisms of action that are consistent with the non-mutagenic nature of the PFAS class.
... There is evidence that suggests that TGCTs imitate embryonic development to a certain extent, retaining the molecular and biochemical characteristics of embryonic stem cells (ESCs). ESCs are a type of stem cell known for their continuous growth, pluripotency, and self-renewal capacity [23]. Notably, ESCs express specific clusters of miRNAs, particularly miR-371-3 and miR-302/367, which play important roles in pluripotency and differentiation. ...
Testicular germ cell tumors (TGCTs) are relatively common in young men, making accurate diagnosis and prognosis assessment essential. MicroRNAs (miRNAs), including microRNA-371a-3p (miR-371a-3p), have shown promise as biomarkers for TGCTs. This review discusses the recent advancements in the use of miRNA biomarkers in TGCTs, with a focus on the challenges surrounding the noninvasive detection of teratomas. Circulating miR-371a-3p, which is expressed in undifferentiated TGCTs but not in teratomas, is a promising biomarker for TGCTs. Its detection in serum, plasma, and, potentially, cystic fluid could be useful for TGCT diagnosis, surveillance, and monitoring of therapeutic response. Other miRNAs, such as miR-375-3p and miR-375-5p, have been investigated to differentiate between TGCT subtypes (teratoma, necrosis/fibrosis, and viable tumors), which can aid in treatment decisions. However, a reliable marker for teratoma has yet to be identified. The clinical applications of miRNA biomarkers could spare patients from unnecessary surgeries and allow for more personalized therapeutic approaches. Particularly in patients with residual masses larger than 1 cm following chemotherapy, it is critical to differentiate between viable tumors, teratomas, and necrosis/fibrosis. Teratomas, which mimic somatic tissues, present a challenge in differentiation and require a comprehensive diagnostic approach. The combination of miR-371 and miR-375 shows potential in enhancing diagnostic precision, aiding in distinguishing between teratomas, viable tumors, and necrosis. The implementation of miRNA biomarkers in TGCT care could improve patient outcomes, reduce overtreatment, and facilitate personalized therapeutic strategies. However, a reliable marker for teratoma is still lacking. Future research should focus on the clinical validation and standardization of these biomarkers to fully realize their potential.
... The 6.5-to 7.0-day-old epiblast carries the genetic and epigenetic information necessary for germline specification. According to researchers, PGC specification involves three key events: (i) repression of somatic programming, (ii) regaining of pluripotency, and (iii) genomewide epigenetic reprogramming [110,111]. Primordial PGCs, which are precursors of various maturation stages of germ cell lineages, undergo a process of proliferation and migration from the yolk sac through the hindgut toward the genital ridge, where subsequent sex determination occurs [112]. However, they can also migrate further along the midline of the body, which explains the emergence and topography of extragonadal germ cell tumors (GCTs). ...
... Lobo et al. [111] also argue for non-mutagenic evolution. More than 95% of testicular neoplasms originate from germ cells arrested in their differentiation. ...
... The 6.5-to 7.0-dayold epiblast carries the genetic and epigenetic information necessary for germline specification. According to researchers, PGC specification involves three key events: (i) repression of somatic programming, (ii) regaining of pluripotency, and (iii) genome-wide epigenetic reprogramming [106,107]. Primordial PGCs, which are precursors of various maturation stages of germ cell lineages, undergo a process of proliferation and migration from the yolk sac through the hindgut toward the genital ridge, where subsequent sex determination occurs [108]. However, they can also migrate further along the midline of the body, which explains the emergence and topography of extragonadal germ cell tumors (GCTs). ...
... Lobo et al. also argue for non-mutagenic evolution [107]. More than 95% of testicular neoplasms originate from germ cells arrested in their differentiation. ...
... Consequently, the mutagenic theory, which suggests that mutations are solely responsible for malignant transformation, is increasingly being challenged. This challenge is supported by a growing body of evidence in the field of cell biology [105,107,[109][110][111]115,116]. ...
Background: One of the most astounding discoveries of recent times is the recognition that cancer embodies a transition from a higher level of metazoan cell organization to a more foundational pre-metazoic state. This shift is steered by genes housed within the ancestral genome compartment, pervasive across all metazoan genomes, encompassing humans, and governed by a pre-metazoic gene regulatory mechanism (aGRN). This work aims to highlight the emerging field of evolutionary cancer cell biology (ECCB), which points to the deep homology between cancer and protist life cycles tracing back to the common ancestor of amoebozoans, metazoans, and fungi (AMF). The ECCB analysis reveals the essence of the non-gametogenic germline of the AMF ancestor, which serves as a blueprint for all metazoan germlines and stem cell lineages and controls the life cycle of cancer. Every germ and stem cell lineage of humans and metazoans traces its lineage back to this Urgermline, transmitting crucial processes such as asymmetric cell cycling, differentiation, stemness, and phenomena like GST and SGT (aka EMT and MET) to their subsequent evolutionary descendants. Oxygen-sensitive germline and stem cells suffer DNA-DSB due to stress and oxygen ranges reminiscent of ancestral hyperoxia, leading to cell senescence. Cells that can overcome senescence can proliferate as DSCD cells with defective symmetric cell division, paving the way for malignancy and PGCC cancers. Conclusions: Understanding cancer from its evolutionary origins may help break some of the logjams in cancer prevention and open up new therapeutic pathways.
... The genesis of TGCTs could be driven by genetic factors, but environmental factors is also suspected to influence malignant transformation (Litchfield et al., 2017;Lobo et al., 2019). Due to the putative carcinogenesis and strong association with other reproductive disorders, environmental endocrine disrupting compounds (EDCs) have been blamed for the rise in testicular cancers (Ghazarian et al., contain bisphenol A (BPA). ...
Testicular cancer is an increasing burden in modern societies and the most common malignancy among young adult males. Environment contaminants, especially endocrine disrupting compounds (EDC), may play a significant role in the development of these cancers through epigenetic alterations occurring during fetal and neonatal development. As long-term studies in humans and suitable experimental models with the potential to develop testicular cancer are lacking, no causal link can be established between endocrine disruptor exposure and testicular cancer incidence. Therefore, we developed an experimental model that recapitulates the differentiation of germ cells from primordial germ cells (pluripotency) into spermatocytes (meiosis) by using xenografted human fetal testis combined with germ cell transplantation into adult testis compartments. Using this model, we demonstrate that long-term fetal exposure (until 12 weeks) to a mixture of Di-2-ethylhexylphthalate (DEHP) and Bisphenol A (BPA), two most prevalent plasticizers, could interfere with fetal germ cell differentiation, leading to carcinogenesis and seminomas. Transcriptome, methylome, and histological analyses reveal that BPA/DEHP exposure induced some significant hallmarks of germ cell tumors to occur: persistent pluripotent and proliferative germ cells, global hypomethylation of CpGs in germ cells, abnormal expression of meiotic markers and fibrotic signatures in fetal testis. Additionally, we found that EDC-exposed fetal germ cells were more likely to develop seminoma in a context that allows spermatogenesis to begin. This study proposes the first experimental evidence that EDC exposure can cause long-term, irreversible lesions in fetal germ cells, which then lead to testicular tumorigenesis in adults.
