Testicular cancer

Cheng, Liang; Albers, Peter; Berney, Daniel M.; Feldman, Darren R.; Daugaard, Gedske; Gilligan, Timothy D.; Looijenga, Leendert H. J.

doi:10.1038/s41572-018-0029-0

Cited by 342 publications

(355 citation statements)

References 246 publications

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“…Individual miRNAs from the cluster miR‐371‐373 on chromosomal location 19q13 are expressed in all malignant (T)GCTs, regardless of patient age, tumor site, and subtype (Murray et al ., , ). The cluster miR‐371‐373 is expressed in all histological elements of primary as well as metastatic TGCT, except for pure teratoma (Voorhoeve et al ., ; Cheng et al ., ; Leao et al ., ; Terbuch et al ., ). The different tumor subtypes display differential expression of miR‐371a‐3p, depending on the level of differentiation (Vilela‐Salgueiro et al ., ).…”

Section: Discussionmentioning

confidence: 99%

Cellular origin of microRNA‐371a‐3p in healthy males based on systematic urogenital tract tissue evaluation

et al. 2019

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Background The microRNA‐371a‐3p (miR‐371a‐3p) has been reported to be an informative liquid biopsy (serum and plasma) molecular biomarker for both diagnosis and follow‐up of patients with a malignant (testicular) germ cell tumor ((T)GCT). It is expressed in all histological cancer elements, with the exception of mature teratoma. However, normal testis, semen, and serum of males with a disrupted testicular integrity without a TGCT may contain miR‐371a‐3p levels above threshold, of which the cellular origin is unknown. Objectives Therefore, a series of relevant tissues (frozen and formalin‐fixed paraffin‐embedded (FFPE), when available) from the complete male urogenital tract (i.e., kidney to urethra and testis to urethra) and semen was investigated for miR‐371a‐3p levels using targeted quantitative RT‐PCR (qRT‐PCR). Materials and methods In total, semen of males with normospermia (n = 11) and oligospermia (n = 3) was investigated, as well as 88 samples derived from 32 different patients. The samples represented one set of tissues related to the entire male urogenital tract (11 anatomical locations), three sets for 10 locations, and four sets for six locations. Results All testis parenchyma (n = 17) cases showed low miR‐371a‐3p levels. Eight out of 14 (57%) semen samples showed detectable miR‐371a‐3p levels, irrespective of the amount of motile spermatozoa, but related to sperm concentration and matched Johnsen score (Spearman's rho correlation coefficient 0.849 and 0.871, p = 0.000, respectively). In all other tissues investigated, miR‐371a‐3p could not be detected. Discussion This study demonstrates that the miR‐371a‐3p in healthy adult males is solely derived from the germ cell compartment. Conclusions The observation is important in the context of applying miR‐371a‐3p as molecular liquid biopsy biomarker for diagnosis and follow‐up of patients with malignant (T)GCT. Moreover, miR‐371a‐3p might be an informative seminal biomarker for testicular germ cell composition.

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Section: Discussionmentioning

confidence: 99%

Cellular origin of microRNA‐371a‐3p in healthy males based on systematic urogenital tract tissue evaluation

et al. 2019

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“…Multiple risk factors for testicular germ cell tumors are known, including undescended testicle, personal history of testicular cancer, infertility, and disorders of sexual dysfunction though the majority are sporadic (Cheng et al ., ). Familial studies including twin and fraternal studies suggest a strong heritable component, and a recent population‐based genomic analysis attributed 48.9% of GCTs to heritable components with known single nucleotide polymorphisms accounting for 9.1% of total heritability (Litchfield et al ., b).…”

