Materiały źródłowe

• #1 Molecular and epigenetic pathogenesis of germ cell tumors

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8099689/

  The development of germ cell tumors (GCTs) is a unique pathogenesis occurring at an early developmental stage during specification, migration or colonization of primordial germ cells (PGCs) in the genital ridge. […] Since driver mutations could not be identified so far, the involvement of the epigenetic machinery during the pathogenesis seems to play a crucial role. […] Currently, it is investigated whether epigenetic modifications occurring between the omnipotent two-cell stage and the pluripotent implanting PGCs might result in disturbances eventually leading to GCTs. […] Although progress in understanding epigenetic mechanisms during PGC development is ongoing, little is known about the complete picture of its involvement during GCT development and eventual classification into clinical subtypes.

• #1 Molecular Biology of Pediatric and Adult Male Germ Cell Tumors

  https://www.mdpi.com/2072-6694/13/10/2349

  Curiously, the pathogenesis of TGCT begins in utero during embryogenesis, when embryonic stem cells give rise to the primordial germ cells in the genital crest present in the midline of the embryo. […] Pathogenesis differs in some aspects of differentiation, histogenesis, and genomic instability between adults and children. Primordial germ cells are the most implicated in studies on the tumorigenesis of germ cell tumors, and due to their totipotent nature, TGCTs have a wide range of possible histologies. In Type I TGCTs, prepubertal teratomas, as benign tumors, have limited developmental potential and may arise during the migration of primordial germ cells. However, the chromosomal loss of 1p, 4, and 6q, in addition to 1q, 12, 20q, and 22, are implicated in the development of malignant YSTs, the histology most frequently found in testicular tumors in childhood.

• #1 Genome Wide DNA Methylation Profiles Provide Clues to the Origin and Pathogenesis of Germ Cell Tumors | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122146

  The cell of origin of the five subtypes (I-V) of germ cell tumors (GCTs) are assumed to be germ cells from different maturation stages. This is (potentially) reflected in their methylation status as fetal maturing primordial germ cells are globally demethylated during migration from the yolk sac to the gonad. […] Germ cell tumors (GCT) originate from germ cells at different developmental stages and are thought to inherit their methylation profile from their ancestors. The WHO classification supports five GCT subtypes. Each subtype has specific molecular, clinical and histopathological properties. […] This study aims to identify specific and global differences between the genome-wide methylation profiles of GCT subtypes. Type I, II, III and IV GCTs and four cell lines representative of type II GCTs are investigated. Differences in methylation profile provides insight into the developmental timing and underlying biology of GCTs.

• #1

  https://journals.lww.com/ajandrology/fulltext/2015/17030/etiology_and_early_pathogenesis_of_malignant.6.aspx

  Malignant testicular germ cell tumors (TGCT) are the most frequent cancers in Caucasian males (20-40 years) with an 70% increasing incidence the last 20 years, probably due to combined action of (epi)genetic and (micro)environmental factors. […] It is expected that TGCT have carcinoma in situ (CIS) as their common precursor, originating from an embryonic germ cell blocked in its maturation process. […] The origin of TGCT probably starts at early embryogenesis, and is hypothesized to be part of the Testicular Dysgenesis Syndrome (TDS). […] This impaired testicular development means that some early PGC/gonocytes are blocked in their process of differentiation, and as such, these germ cells retain their early (embryonic) marker profile. […] The reason for this development block is not yet entirely clear. It is probably a combination of (micro)environmental factors and (epi)genetic defects.

• #1 Germ cell tumor – Wikipedia

  https://en.wikipedia.org/wiki/Germ_cell_tumor

  A germ cell tumor (GCT) is a neoplasm derived from primordial germ cells. Germ-cell tumors can be cancerous or benign. Germ cell tumors typically originate from the gonads (ovary and testis), but can arise in other areas of the body. Extragonadal GCTs are thought to result from abnormal migration of germ cell precursors during development of the embryo. […] Extragonadal GCTs were thought initially to be isolated metastases from an undetected primary tumor in a gonad, but many germ cell tumors are now known to be congenital and originate outside the gonads. The most notable of these is sacrococcygeal teratoma, the single most common tumor diagnosed in babies at birth. […] Males with Klinefelter syndrome have a 50 times greater risk of GSTs. In these persons, GSTs usually contain nonseminomatous elements, present at an earlier age, and seldom are gonadal in location.

• #1 Molecular and epigenetic pathogenesis of germ cell tumors

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8099689/

  Misrouting of PGCs and failures in downregulating the pluripotency program could lead to type I GCTs. […] The testicular dysgenesis syndrome and formation of GCNIS TDS results from disturbed hormonal microenvironmental factors during fetal development. […] TDS is related to TGCT development. […] Impaired Sertoli and Leydig cell function are not the only triggers leading to GCNIS formation. […] TFAP2C expression is associated with a PGC-like cell fate. […] TFAP2C in GCTs allows maintenance of a latent pluripotent state this review. […] SOX2 and SOX17 share a common set of overlapping target genes, such as NANOG, OTX2, PIM1/2, PRDM14, DPP4, TDGF1, LIN28A, and TRIM71. […] Epigenetic re-arrangements might contribute to SOX17 target gene accessibility including GC-fate and pluripotency genes in PGCs this review.

