Materiały źródłowe

• #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.

• #2 Testicular Cancer (Germ Cell Tumors) | Memorial Sloan Kettering Cancer Center

  https://www.mskcc.org/cancer-care/types/testicular-germ-cell-tumors

  Testicular cancer is not a common disease. Each year, only about 9,000 people in the United States get testicular cancer. Many of them between the ages of 15 and 35. Most cases of testicular cancer can be cured. […] About 95 out of every 100 testicular cancers start in germ cells. These are cells in the testicles that make sperm. […] Two of the most common germ cell tumors are seminoma and nonseminoma. […] Seminomas make up about half of all germ cell tumors. They often grow slowly. Most early-stage seminoma can be cured by removing the testicle during surgery. […] Nonseminomas are often more aggressive than seminomas. They’re more likely to spread beyond the testicle. You may need chemotherapy, surgery, or both to cure this cancer. […] There have been new advances in the diagnosis and treatment of this cancer. Most people can survive the disease, especially if the tumor is found at an early stage.

• #3 Testicular Cancer: Diagnosis and Treatment | AAFP

  https://www.aafp.org/pubs/afp/issues/2018/0215/p261.html

  Testicular cancer is the most common solid tumor among males 15 to 34 years of age, with an estimated 8,850 new cases and 410 deaths during 2017 in the United States. […] Risk factors for testicular cancer include undescended testis (cryptorchidism), personal or family history of testicular cancer, age, ethnicity, and infertility. […] The incidence of testicular cancer has increased over the past several decades for unclear reasons. […] Well-established risk factors for testicular cancer include history of an undescended testis (cryptorchidism), personal or family history of testicular cancer, age, and ethnicity. […] In patients with cryptorchidism, the relative risk of developing testicular cancer ranges from 2.9 to 6.3; the risk is increased in both testes, although the risk is much higher in the ipsilateral testis (6.3 vs. 1.7).

• #4 Testicular Cancer: Pathogenesis, Diagnosis and Management with Focus on Endocrine Aspects – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK278992/

  Testicular cancer comprises different neoplasms, depending on the cell of origin and the typical age at presentation, but germ cell-derived tumors constitute the vast majority of cases. […] Pathogenesis of TGCT associated with GCNIS partly overlaps with that of other developmental disorders of the male reproductive system within the testicular dysgenesis syndrome (TDS). […] Pathogenesis of testicular germ cell tumors (TGCT) of young adults partly overlaps with that of other developmental disorders of the male reproductive system, within the testicular dysgenesis syndrome (TDS). […] The TGCT of young adults originate from a common precursor, germ cell neoplasia in situ (GCNIS), initially termed carcinoma in situ testis. […] GCNIS is considered to originate from developmentally arrested immature germ cells (gonocytes) that fail to differentiate to spermatogonia.

• #5 Testicular Cancer: Pathogenesis, Diagnosis and Management with Focus on Endocrine Aspects – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/sites/books/NBK278992/

  Testicular cancer comprises different neoplasms, depending on the cell of origin and the typical age at presentation, but germ cell-derived tumors constitute the vast majority of cases. […] Pathogenesis of TGCT associated with GCNIS partly overlaps with that of other developmental disorders of the male reproductive system within the testicular dysgenesis syndrome (TDS). […] Pathogenesis of testicular germ cell tumors (TGCT) of young adults partly overlaps with that of other developmental disorders of the male reproductive system, within the testicular dysgenesis syndrome (TDS). […] The TGCT of young adults originate from a common precursor, germ cell neoplasia in situ (GCNIS), initially termed carcinoma in situ (CIS) testis. […] GCNIS is considered to originate from developmentally arrested immature germ cells (gonocytes) that fail to differentiate to spermatogonia.

