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

ABSTRACTEmbryonal 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 regulatesTFAP2C,PRDM1andPRDM14, thereby maintaining latent pluripotency and supressing somatic differentiation. In contrast, in somatic cells canonical motifs are not bound by SOX17. In sum only 11% 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 EC-like 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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Paraduodenal mass as initial presentation of burned-out testicular tumour: case report and literature review

Journal of Surgical Case Reports ◽

10.1093/jscr/rjaa006 ◽

2020 ◽

Vol 2020 (3) ◽

Author(s):

Miguel Almeida ◽

Luís Amaral ◽

Duarte Viveiros ◽

Victor Carneiro ◽

Carlos Sebastião ◽

...

Keyword(s):

Germ Cell ◽

Germ Cell Tumour ◽

Surgical Excision ◽

Complete Response ◽

Complete Regression ◽

Testicular Germ Cell ◽

Testicular Germ Cell Tumours ◽

Ultrasound Study ◽

Histopathologic Findings ◽

Difficult Cases

Abstract Testicular germ cell tumours (TGCTs) are relatively rare overall and are mainly encountered in young adults and teenagers. The ‘burned-out’ phenomenon refers to the spontaneous regression of the primary testicular lesion, generally with the presence of a metastatic germ cell tumour. Regressed tumours with retroperitoneal metastasis, as the first manifestation, represent difficult cases prone to misdiagnosis. Burned-out TGCT is a rare but well-recognized entity, with defined clinical features and diagnostic criteria; however, its etiopathogenesis is still not well defined. We present a case of 37-year-old man with a retroperitoneal mass adjacent to the duodenum identified on CT scan. After surgical excision, histopathologic findings evidenced metastatic non-seminomatous GCT. Testicular examination was normal, but a right testis suspicious lesion was found on ultrasound study. Radical right orchidectomy was performed, and histological examination showed complete regression of TGCT. He underwent first-line chemotherapy with complete response and no evidence of recurrence.

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Germ cell tumour subtypes display differential expression of microRNA371a-3p

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2017.0338 ◽

2018 ◽

Vol 373 (1748) ◽

pp. 20170338 ◽

Cited By ~ 18

Author(s):

Bárbara Vilela-Salgueiro ◽

Daniela Barros-Silva ◽

João Lobo ◽

Ana Laura Costa ◽

Rita Guimarães ◽

...

Keyword(s):

Germ Cell ◽

Germ Cell Tumour ◽

High Sensitivity ◽

Serum Markers ◽

Disease Monitoring ◽

Testicular Germ Cell ◽

Tissue Samples ◽

Adequate Treatment ◽

Expression Levels ◽

Testicular Germ Cell Tumours

Testicular germ cell tumours (TGCTs) are a heterogeneous group of neoplasms, mostly affecting young men. Curability rates are high and adequate treatment relies on careful and accurate pathological and clinical assessment. Indeed, TGCTs' histopathological subtyping is critical for adequate therapeutic decision. Considering the limitation of currently available serum biomarkers, novel candidates have been proposed, most notably miR-371a-3p, which outperformed classical serum markers, but no detailed information concerning TGCT subtype was available. Thus, we carried out evaluation of miR-371a-3p expression levels among TGCT subtypes using a consecutive cohort of tissue samples. MiR-371a-3p discriminated TGCTs from control tissues with high sensitivity and specificity (AUC = 0.99). Furthermore, seminomas displayed higher miR-371a-3p expression levels compared to non-seminomatous TGCTs, which also showed significant differences among them. Nonetheless, prepubertal TGCTs depicted lower miR-371a-3p expression levels than postpubertal TGCTs. Globally, miR-371a-3p expression levels decreased in parallel with progressive cell differentiation. We concluded that miR-371a-3p is TGCTs-specific and it might be clinically useful for early detection and disease monitoring. This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.

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A rare case of testicular mixed germ cell tumour with adrenal metastasis

Journal of Clinical Urology ◽

10.1177/20514158211007988 ◽

2021 ◽

pp. 205141582110079

Author(s):

Shenthiuiyan Theivendrampillai ◽

Richard Lockyer ◽

Matthew Wheater ◽

Leon Veryard ◽

Alexander King

Keyword(s):

Germ Cell ◽

Germ Cell Tumour ◽

Cell Tumour ◽

Germ Cell Tumours ◽

Level Of Evidence ◽

Testicular Germ Cell ◽

Testicular Germ Cell Tumours ◽

Positron Emission ◽

Management Protocol ◽

Younger Men

Testicular cancer commonly affects younger men, with testicular germ cell tumours comprising the vast majority of cases. They are classified into either seminomatous or non-seminomatous germ cell tumours, with mixed germ cell tumours treated as non-seminomas. In the following case report, we describe the clinical course and management of a 38-year-old male patient who presented with a right unilateral testicular mixed germ cell tumour, predominantly seminoma that had metastasized to the adrenal gland. This pattern of spread is indeed a rare occurrence. It also highlights the significance of the current diagnostic and management protocol and the benefits of using positron emission tomography as a diagnostic tool. Level of evidence: 4