• #1 Molecular Biology of Pediatric and Adult Male Germ Cell Tumors

  https://www.mdpi.com/2072-6694/13/10/2349

  In Type II TGCTs, primordial germ cells and gonocytes may fail to be differentiated in spermatogonia, and the early onset of polyploidization coupled with OCT3/4 switch off failure and changes in genomic imprinting leads to germ cell neoplasia in situ (GCNIS). The GCNIS pathway is the origin of seminomatous and non-seminomatous TGCTs in adolescents and adults. This pre-invasive precursor of malignant tumors is histologically observed adjacent to normal tissue and is composed of undifferentiated germ cells that proliferate within a seminiferous tubule driven by the testis-specific Y-encoded protein (TSPY). […] GCNIS commonly progresses to seminomas, and GCNIS and seminomas are able to reprogram the pluripotent embryonal carcinoma, the malignant counterpart of embryonal stem cell. […] Differentiation steps lead to the emergence of other histologies from embryonal carcinoma, such as postpubertal teratoma, YST, and choriocarcinoma.

• #1 Etiology and early pathogenesis of malignant testicular germ cell tumors: towards possibilities for preinvasive diagnosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4430936/

  The reason for this development block is not yet entirely clear. […] It is probably a combination of (micro)environmental factors and (epi)genetic defects. […] For the onset of CIS and the development of CIS into an invasive tumor, there is likely an interplay between genetic, epigenetic, and (micro)environmental factors also referred as the genvironment. […] Key aspects of the etiology of TGCT were discovered in the past few years. […] Many of these genes are involved in the early gonadal development, which explains their involvement in the pathogenesis of CIS. […] Prenatal, perinatal, and postnatal risk factors also influence the onset of CIS. […] These genetic and environmental factors play an essential role in the pathogenesis of TGCT but are individually insufficient to identify men at high risk for TGCT. […] Further research is needed to develop a well-defined TGCT risk profile, based on environmental interactions, and a noninvasive detection method, in which the miRNA detection in semen seems to be very promising.

• #1 Human Germ Cell Tumors are Developmental Cancers: Impact of Epigenetics on Pathobiology and Clinic

  https://www.mdpi.com/1422-0067/20/2/258

  Importantly, a model of true interplay between environmental and genetic factors is the most likely scenario in TGCTs the ‘genvironment’. […] This model fits TGCTs genesis and places epigenetic deregulation as the perfect culprit mechanism for mediating this environment-genetics interaction and for explaining clinical findings that compose the TDS and that associate with increased risk of TGCTs. […] An interplay between the aforementioned genetic and environmental factors has been demonstrated to occur in various studies on TGCTs, with epigenetics serving as a bridge between these two aspects of the disease. […] This is illustrated, for instance, by the spectrum of clinical manifestations that is TDS. […] The first attempt to classify the various subtypes of TGCTs was accomplished by Friedman and Moore in 1946, when they organized tumors into four groups: SEs, embryonal carcinomas (ECs), teratomas (TEs), and teratocarcinomas.

• #1 Origins and molecular biology of testicular germ cell tumors | Modern Pathology

  https://www.nature.com/articles/3800309

  Testicular germ cell tumors can be divided into three groups (infantile/prepubertal, adolescent/young adult and spermatocytic seminoma), each with its own constellation of clinical histology, molecular and clinical features. […] The most common testicular cancers arise in postpubertal men and are characterized genetically by having one or more copies of an isochromosome of the short arm of chromosome 12 [i(12p)] or other forms of 12p amplification and by aneuploidy. […] The consistent gain of genetic material from chromosome 12 seen in these tumors suggests that it has a crucial role in their development. […] Several factors have been associated with their pathogenesis, including cryptorchidism, elevated estrogens in utero and gonadal dysgenesis. […] The pathogenesis of prepubertal GCT and SS is poorly understood.

• #1 Germ Cell Tumors

  https://www.csh.org.tw/dr.tcj/educartion/f/web/Germ%20cell%20tumor/index.htm

  Recent studies of GCTs have suggested that cyclin D2 is overexpressed in malignant germ cells and is oncogenic. […] GCT differentiation may be influenced by several interacting pathways, such as regulators of germ-cell totipotentiality, embryonic development, and genomic imprinting. Sensitivity and resistance to chemotherapy may be based in part on a p53-dependent apoptotic pathway. […] Almost 100% of tumors show increased copy number of 12p. This chromosomal marker has been noted in carcinoma in situ (CIS), suggesting that it is one of the early changes associated with the origin of GCT. CIS is considered to be a precursor of all GCTs. […] Model 1: Fetal gonocytes that escape normal development into spermatogonia undergo abnormal cell division and proliferation. These gonocytes are prone to invasive growth, mediated by postnatal and pubertal gonadotrophin stimulation.

• #1 Testicular germ cell tumors: pathogenesis, diagnosis and treatment | Nature Reviews Endocrinology

  https://www.nature.com/articles/nrendo.2010.196

  Testicular germ cell tumors represent the most common solid malignancy of young men aged 15-40 years. […] The pathogenesis of testicular germ cell tumors remains unknown; however, cryptorchidism is the main risk factor, and molecular studies have shown strong evidence of an association between genetic alterations and testicular germ cell tumors. […] Molecular events in germ cell tumours: linking chromosome-12 gain, acquisition of pluripotency and response to cisplatin.