• #6 EAU Guidelines on Testicular Cancer – Uroweb

  https://uroweb.org/guidelines/testicular-cancer/chapter/epidemiology-aetiology-amp-pathology

  Testicular cancer represents 1% of adult neoplasms and 5% of urological tumours, with three to ten new cases per 100,000 males/per year in Western societies. The incidence of TC has increased during recent decades, predominantly in industrialised countries, and it continues to rise. At diagnosis, 1-2% are bilateral and 90-95% of cases are germ cell tumours (GCT). The peak incidence is in the third decade of life for non-seminomatous germ cell tumour (NSGCT) and mixed GCT patients, and in the fourth decade for seminoma testis (ST) patients. In 5% of GCT patients, the primary site is at an extragonadal location. […] There are two fundamental categories of GCTs based on their development and epigenetic features. Most malignant post-pubertal GCTs originate from germ cell neoplasia in situ (GCNIS). Histologically and clinically, these are subdivided into seminomas and non-seminomas, the latter encompassing somatic and extra-embryonal elements of embryonal carcinoma, yolk sac, choriocarcinoma and post-pubertal teratoma (PPT).

• #7 Testicular Cancer: Pathogenesis, Diagnosis and Management with Focus on Endocrine Aspects – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK278992/

  The immunohistochemical profiles of GCNIS and gonadoblastoma cells are virtually identical and resemble very closely those of primordial germ cells and fetal gonocytes. […] Tumors derived from germ cells via GCNIS stage are characterized by the presence of a nearly universal aneuploidy (polyploidization) and amplification of chromosome 12p, often in the form of an isochromosome. […] The mechanisms of neoplastic transformation of early germ cell are not known. There is a growing consensus that there may be multiple mechanisms and testicular cancer is a multifactorial and polygenic disorder. […] A disturbance in the fetal programming of gonadal development may be a result of an intrauterine hormonal imbalance, which in turn may be caused by a genetic disorder or by an impact of an exogenous factor targeting a key pathway, e.g., androgen signaling, KIT-KITLG signaling, DMRT1 signaling and regulation of meiosis, the TGF-beta superfamily regulation (including Nodal pathway) or the WNT pathway, leading to a delay in the testis development and maturation of fetal gonocytes.

• #8 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

  Testicular germ cell cancer manifests mainly in young adults as a seminoma or non-seminoma. The solid tumors are preceded by the presence of a non-invasive precursor cell, the carcinoma in situ cell (CIS), which shows great similarity to fetal germ cells. It is therefore hypothesized that the CIS cell is a fetal germ cell that has been arrested during development due to testicular dysgenesis. […] We here review the possible involvement of epigenetic modifiers with a focus on jumonji C enzymes in the development of testicular dysgenesis and germ cell cancer in men. […] It is believed that the CIS is formed in utero as studies of protein markers, global gene expression profiles of CIS cells and microRNAs 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. […] 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. 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.

• #9 Testicular Cancer: Pathogenesis, Diagnosis and Management with Focus on Endocrine Aspects – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/sites/books/NBK278992/

  The immunohistochemical profiles of GCNIS and gonadoblastoma cells are virtually identical and resemble very closely those of primordial germ cells and fetal gonocytes. […] The mechanisms of neoplastic transformation of early germ cell are not known. […] There is a growing consensus that there may be multiple mechanisms and testicular cancer is a multifactorial and polygenic disorder. […] A disturbance in the fetal programming of gonadal development may be a result of an intrauterine hormonal imbalance, which in turn may be caused by a genetic disorder or by an impact of an exogenous factor targeting a key pathway, e.g., androgen signaling, KIT-KITLG signaling, DMRT1 signaling and regulation of meiosis, the TGF-beta superfamily regulation (including Nodal pathway) or the WNT pathway, leading to a delay in the testis development and maturation of fetal gonocytes.

• #10 Testicular cancer – Wikipedia

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

  Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system. Symptoms may include a lump in the testicle or swelling or pain in the scrotum. Treatment may result in infertility. […] Risk factors include an undescended testis, family history of the disease, and previous history of testicular cancer. More than 95% are germ cell tumors which are divided into seminomas and non-seminomas. Other types include sex-cord stromal tumors and lymphomas. Diagnosis is typically based on a physical exam, ultrasound, and blood tests. Surgical removal of the testicle with examination under a microscope is then done to determine the type. […] Most testicular germ cell tumors have too many chromosomes, and most often they are triploid to tetraploid. An isochromosome 12p (the short arm of chromosome 12 on both sides of the same centromere) is present in about 80% of testicular cancers, and also other cancers usually have extra material from this chromosome arm through other mechanisms of genomic amplification.