Section: Genetic Risk Factors and Germ Cell Tumor Developmentmentioning

confidence: 97%

New insights into germ cell tumor genomics

et al. 2019

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Background: Testicular germ cell tumors (GCTs) represent the most common malignancy in young men. While GCTs represent a model for curable solid tumors due to exquisite chemosensitivity, mortality for patients with GCT comprises the most life years lost for non-pediatric malignancies. Given limited options for patients with platinum-resistant disease, improved insight into GCT biology could identify novel therapeutic options for patients with platinum-resistant disease. Recent studies into molecular characteristics of both early stage and advanced germ cell tumors suggest a role for rationally targeted agents and potentially immunotherapy. Recent developments: Recent GWAS meta-analyses have uncovered additional susceptibility loci for GCT and provide further evidence that GCT risk is polygenic. Chromosome arm level amplifications and reciprocal loss of heterozygosity have been described as significantly enriched in GCT compared to other cancer types. Contemporary analyses confirm ubiquitous gain of isochromosome 12 and mutations in addition to previously described GCT-associated genes such as KIT and KRAS. Alterations within the TP53-MDM2 signal transduction pathway appear to be enriched among patients with platinum-resistant disease. Potentially actionable targets, including alterations in TP53-MDM2, Wnt/b-catenin, PI3K, and MAPK signaling, are present in significant proportions of patients with platinum-resistant disease and may be exploited as therapeutic options. Pre-clinical and early clinical data also suggest a potential role for immunotherapy among patients with GCTs. Conclusion: Molecular characterization of GCT patients may provide biologic rationale for novel treatment options in patients with platinum-resistant disease.

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“…Testicular cancer is the most common malignancy in young men 1 . The most frequent testicular tumours are the type II germ cell tumours (TGCTs).…”

Section: Introductionmentioning

confidence: 99%

“…The most frequent testicular tumours are the type II germ cell tumours (TGCTs). Based on epigenetic profile, morphology and marker expression TGCTs are classified as seminomas or non-seminomas 1 . Non-seminomas initially present as embryonal carcinomas (ECs), which can further differentiate into mixed non-seminoma 1 .…”

Section: Introductionmentioning

confidence: 99%

“…Based on epigenetic profile, morphology and marker expression TGCTs are classified as seminomas or non-seminomas 1 . Non-seminomas initially present as embryonal carcinomas (ECs), which can further differentiate into mixed non-seminoma 1 . Seminomas and ECs arise from the same precursor lesion (germ cell neoplasia in situ / GCNIS), which is believed to result from primordial germ cells (PGCs) arrested in development 2 .…”

Section: Introductionmentioning

confidence: 99%

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Unique and redundant roles of SOX2 and SOX17 in regulating the germ cell tumour fate

Jostes

Fellermeyer

Merges

et al. 2019

Preprint

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Embryonal carcinomas (ECs) and seminomas are testicular germ cell tumours. ECs display expression of SOX2, while seminomas display expression of SOX17. In somatic differentiation, SOX17 drives endodermal cell fate. However, seminomas lack expression of endoderm markers, but show features of pluripotency. Here, we use ChIP-sequencing to report and compare the binding pattern of SOX17 in seminoma-like TCam-2 cells to SOX2 in EC-like 2102EP cells and SOX17 in somatic cells. In seminoma-like cells, SOX17 was detected at canonical (SOX2/OCT4), compressed (SOX17/OCT4) and other SOX family member motifs. SOX17 directly regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and supressing somatic differentiation. In contrast, in somatic cells canonical motifs are not bound by SOX17. In sum only 10% of SOX17 binding sites overlap in seminoma-like and somatic cells. This illustrates that binding site choice is highly dynamic and cell type specific. Deletion of SOX17 in seminoma-like cells resulted in loss of pluripotency, marked by a reduction of OCT4 protein level and loss of alkaline phosphatase activity. Further, we found that in EClike cells SOX2 regulates pluripotency-associated genes, predominantly by partnering with OCT4. In conclusion, SOX17 (in seminomas) functionally replaces SOX2 (in ECs) to maintain expression of the pluripotency cluster.

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Testicular cancer

Cited by 342 publications

References 246 publications

Cellular origin of microRNA‐371a‐3p in healthy males based on systematic urogenital tract tissue evaluation

Cellular origin of microRNA‐371a‐3p in healthy males based on systematic urogenital tract tissue evaluation

New insights into germ cell tumor genomics

Unique and redundant roles of SOX2 and SOX17 in regulating the germ cell tumour fate

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