• #1 Testicular germ cell tumors: the changing role of the pathologist

  https://atm.amegroups.org/article/view/26967/html

  Testicular germ cell tumors (TGCTs) are a heterogeneous group of neoplasms derived from neoplastic transformation of germ cells in the testis, but with different epidemiological, biological and clinical settings, from early life to adulthood. […] In the latest years, several studies led to a deeper understanding of the genetic and biological events characterizing the development and progression of these neoplasms, at the basis of their divergent clinical behaviour. […] The latest WHO classification of TGCTs assigns a primary taxonomic role to germ cell neoplasia in situ (GCNIS), which is considered the main precursor lesion of TGCTs. […] The distinction of TGCTs in GCNIS-related forms and GCNIS-unrelated forms reflects underlying pathogenetic differences. […] In fact, GCNIS-related TGCTs are associated with aneuploidy or triploidy, gain of chromosomes X, 7, 8, 12p, 21 and loss of chromosomes Y, 1p, 11, 13, 18; rarely, mutation of KIT, K-RAS and TP53 are found.

• #1 Molecular Biology of Pediatric and Adult Male Germ Cell Tumors

  https://www.mdpi.com/2072-6694/13/10/2349

  Type III TGCTs are represented by spermatocytic tumors and are more common in patients older than 50 years of age. They arise from differentiated spermatogonia, and the most important event in the oncogenesis appears to be the tumor-specific gain of chromosome 9 and, less frequently, mutations in HRAS and FGFR3. […] Although most studies have evaluated the biology and molecular changes in adults, and there is a lack of information in children, the molecular mechanisms involved in the development of adult TGCTs are beginning to be defined, and share significant differences and similarities with pediatric GCTs. The search for cytogenetic alterations, epigenetics, and events related to resistance has been explored in TGCTs. In this study, we review the molecular aspects of TGCTs, drawing a parallel between the findings in the adult and pediatric groups.

• #1 Human Germ Cell Tumors are Developmental Cancers: Impact of Epigenetics on Pathobiology and Clinic

  https://www.mdpi.com/1422-0067/20/2/258

  Type II GCTs are always malignant. […] Type II TGCTs are the most common malignancies in Caucasian males aged between 25 and 45 years-old in Western populations; of these, slightly more than 50% are pure SEs, the second most common being mixed tumors. […] Also, they are consistently peritriploid, being characterized by gains of the short arm of chromosome 12 (frequently in the form of isochromosome 12p, [i(12p)]). […] Polyploidization, in addition to a hypomethylated genome, contribute to chromosomal instability in these neoplasms, which further drives tumor progression. […] However, mutations and amplifications of oncogenes are rather rare in TGCTs, with KIT mutation being the most common, especially in SEs and in bilateral cases. […] In fact, recent work by Dorssers et al. has showed, by use of whole genome and targeted-sequencing, that NSTs are initiated by genome duplication, followed by chromosome copy number alterations in cancer stem cells, with very low accumulation of somatic mutations, even in cases resistant to therapy.

• #1 Genomic Evaluation of Testicular Germ Cell Tumors and its Role in Treatment Planning – Bulletin of Urooncology

  https://uroonkolojibulteni.com/articles/genomic-evaluation-of-testicular-germ-cell-tumors-and-its-role-in-treatment-planning/doi/uob.1101

  The association between TGCT and various anomalies (polyploidization, amplification, etc.) in chromosome 12 has been known for many years. Gains in chromosome 12 and formation of i(12p) on karyotype analysis in many TGCT specimens (nearly 80%) was the first genetic marker discovered in TGCT. […] The KIT gene is located at the 4q12 chromosomal region and belongs to the receptor tyrosine kinase family. It plays crucial roles in cell survival and proliferation and is well characterized in TGCT. […] Single nucleotide polymorphisms (SNPs) in the KITLG gene, which is the ligand for the KIT receptor tyrosine kinase, are associated with a 2.5-fold increased TGCT risk. […] GWAS for TGCT have revealed high telomerase activity in seminoma due to reactivation of TERT gene, which encodes the catalytic subunit of telomerase reverse transcriptase and protects from shorten the chromosomal ends in somatic cells, while this activity was low in teratomas.

• #1 Advances in genetic abnormalities, epigenetic reprogramming, and immune landscape of intracranial germ cell tumors | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-023-01682-y

  Intracranial germ cell tumors (IGCTs) are a rare subtype of central nervous system neoplasms that predominantly affect young individuals and exhibit a higher incidence in East Asia. […] Despite the low incidence of IGCTs and significant variation in incidence rates worldwide, there exists a relatively small body of basic research on IGCTs, with a considerable portion originating from Japan. In recent years, with the rapid development of molecular biology techniques such as next-generation sequencing (NGS), research into the pathogenesis and pathological characteristics of IGCTs has been actively pursued. Genomic mutation spectrum and copy number analyses have revealed the importance of the KIT/RAS/MAPK and PI3K/AKT/mTOR pathways in the pathogenesis of IGCTs. […] In summary, current research indicates that the genetic driving factors of IGCTs pathogenesis primarily involve the KIT/RAS/MAPK and PI3K/AKT/mTOR pathways. Gene mutations within the MAPK pathway, such as KIT and RAS, are mutually exclusive, while mTOR represents the most common mutation within the PI3K/AKT/mTOR pathway.