• #11 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.

• #12 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.

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

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

  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. […] 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. […] 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).

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

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

  The consistent gain of 12p genetic material is supported by gene array and comparative genomic hybridization data. […] Data suggest that the consistent gain of genetic material from chromosome 12 is crucial for the development of an invasive GCT resulting in efforts to identify the specific genes involved. […] A significant number of these transcripts are located telomeric to the 12p11-12p12 region. […] While virtually all adult cases are aneuploid, pediatric cases are mostly diploid, particularly teratomas, although yolk sac tumors may be nondiploid.

• #15

  https://link.springer.com/article/10.1007/BF00184608

  Molecular investigations into the neoplastic transformation of a normal spermatogenic precursor cell into a germ-cell malignancy have implicated a wide array of DNA and RNA alterations. […] In particular, mutations in cellular oncogenes such as c-kit and tumor-suppressor genes such as the retinoblastoma gene product have been identified as putative etiologic agents in the development and progression of testicular germ-cell tumors. […] Additionally, alterations in the transcription of RNA that are regulated through a process of genomic imprinting have been identified in human testis cancers. […] This report provides a framework for integrating this growing literature on the molecular biology of testicular germ-cell tumors into a potential etiologic hypothesis.

• #16 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.

• #17 Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors

  https://www.mdpi.com/2072-6694/13/7/1506

  Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors […] This minireview focuses on the role of epigenetics in testicular cancer. A working model is developed that postulates that epigenetic features that drive testicular cancer malignancy also enable these tumors to be cured at a high rate with chemotherapy. Chemoresistance may occur by epigenetic uncoupling of malignancy and chemosensitivity, a scenario that may be amenable to epigenetic-based therapies. […] Compared to many common solid tumors, the main genetic drivers of most testicular germ cell tumors (TGCTs) are unknown. […] In the past decade there has been a greater appreciation that epigenetics may play an especially prominent role in TGCT etiology, progression, and hypersensitivity to conventional chemotherapy. […] In general, the low frequency of somatic mutations in TGCTs, especially in nonseminomas compared to other cancers, suggest that epigenetic mechanisms play an especially prominent role in their pathogenesis. […] Distinct epigenetics may render TGCTs distinctly susceptible to epigenetic targeted therapies.

• #18 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

  Our current hypothesis is that developmental arrest of gonocytes is caused by disruption of the endocrine environment in the testes, 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. […] The epigenetic state of CIS cells shows high similarity to the epigenetic patterns found in fetal germ cells. CIS cells contain very low levels of DNA methylation when detected by immunohistochemical staining for 5-methylcytosine, and apparently this unmethylated state is actively maintained by expression of APOBEC1 and base excision repair proteins. […] Taken together, the emerging picture of the epigenetic profile of CIS cells is an open and permissive chromatin structure that resembles the profile found in fetal germ cells.

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

  https://www.degruyterbrill.com/document/doi/10.1515/bmc-2015-0006/html?srsltid=AfmBOopox4C-xJsSNrHZ7427yJ3WL8No4JQjdLstuSQ8cGTpIWcPqjPi

  Testicular germ cell cancer manifests mainly in young adults as a seminoma or non-seminoma. The solid tumors are preceded by the presence of a non-invasive precursor cell, the carcinoma in situ cell (CIS), which shows great similarity to fetal germ cells. It is therefore hypothesized that the CIS cell is a fetal germ cell that has been arrested during development due to testicular dysgenesis. […] The epigenetic state of CIS cells shows high similarity to the epigenetic patterns found in fetal germ cells. CIS cells contain very low levels of DNA methylation when detected by immunohistochemical staining for 5-methylcytosine (5mC), and apparently this unmethylated state is actively maintained by expression of APOBEC1 and base excision repair proteins MBD4, APEX1 and PARP1. […] Malignant transformation of the neoplastic CIS cells results in either a seminoma or a non-seminoma, and each tumor type develops a distinct epigenetic profile. In general, the non-seminoma, embryonal carcinoma, gains high levels of 5mC (and concurrent upregulation of DNMTs) but retains permissive histone modifications, whereas the seminoma maintains low levels of 5mC but loses the permissive histone modifications.

