Wilms tumor gene 1 (WT1), TP53, RAS/BRAF and KIT aberrations in testicular germ cell tumors

Boublíková, Ludmila; Bakardjieva-Mihaylova, Violeta; Kramarzova, Karolina Skvarova; Kužílková, Daniela; Dobiasova, Alena; Fišer, Karel; Stuchlý, Jan; Kotrová, Michaela; Büchler, Tomáš; Dušek, Pavel; Grega, Marek; Rosova, Blanka; Vernerová, Zdeňka; Klézl, Petr; Pesl, M.; Zachoval, Reinhart; Krolupper, Marek; Kubecová, M; Stahalova, V.; Abrahámová, Jitka; Babjuk, Marko; Kodet, Roman; Trka, Jan

doi:10.1016/j.canlet.2016.04.016

Cited by 18 publications

(19 citation statements)

References 42 publications

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“…A combined gene sequencing and immunohistochemical analysis, performed on both seminomas and non seminomas [18], revealed low p53 protein expression in most samples, with low p53 expression occurring in seminomas and high expression mostly in non-seminomas. No p53 mutation was detected in these tumor samples.…”

Section: P53 and Mdm2 : Two Sides Of The Same Coinmentioning

confidence: 99%

“…ATM single nucleotide variants (SNV) were detected in 42% of TGCT samples, as well as the highest number of variants for a single gene - 21 (48% of all variants)[18]. The meaning of these SNV is still obscure: it might be interesting to study the activity of the proteins encoded by these genes to understand their role in the “economy” of the cancer cell, discriminating between “passengers” and “drivers” mutations.…”

Section: Dna Repair Machinery In the Testis Cancermentioning

confidence: 99%

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Role of DNA repair machinery and p53 in the testicular germ cell cancer: a review

et al. 2016

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Notwithstanding the peculiar sensitivity to cisplatin-based treatment, resulting in a very high percentage of cures even in advanced stages of the disease, still we do not know the biological mechanisms that make Testicular Germ Cell Tumor (TGCT) “unique” in the oncology scene. p53 and MDM2 seem to play a pivotal role, according to several in vitro observations, but no correlation has been found between their mutational or expression status in tissue samples and patients clinical outcome. Furthermore, other players seem to be on stage: DNA Damage Repair Machinery (DDR) , especially Homologous Recombination (HR) proteins, above all Ataxia Telangiectasia Mutated (ATM), cooperates with p53 in response to DNA damage, activating apoptotic cascade and contributing to cell “fate”. Homologous Recombination deficiency has been assumed to be a Germ Cell Tumor characteristic underlying platinum-sensitivity, whereby Poly(ADP-ribose) polymerase (PARP), an enzyme involved in HR DNA repair, is an intriguing target: PARP inhibitors have already entered in clinical practice of other malignancies and trials are recruiting TGCT patients in order to validate their role in this disease. This paper aims to summarize evidence, trying to outline an overview of DDR implications not only in TGCT curability, but also in resistance to chemotherapy.

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Section: P53 and Mdm2 : Two Sides Of The Same Coinmentioning

confidence: 99%

Section: Dna Repair Machinery In the Testis Cancermentioning

confidence: 99%

Role of DNA repair machinery and p53 in the testicular germ cell cancer: a review

et al. 2016

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“…In TGCT, p53 mutations are rare, in contrast to what is observed in other solid cancers (Guillou et al ., ; Lutzker, ; Olivier et al ., ). The protein expression level has been shown to differ between the two major histological subtypes, with low levels in seminoma and high levels mostly occurring in non‐seminoma (Boublikova et al ., ). Furthermore, p53 protein expression was lower in TGCT metastases compared to the primary tumours.…”