• #1 Testicular Cancer: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/279007-overview

  Malignant transformation of germ cells is the result of a multistep process of genetic changes. One of the earliest events is the increased copy number of 12p, either as 1 or more copies of i(12p) or as tandem duplications of chromosome arm 12p. This abnormality is found in occult carcinoma in situ lesions as well as more advanced disease. Further studies indicate that CCND2 is present at chromosome band 12p13 and that CCND2 is overexpressed in most germ cell tumors, including carcinoma in situ. Amplification of CCND2 activates cdk4/6, allowing the cell to progress through the G1-S checkpoint.

• #1 Germ Cell Tumor – Creative Diagnostics

  https://www.creative-diagnostics.com/resources/germ-cell-tumor.htm

  GDNF signaling pathway is closely related to the pathogenesis of testicular germ cell tumors. […] In this pathway, GDNF binds to its receptor GFRA to form a complex, which then binds to Ret to activate the downstream cascade, affecting the proliferation and differentiation of germ cells. […] Moreover, cAMP/PKA, ERK1/2, PI3K/Akt, and mTORC1/p70SK6 pathways have been demonstrated to be the main signal transduction pathways involved in Sertoli cell proliferation. […] c-Myc and hypoxia inducible factor are transcription factors that participate in the induction by FSH of various genes of relevance in cell cycle progression.

• #1 Human Germ Cell Tumors are Developmental Cancers: Impact of Epigenetics on Pathobiology and Clinic

  https://www.mdpi.com/1422-0067/20/2/258

  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 pathogenesis, referred to as ‘genvironment’. […] Moreover, it could also explain various epidemiological findings, including the rising incidence of this type of cancer in Western societies. […] The current status of these findings will be discussed, including the use of high throughput DNA methylation profiling for determination of differentially methylated regions (DMRs) as well as chromosomal copy number variation (CNV). […] Finally, the potential value of methylation-specific tumor DNA fragments (i.e., XIST promotor) as well as embryonic microRNAs as molecular biomarkers for cancer detection in liquid biopsies will be presented.

• #1 Childhood Central Nervous System Germ Cell Tumors Treatment (PDQ®) – NCI

  https://www.cancer.gov/types/brain/hp/child-cns-germ-cell-treatment-pdq

  Global hypomethylation that mirrors primordial germ cells in early development has also been observed in CNS GCTs. […] In an evaluation of 21 cases of CNS germinomas diagnosed between 2000 and 2016, programmed death-ligand 1 (PD-L1) and programmed cell death-1 (PD-1) expression was assessed by immunohistochemistry. Ninety percent of germinomas had germ cell components that stained positively for PD-L1. In addition, tumor-associated lymphocytes stained positive for PD-L1 in more than 75% of cases.

• #1 Involvement of epigenetic modifiers in the pathogenesis of testicular dysgenesis and germ cell cancer

  https://www.degruyter.com/document/doi/10.1515/bmc-2015-0006/html?lang=en

  The epigenetic state of CIS cells shows high similarity to the epigenetic patterns found in fetal germ cells. […] Moreover, CIS cells show high levels of H4/H2AR3me2 along with expression of BLIMP1/PRMT5, which are thought to repress HOX genes and somatic differentiation programs. […] In summary, adult totipotent CIS cells retain a fetal germ-cell-like epigenetic profile that, after malignant transformation, evolves into distinct signatures reflecting the tumor types. […] Epigenetic regulation is a dynamic process where modifications like methyl-groups are not only added to DNA and histones but are also actively removed by demethylases with different specificity. […] Jumonji C domain-containing proteins play important regulatory roles during fetal gonadal development by regulating histone lysine methylation marks of, e.g. the Sry promoter in somatic gonadal cells.

• #1 Molecular and epigenetic pathogenesis of germ cell tumors

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8099689/

  The influence of microenvironmental components and BMP-inhibiting factors could directly differentiate SE into EC. […] Summarizing, so far not enough is known about the interaction between the microenvironment and PGCs and how disturbances could result in misguided or miscolonized PGCs eventually leading to TGCTs. […] Nevertheless, it seems that it is rather colonization than migration being influenced by factors, such as chemokines and cytokines, which are secreted by surrounding Sertoli, Leydig, and immune cells or the ECM.

• #1 Molecular and epigenetic pathogenesis of germ cell tumors

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8099689/

  We questioned how misguided migrating and/or colonizing PGCs develop to either type I or type II GCTs. […] Additionally, we asked how pluripotency can be regulated during PGC development and which epigenetic changes contribute to GCT pathogenesis. […] We propose that SOX2 and SOX17 determine either embryonic stem cell-like (embryonal carcinoma) or PGC-like cell fate (seminoma). […] Finally, we suggest that factors secreted by the microenvironment, i.e. BMPs and BMP inhibiting molecules, dictate the fate decision of germ cell neoplasia in situ (into seminoma and embryonal carcinoma) and seminomas (into embryonal carcinoma or extraembryonic lineage), indicating an important role of the microenvironment on GCT plasticity. […] The surrounding tissue and extracellular matrix might influence BMP and WNT signaling pathways this review.