• #20 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

  Malignant transformation of the neoplastic CIS cells results in either a seminoma or a non-seminoma, and each tumor type develops a distinct epigenetic profile. […] 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. […] Multiple lines of evidence suggest a close relationship between sex determination, testicular dysgenesis and development of testicular cancer. Germ cells undergo a tightly regulated epigenetic program as they develop and consequently position epigenetic modifiers as key players. […] We speculate that the regulation of JmjC proteins may be central in the aetiology and pathogenesis of testicular dysgenesis, including testicular cancer.

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

  https://www.degruyterbrill.com/document/doi/10.1515/bmc-2015-0006/html?srsltid=AfmBOopox4C-xJsSNrHZ7427yJ3WL8No4JQjdLstuSQ8cGTpIWcPqjPi

  Multiple lines of evidence suggest a close relationship between sex determination, testicular dysgenesis and development of testicular cancer. Germ cells undergo a tightly regulated epigenetic program as they develop and consequently position epigenetic modifiers as key players. Jumonji C domain-containing proteins seem to be implicated in many of the processes that are necessary for both proper fetal testicular development and maintenance of testicular function in adult life.

• #22 Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors

  https://www.mdpi.com/2072-6694/13/7/1506

  The etiology of TGCTs is still largely unknown. […] However, several low penetrant, inherited germline alleles have been identified including KITGL, SPRY4, and BAK1 suggesting a polygenetic nature to TGCT risk. […] The recent realization that environmental factors likely play a significant role in the pathogenesis of testicular cancer has led to a “genvironmental” model suggests that an interaction between environmental factors (that mediate epigenetic changes) and genetic alterations can explain the shifting epidemiology of TGCTs and its intricate association with DSD and TDS. […] Thus, from an epigenetic-centric view, epigenetic perturbations that arrest PGC/gonocyte differentiation leading to tumorigenic prone states are dominant events downstream of the many risk factors outlined in this section including environmental exposures, inheritable genetic factors and developmental reproductive disorders predicted to alter the microenvironment of the developing germ cell. […] This at least suggests that an epigenetic mediated tumorigenic state or states may be the true driver of TGCTs.

• #23 Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors

  https://www.mdpi.com/2072-6694/13/7/1506

  A defining feature of metastatic TGCTs is a unique hypersensitivity to conventional chemotherapeutics especially to cisplatin-based therapies. […] Similar to etiology and initiation, the mechanisms responsible for TGCT chemosensitivity and resistance have been elusive and appear for the most part to be independent of acquired genetic mutations or alterations. […] In an epigenetic-centric view of TGCTs one would postulate that even traditional mechanisms of chemotherapy resistance like dysregulation of the DNA repair and the DNA damage response could in actuality be downstream consequences of altered epigenetic states that provide, for example, more efficient DNA repair or increased tolerance of cellular DNA damage. […] Despite involvement of genetic factors, TGCTs are clearly not a disease of accumulating mutations like most solid tumors, and again unlike most cancers, genetic alterations appear to poorly explain the initiation and the unique curability of TGCTs. […] The unique epigenetic states of TGCTs may not only be responsible for tumorigenicity and chemosensitivity but may also be exploitable as therapeutic targets.