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Microinvasive germ cell tumour (MGCT) adjacent to testicular germ cell tumours

Histopathology ◽

10.1111/j.1365-2559.2004.01889.x ◽

2004 ◽

Vol 44 (6) ◽

pp. 547-554 ◽

Cited By ~ 13

Author(s):

F E von Eyben ◽

G K Jacobsen ◽

M Rorth ◽

H Von Der Maase

Keyword(s):

Germ Cell ◽

Germ Cell Tumour ◽

Cell Tumour ◽

Germ Cell Tumours ◽

Testicular Germ Cell ◽

Testicular Germ Cell Tumours

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Biology of human testicular germ cell tumours

Reproductive Medicine Review ◽

10.1017/s0962279999000265 ◽

1999 ◽

Vol 7 (2) ◽

pp. 141-154

Author(s):

Martin F Pera

Keyword(s):

Stem Cells ◽

Germ Cell ◽

Germ Cells ◽

Primordial Germ Cells ◽

Germ Cell Tumour ◽

Early Embryo ◽

Germ Cell Tumours ◽

Testicular Germ Cell ◽

Testicular Germ Cell Tumours ◽

Wide Range

Testicular germ cell tumours are a rare and bizarre diversion in the life cycle of the male germ line. These neoplasms are thought to originate during embryonic life from primordial germ cells (PGCs) which fail to undergo maturation into prospermatogonia. Maturation arrest and the development of aneuploidy in the PGC give rise to the precursor of germ cell malignancy, the testicular carcinoma in situ (CIS) cell. Thereafter, a complex series of genetic changes, coupled with the onset of puberty, can either convert the CIS cell into a malignant tumour made up of cells resembling primordial germ cells (a seminoma), or drive it down a pathway akin to parthenogenesis, so that it acquires a special property shared with cells of the early embryo – pluripotentiality, or the ability to differentiate into a wide range of somatic cells. The latter form of germ cell tumour, a teratocarcinoma, will contain primitive undifferentiated stem cells and multiple somatic tissues representing derivatives of all three germ layers plus the extraembryonic membranes which support development. Pluripotentiality is a property common to the oocyte, the cells of the early embryo up to the stage just after implantation, primordial germ cells, and the stem cells of germ cell tumours (Figure 1).

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The Potential of Artificial Intelligence to Detect Lymphovascular Invasion in Testicular Cancer

Cancers ◽

10.3390/cancers13061325 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1325

Author(s):

Abhisek Ghosh ◽

Korsuk Sirinukunwattana ◽

Nasullah Khalid Alham ◽

Lisa Browning ◽

Richard Colling ◽

...

Keyword(s):

Artificial Intelligence ◽

Testicular Cancer ◽

Germ Cell ◽

Lymphovascular Invasion ◽

Automatic Segmentation ◽

Prognostic Significance ◽

Germ Cell Tumours ◽

Testicular Germ Cell ◽

Testicular Germ Cell Tumours ◽

Whole Slide Images

Testicular cancer is the most common cancer in men aged from 15 to 34 years. Lymphovascular invasion refers to the presence of tumours within endothelial-lined lymphatic or vascular channels, and has been shown to have prognostic significance in testicular germ cell tumours. In non-seminomatous tumours, lymphovascular invasion is the most powerful prognostic factor for stage 1 disease. For the pathologist, searching multiple slides for lymphovascular invasion can be highly time-consuming. The aim of this retrospective study was to develop and assess an artificial intelligence algorithm that can identify areas suspicious for lymphovascular invasion in histological digital whole slide images. Areas of possible lymphovascular invasion were annotated in a total of 184 whole slide images of haematoxylin and eosin (H&E) stained tissue from 19 patients with testicular germ cell tumours, including a mixture of seminoma and non-seminomatous cases. Following consensus review by specialist uropathologists, we trained a deep learning classifier for automatic segmentation of areas suspicious for lymphovascular invasion. The classifier identified 34 areas within a validation set of 118 whole slide images from 10 patients, each of which was reviewed by three expert pathologists to form a majority consensus. The precision was 0.68 for areas which were considered to be appropriate to flag, and 0.56 for areas considered to be definite lymphovascular invasion. An artificial intelligence tool which highlights areas of possible lymphovascular invasion to reporting pathologists, who then make a final judgement on its presence or absence, has been demonstrated as feasible in this proof-of-concept study. Further development is required before clinical deployment.

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