• #1 Central Nervous System Germinoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/281714-overview

  The cell of origin of CNS GCTs remains controversial. The germ cell theory postulates that these tumors arise from primordial germ cells that have migrated aberrantly during embryonic development and subsequently undergone malignant transformation. Evidence in support of this theory includes a genome-wide methylation profiling study of 61 GCTs that found pure germinomas are characterized by global low DNA methylation, a unique epigenetic feature making them distinct from all other GCT subtypes. The patterns of methylation strongly resemble that of primordial germ cells (PGC) at the migration phase, possibly indicating the cell of origin for these tumors. […] In contrast, the embryonic cell theory suggests that GCTs arise from a mismigrational pluripotent embryonic cell. It has also been postulated that pure germinomas arise from germ cells whereas mixed NGGCTs result from misfolding and misplacement of embryonic cells into the lateral mesoderm, causing these cells to become entrapped in different areas of the brain. […] Current evidence suggests that GCTs arise from germinal elements at various stages of development.

• #1 Central Nervous System Germinoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/281714-overview

  Intracranial GCTs express the germ cell-specific proteins MAGE-A4, NY-ESO-1, and TSPY, which are associated with embryonic stem cell pluripotency. This indicates that GCTs may originate from primordial germ cells. […] Studies of malignant testicular tumors have shown that the most common chromosomal abnormality is an isochromosome of the short arm of chromosome 12 (i[12p]). Chromosomal comparison of CNS GCTs with gonadal tumors using genomic hybridization analysis has found the two to be essentially identical. […] In children, cytogenetic abnormalities include loss of 1p and 6q, alterations in sex chromosomes, and abnormalities in 12p. A study in children revealed that a subset of patients with pineal tumors demonstrated a gain of chromosomal material at 12p. […] The most common chromosomal imbalance comprises gains of 1p, 8p, and 12q and losses of 13q and 18q. […] Increased copies of the X chromosome are seen in CNS GCTs; the most frequent genotype abnormality is XXY, similar to that in Klinefelter syndrome. Individuals with Klinefelter syndrome are prone to develop intracranial GCTs, as are those with Down syndrome and those with neurofibromatosis type 1. […] Frequent alterations of the p14 gene have been detected, especially in intracranial pure germinomas, suggesting that this gene plays an important role in the development of these tumors. Mutations of the c-kit gene have been found in 23-25% of intracranial germinomas. […] These mutations are believed to promote the development of intracranial GCTs. C-myc and N-myc amplifications have been seen in a minority of tumors.

• #1 Pathogenesis of intracranial germ cell tumors reconsidered in: Journal of Neurosurgery Volume 90 Issue 2 (1999) Journals

  https://thejns.org/view/journals/j-neurosurg/90/2/article-p258.xml

  Object. To determine the pathogenesis of intracranial germ cell tumors (GCTs), the author studied 153 cases of these tumors encountered through 1994, 62.7% of which showed monotypic histological patterns and 37.3% of which were shown to be mixed tumors. […] Germ cell tumors other than germinomas may not originate from one single type of cell (primordial germ cells). The embryonic cells of various stages of embryogenesis may perhaps be misplaced in the bilaminar embryonic disc at the time of the primitive streak formation, becoming involved in the stream of lateral mesoderm and carried to the neural plate area to become incorrectly enfolded into the brain at the time of neural tube formation. The author propounds the following hypothesis: tumors composed of cells resembling the cells that appear in the earlier stages of embryogenesis (ontogenesis) are more malignant than those composed of cells resembling the cells that appear in the later stages of embryogenesis.

• #1 Origins and molecular biology of testicular germ cell tumors | Modern Pathology

  https://www.nature.com/articles/3800309

  Some have suggested performing testicular biopsies in an attempt to identify IGCNU, which has been reported in up to 4% of cases. […] Patients with various intersex syndromes are at increased risk for the development of TGCT. […] Patients with androgen insensitivity syndrome (testicular feminization) have a 5-10% risk of developing GCT, usually after the complete development of secondary female sexual characteristics. […] Gonadal dysgenesis in patients who carry a Y chromosome is a significant risk factor for germ cell tumor development. […] If this is true, it suggests that a specific genetic mutation may not be required to initiate the process of tumor development, but rather environmental factors are sufficient as initiating events. […] The initiating genetic events that lead to IGCNU and subsequent invasive GCT have yet to be agreed upon.

• #1 Testicular Cancer: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/279007-overview

  The cause of testicular cancer is not known. The characteristic genetic change found is an isochromosome of the short arm of chromosome 12 [i(12p)], which is often seen in sporadic cancers. This suggests that genes in this region are important in the development of germ cell tumors. A number of other genes that have a relatively weak effect are also involved in the development of testicular cancer. […] That genetic factors have a role in the development of testicular cancer is shown by the fact that the risk for the disease is higher in first-degree relatives of cancer patients than in the general population. About 2% of testicular cancer patients report having an affected relative. Siblings are at particularly increased risk, with a relative risk of 810. For sons of affected men, the relative risk is 46.