• #24 fig 4 – Endotext

  https://www.endotext.org/chapter/testicular-cancer-pathogenesis-diagnosis-and-endocrine-aspects/fig-4-2/

  Figure 4. Schematic illustration of aetiology and pathogenesis of disorders grouped within Testicular Dysgenesis Syndrome (TDS). The TDS concept implicates disturbed function of testicular somatic cells (Leydig- and Sertoli cells) caused by inherited genetic mutations /polymorphisms or environmental /lifestyle factors acting during early development. Dysfunction of the somatic cells results in disturbed hormonal homeostasis and causes impaired germ cell differentiation. Depending on the severity of the impairment, multiple outcomes or phenotypes may occur, ranging from reduced anogenital distance (AGD), genital malformations to testicular cancer. […] Note that the most severe forms of TDS (disorders of sex development with gonadoblastoma or CIS are the least frequently seen, whereas the mildest forms, such as impaired spermatogenesis are quite common.

• #25 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. […] 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. […] 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. […] Patients with a history of TGCT have an increased incidence of contralateral disease. […] Some testicular tumors appear to be familial with approximately 2% of patients having an affected family member. […] Patients with various intersex syndromes are at increased risk for the development of TGCT.

• #26 Risk Factors for Testicular Cancer: Environment, Genes and Infections—Is It All?

  https://www.mdpi.com/1648-9144/59/4/724

  Germ cell tumors develop secondary to a tumorigenic event in utero, successively leading to an intratubular germ cell neoplasia, which is derived from gonocytes that failed to differentiate into spermatogonia. […] The overall risk of developing testicular cancer in patients who were or are cryptorchid is 3.7–7.5 times higher than in the normal population. […] Although corrective surgery diminishes this risk by half, the former cryptorchid testis becoming cancerous indicates that permanent epigenetic changes are reported in the testis. […] Recent evidence suggests that allelic variants in genes implicated in the development of the testes could be present in a patient with cryptorchidism. […] However, up to now, even if an irrefutable higher risk of testicular cancer in patients affected by previous or current cryptorchidism has been found, the real pathogenetic mechanism underlying this association is still unclear.

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

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

  The higher the position of the undescended testis, the greater the risk of malignancy. Early orchidopexy reduces the tumor risk and allows clinical controls for early detection. […] Data support a polygenic pathogenesis model in which multiple genes with low penetrance cause the disease. […] 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.

• #28 Testicular Cancer: Diagnosis and Treatment | AAFP

  https://www.aafp.org/pubs/afp/issues/2018/0215/p261.html

  Patients with a personal history of testicular cancer have a 12-times greater risk of developing a contralateral testicular cancer than the general population. […] Men with infertility have an increased risk of testicular cancer, with a standardized incidence ratio of 1.6 to 2.8, although the underlying mechanism is unclear. […] Human immunodeficiency virus infection/AIDS increases the risk of seminoma, but this is negated with highly active antiretroviral treatment. […] Testicular cancer may present as a painless scrotal mass, an incidental radiologic finding, posttraumatic symptom, or scrotal pain. […] Scrotal ultrasonography is the preferred initial imaging study for evaluating a testicular mass. […] Before orchiectomy, evaluation includes a chemistry panel, liver function tests, and tumor markers, including measurement of beta human chorionic gonadotropin, lactate dehydrogenase (may be elevated in seminoma), and alpha fetoprotein (may be elevated in nonseminoma).

• #29 EAU Guidelines on Testicular Cancer – Uroweb

  https://uroweb.org/guidelines/testicular-cancer/chapter/epidemiology-aetiology-amp-pathology

  Non GCNIS derived tumours include pre-pubertal type teratoma and yolk sac tumour, which occur in early childhood, and spermatocytic tumours which usually occurs in older men. Although there is overlapping histology between the pre-pubertal type teratoma/yolk sac and the teratoma and yolk sac tumour elements in the GCNIS-derived NSGCT, these have a separate and independent pathogenesis. […] Risk factors for GCNIS-derived GCTs are components of the testicular dysgenesis syndrome, which encompasses cryptorchidism, hypospadias, decreased spermatogenesis and impaired fertility or disorders of sex development. Additional risk factors include a family history of TC among first-degree relatives and the presence of a contralateral testicular tumour or GCNIS although the risk was lower if TC patients previously had received platinum-based chemotherapy. Genome-wide association studies revealed detectable susceptibility loci leading to an increased relative risk to develop TC.