Section: Dna Damage Responsementioning

confidence: 97%

“…Furthermore, p53 protein expression was lower in TGCT metastases compared to the primary tumours. p53 signalling pathway in TGCT may be disrupted by inhibitors like MDM2 and miRNA 372–373 (Voorhoeve et al ., ; Boublikova et al ., ). In TGCTs, high expression of the p53 inhibitor MDM2 was found, and non‐seminomas stained higher for MDM2 than seminomas (Oliver et al ., ).…”

Section: Dna Damage Responsementioning

confidence: 97%

Functions of genes related to testicular germ cell tumour development

2019

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Objective: Testicular germ cell tumour (TGCT) is a malignancy with a high heritable component. The inherited risk is polygenic, and around 50 susceptibility genes are identified. The functional role of the gene products for TGCT development is not well understood. The focus of this review is functional studies of genetic risk factors for TGCT derived from GCNIS and the signalling pathways involved in the pathogenesis. Recent developments: Genome-wide association studies have identified new risk loci for TGCT and confirmed previously identified susceptibility genes. Many of these risk genes are related to male germ cell development, sex determination and genomic integrity. Gain-and loss-of-function studies in animal models and TGCT cell lines, as well as gene and protein expression studies in TGCT patient samples, have contributed to the understanding of TGCT development. KITLG-KIT signalling is of crucial importance, but several other signal transduction pathways may also play a role. Many of the risk loci are in non-coding regions, and studies have revealed that non-coding RNAs may act as oncogenes or tumour suppressors in TGCT development. Conclusions: The risk of TGCT is polygenic, and the underlying molecular mechanisms are complex. Several signalling pathways are related to TGCT development, and both proteins and non-coding RNAs may act as oncogenes or tumour suppressors. Epigenetic studies are of importance to get further knowledge about how the signalling pathways are regulated. Hypermethylation of the 5' CpG island of the gene encoding the serine protease Testisin promotes its loss in testicular tumorigenesis. Br J Cancer 92, 760-769. Manuylov NL, Fujiwara Y, Adameyko II, Poulat F & Tevosian SG. (2007) The regulation of Sox9 gene expression by the GATA4/FOG2 transcriptional complex in dominant XX sex reversal mouse models. Dev Biol 307, 356-367.

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“…The evidence so far for this is mixed, although a number of publications have shown that this pathway has a role in clinical and in‐vitro samples . Two publications have shown mutations in this pathway in cisplatin‐resistant tumours. Unfortunately, initial attempts to use Sunitinib in this setting have been disappointing, although downstream signalling components of this pathway may make better targets …”

Section: Sensitivity To Therapy In Gctsmentioning

confidence: 99%

Postchemotherapy changes in testicular germ cell tumours: biology and morphology

Berney

Shamash

et al. 2016

Histopathology

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Advances in modern chemotherapy and targeted treatments have resulted in lengthened survival in a variety of tumour types in the last decade. Increasingly in the 21st century, postchemotherapy resections are considered as a possible mode of treatment. Due to their exquisite chemosensitivity, resection of postchemotherapy masses has long been part of the armamentarium of treatment in testicular germ cell neoplasia, which has resulted in a variety of new morphological variants being described after treatment. Here we discuss the possible reasons for germ cell tumour chemosensitivity and hypotheses on the biological pathways leading to resistance to treatment, as well as an outline of the diverse morphology of those tumours which prove recalcitrant to standard treatment methods. The large range of morphologies and their diagnostic challenges may throw light upon the future problems to be encountered in non-germ cell solid tumour pathology, as the resection of postchemotherapy masses becomes increasingly important in patient management.

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Wilms tumor gene 1 (WT1), TP53, RAS/BRAF and KIT aberrations in testicular germ cell tumors

Cited by 18 publications

References 42 publications

Role of DNA repair machinery and p53 in the testicular germ cell cancer: a review

Role of DNA repair machinery and p53 in the testicular germ cell cancer: a review

Functions of genes related to testicular germ cell tumour development

Postchemotherapy changes in testicular germ cell tumours: biology and morphology

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