• #1 Etiology and early pathogenesis of malignant testicular germ cell tumors: towards possibilities for preinvasive diagnosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4430936/

  Since 2009, several genome wide association studies (GWAS) have been published, reporting on single-nucleotide polymorphisms (SNPs) with significant associations in or near the genes KITLG, SPRY4, BAK1, DMRT1, TERT, ATF7IP, HPGDS, MAD1L1, RFWD3, TEX14, and PPM1E, likely to be related to TGCT development. […] A noninvasive early detection method for CIS would be highly beneficial in a clinical setting, for which specific miRNA detection in semen seems to be very promising. […] In this review, the early pathogenesis of CIS of the testis and TGCT will be discussed. […] The origin of TGCT probably starts at early embryogenesis, and is hypothesized to be part of the Testicular Dysgenesis Syndrome (TDS). […] This impaired testicular development means that some early PGC/gonocytes are blocked in their process of differentiation, and as such, these germ cells retain their early (embryonic) marker profile.

• #1

  https://journals.lww.com/ajandrology/fulltext/2015/17030/etiology_and_early_pathogenesis_of_malignant.6.aspx

  Key aspects of the etiology of TGCT were discovered in the past few years. Since 2009, several GWAS have found SNPs with significant associations in or near the genes KITLG, SPRY4, BAK1, DMRT1, TERT, ATF7IP, HPGDS, MAD1L1, RFWD3, TEX14, and PPM1E. […] Many of these genes are involved in the early gonadal development, which explains their involvement in the pathogenesis of CIS.

• #1 Germ Cell Tumor of the Testis: TNM-Stages and Diagnosis

  https://www.urology-textbook.com/germ-cell-tumor.html

  Environmental toxins: the increasing incidence in industrialized countries argues for environmental toxins, which increase the risk for germ cell tumors and other diseases (infertility, cryptorchidism, hypospadias, premature births). Numerous substances (endocrine disruptors) in plastics and pesticides are discussed as causal substances.

• #1 Origins and molecular biology of testicular germ cell tumors | Modern Pathology

  https://www.nature.com/articles/3800309

  The relative importance of susceptibility genes vs environmental factors in the etiology of TGCT is a source of great debate among investigators. […] While both factors seem to play a role in this disease, at present their relative importance is not clear. […] Much stronger associations with the development of TGCT exist with factors such as exposure to high levels of maternal estrogen during pregnancy, neonatal jaundice and low and high birth weights. […] These findings suggest that the initiating events that lead to tumor development occur early, possibly during the prenatal period. […] The most widely accepted risk factor for TGCT is cryptorchidism, approximately 10% of the cases having this association. […] There is some evidence that testicular maldescent is associated with prenatal exposure to estrogens.

• #1 Seminoma: Pathogenesis, Clinical Features & Morphology

  https://ilovepathology.com/seminoma-pathogenesis-clinical-morphology-treatment/

  Seminoma is a germ cell tumor and one of the most common types of testicular tumors, comprising about 50% of germ cell tumors. […] Germ cell tumors arise due to: Environmental Factors: Exposure to pesticides and non-steroidal estrogens in utero can lead to testicular dysgenesis syndrome (cryptorchidism, hypospadias, and poor sperm quality). Cryptorchidism is associated with approximately 10% of testicular germ cell tumors including seminomas. Genetic Factors: Mutations in genes like KIT (linked to familial germ cell tumor risk) and BAX (involved in apoptosis) are significant. Germ cell tumors are 4x more common in fathers/sons and 8-10x higher in brothers of affected individuals. […] The process involves: Arrest of differentiation in primordial germ cells due to genetic, epigenetic, or environmental factors. Formation of germ cell neoplasia in situ (GCNIS), a precancerous condition that arises in utero but remains dormant until puberty. Activation during puberty due to hormonal influences or chromosomal alterations, such as duplication of the short arm of chromosome 12, leading to invasive germ cell tumors. Pathogenesis of germ cell tumors.

• #1

  https://journals.lww.com/ajandrology/fulltext/2015/17030/etiology_and_early_pathogenesis_of_malignant.6.aspx

  For example, it is believed that xeno-estrogens and anti-testosterones negatively affect the development of Sertoli cells and Leydig cells, causing a suboptimal environment for germ cell differentiation and leading to development of CIS cells, which are, as mentioned above, blocked embryonic germ cells. […] The current hypothesis is that all patients with this abnormality will develop an invasive TGCT, due to the fact that in the male Caucasian population, the incidence of CIS similar is to the lifetime risk of developing a TGCT. […] However, the exact cause for progression of CIS to TGCT is currently unknown. It has been suggested that loss of PTEN exposure to certain and environmental factors among others play a role. […] For the onset of CIS and the development of CIS into an invasive tumor, there is likely an interplay between genetic, epigenetic, and (micro)environmental factors also referred as the genvironment.

• #1 Human Germ Cell Tumors are Developmental Cancers: Impact of Epigenetics on Pathobiology and Clinic

  https://www.mdpi.com/1422-0067/20/2/258

  While differences in incidence across several regions of the globe demonstrate the relevance of environmental factors in their genesis, contrasting incidence rates in distinct ethnic groups of the same populations underline the contribution of genetic factors—in sum, the role of the aforementioned ‘genvironmental’ model.