• #30 Risk Factors for Testicular Cancer: Environment, Genes and Infections—Is It All?

  https://www.mdpi.com/1648-9144/59/4/724

  The significant increase in testicular cancer in the last years cannot be explained by genetic factors alone and environmental and lifestyle factors have to be considered both for testicular cancer and TDS. […] Furthermore, due to the consideration of the relation between age, androgens, and testicular cancer, the presence of hormonal alterations as well exposure to endocrine-disrupting compounds could represent, in addition to hereditary predisposition and in utero alterations, another side of the coin, due to the potential second hit on testis carcinogenesis processes.

• #31 Exploring the molecular aspects associated with testicular germ cell tumors: a review | Oncotarget

  https://www.oncotarget.com/article/22373/text/

  This is probably due Testicular Dysgenesis Syndrome (TDS), where altered Sertoli and Leydig cell function during testes development modifies the development of germ cells and leads to hypospadias, cryptorchidism, impaired spermatogenesis, decreased testosterone production, microlithiasis and testicular cancer. […] Increased use of endocrine disruptors has been suggested to be one of the environmental factors responsible for the increasing incidence of testicular germ cancer cells in testicular dysgenesis syndrome. […] Different genes are involved in the pathogenesis of TGCTs; however, the role of genetic factors and their association with this pathology is still unclear. […] Interestingly, in recent years the findings regarding the association of different genes, (e.g. c-KIT/KITLG, POU5F1) with the development of this neoplasia, and the identification of aberrant epigenetic patterns in promoter regions of several genes, along with the expression of specific regulatory cluster (miRnas), have shed a better light in the comprehension of the development of this disease.

• #32 Fetal Radiation Exposure Induces Testicular Cancer in Genetically Susceptible Mice | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032064

  The prevalence of testicular germ cell tumors (TGCT), a common solid tissue malignancy in young men, has been annually increasing at an alarming rate of 3%. […] Since testicular cancer cells are derived from primordial germ cells (PGCs) or gonocytes the increase has been attributed to maternal and fetal exposures to environmental factors, with most attention given to endocrine disruptors such as estrogens and antiandrogens. […] In the present study we unequivocally demonstrated that fetal radiation exposure during E10.5E11.5 induces testicular germ cell cancers, most of which show the multiple dermal origins typical of teratomas, in a genetically susceptible mouse model. This is the first demonstration of induction of testicular cancer by an environmental agent when exposed during embryonic period.

• #33 Fetal Radiation Exposure Induces Testicular Cancer in Genetically Susceptible Mice | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032064

  The finding that radiation dramatically increased the incidence of testicular cancer in mice offers a new tool for investigating the mechanism by which the PGCs revert to pluripotent embryonic cells. […] Ionizing radiation itself induces larger numbers of SSBs and produces damaged bases. This radiation-induced damage might perturb signaling pathways involving endogenous SSBs and base-excision repair regulating this epigenetic transformation and allow the cells to retain pluripotency as embryonic stem-like cells that subsequently form the TGCTs. […] The knowledge gained about mechanisms of ionizing radiation-induced testicular cancer in mice can be used to identify other environmental or lifestyle factors that might cause similar damage to fetal germ cells and be responsible for the current increases in testicular cancer incidence in men.

• #34 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

  p53 Hypersensitivity Is the Predominant Mechanism of the Unique Responsiveness of Testicular Germ Cell Tumor (TGCT) Cells to Cisplatin […] 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.

• #35 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

  In the present study, we demonstrate a close relationship between p53 protein levels and the extent of apoptosis in pluripotent TGCT cells. […] Interestingly, this hypersensitivity to the pro-apoptotic function of p53 was not limited to DNA damage-inducing agents, but could also be detected when p53 was stabilized in a non-genotoxic manner. […] Most cell lines derived from EC undergo apoptosis upon exposure to very low concentrations of Cisplatin. […] Importantly, this RNAi-mediated loss of p53 accumulation was sufficient to completely rescue NTERA-2D1 cells from Cisplatin-induced apoptosis. […] The same result was observed for the EC cell line 2102EP. […] In addition, in TGCT cells we found a tight p53 siRNA dose response relationship for the rescue from Cisplatin-induced apoptosis, demonstrating that in these cells the amount of p53 protein is pivotal for their sensitivity to Cisplatin.

• #36 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20230411/Bonn-researchers-elucidate-a-mechanism-underlying-cisplatin-resistance-in-testicular-cancer.aspx

  Cisplatin is used successfully in the chemotherapy of testicular cancer. However, patients who develop resistance to the cytostatic drug urgently need alternative therapy options. Researchers at the University Hospital Bonn (UKB) have now been able to elucidate a mechanism underlying cisplatin resistance in testicular cancer. […] Using CRISPR gene scissors, they identified the NAE1 gene as its driver. Inhibiting this resistance mediator by adding the NAE1 inhibitor MLN4924 not only restores the effect of cisplatin, but also has an additional killing effect on tumor cells. […] To get to the bottom of the causes of cisplatin resistance in testicular cancer, the Bonn research team used CRISPR gene scissors. They used them to activate each gene once in testicular cancer cells. They then treated the genetically modified cell culture with cisplatin and singled out those cells that had survived and in which, as a result, the cytostatic drug was no longer effective.

• #37 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20230411/Bonn-researchers-elucidate-a-mechanism-underlying-cisplatin-resistance-in-testicular-cancer.aspx

  „By analyzing the DNA of these cells, we found where the gene scissors were active and were able to identify the genes responsible for cisplatin resistance. In addition to genes already known for cisplatin resistance, to our surprise we found the gene NAE1, the regulator of the neddylation cascade,” says first author Kai Funke, a PhD student of Prof. Schorle. […] „It appears that tumor suppressor proteins, which act as brakes on cell growth in the presence of DNA damage, are an important target of neddylation. Accordingly, they are degraded to a greater extent and their braking effect is lifted when the neddylation cascade is overactive due to the upregulated gene NAE1,” explains Prof. Schorle. […] In turn, inhibition of the neddylation cascade leads to an accumulation of suppressor proteins and, consequently, to a halt in cell division. With addition of the NAE1 inhibitor MLN4924, the Bonn researchers therefore observed a re-sensitization to the cytostatic drug in cisplatin-resistant testicular cancer cells. […] Thus, the Bonn researchers highlight the additive effect of NAE1 inhibition by MLN4924 in combination with cisplatin as a new treatment option for testicular cancer. „We describe here for the first time neddylation as a therapeutic target in testicular germ cell tumors.”

• #38 Exploring the molecular aspects associated with testicular germ cell tumors: a review | Oncotarget

  https://www.oncotarget.com/article/22373/text/

  Thus, altered or dismantled epigenetic regulation might therefore be one of the underlying factors in the origin and biology of TGCTs. […] Aberrant methylation of the regulatory genes promoter region silences their expression, representing a critical pathway in the development of cancer. […] However, tumor suppressor genes or tumor-related genes aberrant de novo methylation is a rare event in TGCTs respect to testicular malignant lymphomas. […] The presence of somatic mutations (PIK3CA, AKT1, KRAS, HRAS, FGFR3) have been identified in resistant TGCTs. […] In TGCTs elevated wild-type p53 protein intratumoral levels are responsible for upregulating pro-apoptotic factors such as Noxa, Puma and Fas. […] In TGCTs, the association of DNA mismatch repair (MMR) function with chemosensitivity may relate to low NER (nucleotide excision repair) activity.

• #39 Exploring the molecular aspects associated with testicular germ cell tumors: a review | Oncotarget

  https://www.oncotarget.com/article/22373/text/

  However, resistant tumors were frequently found to be associated with defects in MMR and to exhibit microsatellite instability (MSI) resulting from a low expression of the MMR proteins MLH1, MSH6 and MSH2. […] Thus, the responsiveness to therapeutic treatments inducing DNA damage is due to the lower threshold to undergo apoptosis following DNA damage, the decreased capability to repair cisplatin-induced DNA damages and the lack of active pumps able to transport cisplatin outside the cell.