• #1 Testicular Cancer: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/279007-overview

  Two models of testicular carcinoma in situ have been proposed. The first posits that fetal gonocytes whose development into spermatogonia is blocked may undergo abnormal cell division and then invasive growth mediated by postnatal and pubertal gonadotropin stimulation. […] The second model postulates that the most likely target cell for transformation is the zygotene-pachytene spermatocyte. During this stage of germ cell development, aberrant chromatid exchange events associated with crossing over can occur. Normally, these cells are eliminated by apoptosis. On occasion, this crossing over may lead to increased 12p copy number and overexpression of the cyclin D2 gene (CCND2). The cell carrying this abnormality is relatively protected against apoptotic death because of the oncogenic effect of CCND2, leading to re-initiation of the cell cycle and genomic instability.

• #1 Involvement of epigenetic modifiers in the pathogenesis of testicular dysgenesis and germ cell cancer

  https://www.degruyter.com/document/doi/10.1515/bmc-2015-0006/html?lang=en

  It is believed that the CIS is formed in utero as studies of protein markers […] have provided evidence that CIS cells are very similar to fetal germ cells (gonocytes). It is thus very likely that a CIS cell is a gonocyte that failed to mature during development. […] Histone lysine methylation marks are important regulatory set points in both germ and somatic cells during normal fetal gonadal development but also in the neoplastic and malignant transformation in the pathogenesis of TGCTs. […] Our current hypothesis is that developmental arrest of gonocytes is caused by disruption of the endocrine environment in the testes (niche), which is comprised of somatic cells that secrete hormones and paracrine factors that stimulate male-specific germ cell maturation into spermatogonia. […] The aetiology of TDS is unclear, but the apparent rapid increase in male reproductive health problems during a few generations suggests that changes in lifestyle and/or environmental factors are more likely causes than genetic factors.

• #1 Origins and molecular biology of testicular germ cell tumors | Modern Pathology

  https://www.nature.com/articles/3800309

  There are two major theories, the first being championed by Chaganti and Houldsworth. […] They have postulated that the most likely target cell for transformation is the zygotene-pachytene spermatocyte where there appears to be a recombination checkpoint. […] A second and more widely accepted hypothesis is promulgated by Skakkebaek and others. […] This model suggests that fetal gonocytes (primordial germ cells) may undergo abnormal cell division (polyploidization) due to mostly environmental factors in utero and give rise to IGCNU. […] Polyploidization precedes the formation of i(12p). […] The characteristic genetic abnormality of these tumors is excess genetic material of the short arm of chromosome 12, usually in the form of an isochromosome; i(12p). […] Approximately 80% of cases have i(12p) and the remainder have excess 12p genetic material in derivative chromosomes. […] The presence of i(12p) in IGCNU is a matter of controversy with most investigators suggesting it is not present. […] This finding tends to support the Skakkebaek hypothesis that polyploidization is an initiating event followed by i(12p) in the invasive phenotype.

• #1 p53 Hypersensitivity Is the Predominant Mechanism of the Unique Responsiveness of Testicular Germ Cell Tumor (TGCT) Cells to Cisplatin | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0019198

  Consistent with the excellent clinical results in testicular germ cell tumors (TGCT), most cell lines derived from this cancer show an exquisite sensitivity to Cisplatin. […] The role of the tumor suppressor p53 in this response, however, remains controversial. Here we show that siRNA-mediated silencing of p53 is sufficient to completely abrogate hypersensitivity not only to Cisplatin but also to non-genotoxic inducers of p53 such as the Mdm2 antagonist Nutlin-3 and the proteasome inhibitor Bortezomib. […] In conclusion, our data indicate that the hypersensitivity of TGCT cells is a result of their unique sensitivity to p53 activation. Furthermore, in the very specific cellular context of germ cell-derived pluripotent EC cells, p53 function appears to be limited to induction of apoptosis.

• #1 Mechanisms of cisplatin sensitivity and resistance in testicular germ cell tumors and potential therapeutic agents (Review)

  https://www.spandidos-publications.com/10.3892/etm.2025.12832?text=fulltext

  Testicular germ cell tumors (TGCTs) are the most common tumors in men aged 20-40 years and are primarily treated with cisplatin-based drugs. […] Emerging evidence shows that cisplatin resistance in TGCTs is mainly related to the inhibition of apoptotic pathways such as MDM2/p53, OCT4/NOXA, PDGFR/PI3K/AKT, inhibition of cell cycle checkpoints, increased methylation or neddylation and DNA repair balance. […] Studies have shown that most testicular germ cell tumors originate from germ cell neoplasia in situ, which is thought to be due to the stagnation and transformation of the original germ cells. […] The sensitivity of TGCTs to cisplatin may correlate with two key reactions: Inadequate repair of cisplatin-induced DNA damage and a hypersensitive apoptotic response. […] However, ~10-20% of advanced TGCTs are resistant to platinum-based chemotherapy and have a poor prognosis or recurrence, and the treatments for these patients are poorly understood.