• #40 Comparison of clinical characteristics of testicular tumor between children and adult population: a retrospective analysis | BMC Cancer | Full Text

  https://bmccancer.biomedcentral.com/articles/10.1186/s12885-024-12984-2

  Testicular tumor (TT) is a uncommon disease posing serious health problem. […] Yolk sac tumor and seminoma were the most common malignant TT in pediatric and adult population, respectively. […] Pathogenesis differs in differentiation, histogenesis, and genomic instability between adults and children. […] In children, prepubertal teratomas have limited developmental potential during the migration of primordial germ cells. However, yolk sac tumors, the most frequently malignant tumors in childhood, are often involved with chromosomal loss of 1p, 4, and 6q. […] In older adolescents and adults, some primordial germ cells may fail to be differentiated and lead to GCNIS due to the early onset of polyploidization, OCT3/4 switch off failure and changes in genomic imprinting. […] GCNIS commonly are able to reprogram the pluripotent embryonal carcinoma, the malignant counterpart of embryonal stem cell.

• #41 Comparison of clinical characteristics of testicular tumor between children and adult population: a retrospective analysis | BMC Cancer | Full Text

  https://bmccancer.biomedcentral.com/articles/10.1186/s12885-024-12984-2

  Differentiation steps lead to the emergence of other histologies from embryonal carcinoma, such as postpubertal teratoma, YST, and choriocarcinoma. […] Thus, GCNIS is the main player in adult tumorigenesis, in contrast to child tumors, which arise from non-GCNIS pathways. […] The commonly observed changes in adults and pediatric patients are isochromosome 12p and gain at the chromosome 22 and absence of BRAF mutation. […] Gains in 1q, 3, 11q, and 20q are found in pediatric patients, whereas gains of 7, 8, 21, and X are explored in adults. […] It is noteworthy that serum AFP may be physiologically elevated in children before 8 months old. […] In children, TSS is a preferred choice for most small benign tumor in one testis or small bilateral tumors. […] In contrast, TSS in adult with unilateral tumor is not widely recommended because of the high incidence of malignant germ cell testicular tumors in this population, accompanied with the risk of incomplete resection. […] The prognosis of testicular cancers is dependent on tumor stage and patient age. Early-stage tumors have better prognosis than late-stage tumors. TGCTs in children have a higher rate of event-free survival (87.2%) than adults (80.0%).

• #42 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20241114/Scientists-discover-key-genetic-factors-behind-testicular-cancer.aspx

  Scientists have identified new gene faults and evolutionary patterns contributing to testicular cancer. Their findings offer profound insights into the development of the disease and into potential treatment strategies. […] Among the key findings are: New potential cancer drivers in testicular cancer, including drivers specific to certain subtypes, which may help stratify patients based on their tumor characteristics. […] A reconstruction of evolutionary trajectories of genome alterations and probable progression pathways in TGCT. […] Discovery of a broader range of mutational signatures associated with TGCT. These are distinctive patterns of DNA damage, which can reflect various carcinogenic exposures (e.g. smoking, UV light) and enable a retrospective look at exposure-related cancer risk.

• #43 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20241114/Scientists-discover-key-genetic-factors-behind-testicular-cancer.aspx

  Previously unidentified recurrent mutational hotspots in testicular cancer. […] Identification of a genomic immune mechanism unique to TGCT, predominantly in seminomas, the most common tumor subtype. […] We have taken a major leap forward in our understanding of how this disease develops and gained important insights into potential treatment strategies, which is of course key as we seek better patient outcomes. […] This research aimed to transform genomic insights into meaningful patient outcomes, bridging fundamental discoveries with translational applications, and it also serves as a good example of how large volumes of patient data and samples can provide us with a more detailed view of a disease.

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