• #1

  https://www.jci.org/articles/view/143884

  The untimely activation of the latent non-neoplastic germ cell developmental program, also called reprogramming, is a crucial mechanism in the pathogenesis of GCTs. […] The only GCTs that are malignant per se are seminomas and nonseminomas (type II); even these malignant GCTs are rarely initiated by mutations. […] Notably, late PGCs that escaped apoptosis after lodging in gonadal and thymic niches as well as the midline of the brain give rise to malignant GCTs. […] An important bycatch of Taylor, Donoghue, et al. (12) is the data on mutations in primary mediastinal seminomas and PMNs, which allows comparison with similar data for primary type II GCTs of the testis and brain. […] The high rate of TP53 mutations in PMNs is probably an important factor underlying platinum resistance, as loss of function of p53 permits accumulation of CNVs as well as mutations, and interferes with DNA-damage-induced apoptosis. […] The thymic microenvironment likely favors differentiation of ECCs along hematopoietic lineages.

• #2 Germ cell tumours – Libre Pathology

  https://librepathology.org/wiki/Germ_cell_tumours

  Most common cytogenetic abnormality in GCTs: […] Isochromosome 12p. […] Isochromosome = one arm (p or q) is lost and replaced with a duplicate of the remaining one. […] Example: isochromosome 12p = chromosome 12 where q is lost and two p arms are present. […] Pathogenesis of testicular germ cell tumours.

• #2

  https://journals.lww.com/ajandrology/fulltext/2015/17030/etiology_and_early_pathogenesis_of_malignant.6.aspx

  Key aspects of the etiology of TGCT were discovered in the past few years. Since 2009, several GWAS have found SNPs with significant associations in or near the genes KITLG, SPRY4, BAK1, DMRT1, TERT, ATF7IP, HPGDS, MAD1L1, RFWD3, TEX14, and PPM1E. […] Many of these genes are involved in the early gonadal development, which explains their involvement in the pathogenesis of CIS.

• #2 Seminoma: Pathogenesis, Clinical Features & Morphology

  https://ilovepathology.com/seminoma-pathogenesis-clinical-morphology-treatment/

  Seminoma is a germ cell tumor and one of the most common types of testicular tumors, comprising about 50% of germ cell tumors. […] Germ cell tumors arise due to: Environmental Factors: Exposure to pesticides and non-steroidal estrogens in utero can lead to testicular dysgenesis syndrome (cryptorchidism, hypospadias, and poor sperm quality). Cryptorchidism is associated with approximately 10% of testicular germ cell tumors including seminomas. Genetic Factors: Mutations in genes like KIT (linked to familial germ cell tumor risk) and BAX (involved in apoptosis) are significant. Germ cell tumors are 4x more common in fathers/sons and 8-10x higher in brothers of affected individuals. […] The process involves: Arrest of differentiation in primordial germ cells due to genetic, epigenetic, or environmental factors. Formation of germ cell neoplasia in situ (GCNIS), a precancerous condition that arises in utero but remains dormant until puberty. Activation during puberty due to hormonal influences or chromosomal alterations, such as duplication of the short arm of chromosome 12, leading to invasive germ cell tumors. Pathogenesis of germ cell tumors.

• #2 Germ Cell Tumors

  https://www.csh.org.tw/dr.tcj/educartion/f/web/Germ%20cell%20tumor/index.htm

  Recent studies of GCTs have suggested that cyclin D2 is overexpressed in malignant germ cells and is oncogenic. […] GCT differentiation may be influenced by several interacting pathways, such as regulators of germ-cell totipotentiality, embryonic development, and genomic imprinting. Sensitivity and resistance to chemotherapy may be based in part on a p53-dependent apoptotic pathway. […] Almost 100% of tumors show increased copy number of 12p. This chromosomal marker has been noted in carcinoma in situ (CIS), suggesting that it is one of the early changes associated with the origin of GCT. CIS is considered to be a precursor of all GCTs. […] Model 1: Fetal gonocytes that escape normal development into spermatogonia undergo abnormal cell division and proliferation. These gonocytes are prone to invasive growth, mediated by postnatal and pubertal gonadotrophin stimulation.

• #2 Origins and molecular biology of testicular germ cell tumors | Modern Pathology

  https://www.nature.com/articles/3800309

  There are two major theories, the first being championed by Chaganti and Houldsworth. […] They have postulated that the most likely target cell for transformation is the zygotene-pachytene spermatocyte where there appears to be a recombination checkpoint. […] A second and more widely accepted hypothesis is promulgated by Skakkebaek and others. […] This model suggests that fetal gonocytes (primordial germ cells) may undergo abnormal cell division (polyploidization) due to mostly environmental factors in utero and give rise to IGCNU. […] Polyploidization precedes the formation of i(12p). […] The characteristic genetic abnormality of these tumors is excess genetic material of the short arm of chromosome 12, usually in the form of an isochromosome; i(12p). […] Approximately 80% of cases have i(12p) and the remainder have excess 12p genetic material in derivative chromosomes. […] The presence of i(12p) in IGCNU is a matter of controversy with most investigators suggesting it is not present. […] This finding tends to support the Skakkebaek hypothesis that polyploidization is an initiating event followed by i(12p) in the invasive phenotype.

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