Epigenetics and testicular germ cell tumors

Buljubašić, Robert; Buljubašić, Maja; Bojanac, Ana Katušić; Ulamec, Monika; Vlahović, Maja; Ježek, Davor; Bulić-Jakuš, Floriana; Sinčić, Nino

doi:10.1016/j.gene.2018.03.072

Cited by 38 publications

(35 citation statements)

References 144 publications

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“…In addition, two TF-coding genes (POU5F1 and SOX2) are candidate biomarkers in TGCT 56 . Their roles have been reported in testicular cancer 7,8 . This motivated us to explore the regulatory features of the Yamanaka factors in two TGCT subtypes: NSE and SE.…”

Section: Common and Subtype-specific Regulatory Network Topologicalmentioning

confidence: 97%

MicroRNA and transcription factor co-regulatory networks and subtype classification of seminoma and non-seminoma in testicular germ cell tumors

Qin

Mallik

Mitra

et al. 2020

Sci Rep

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Recent studies have revealed that feed-forward loops (FFLs) as regulatory motifs have synergistic roles in cellular systems and their disruption may cause diseases including cancer. FFLs may include two regulators such as transcription factors (TFs) and microRNAs (miRNAs). In this study, we extensively investigated TF and miRNA regulation pairs, their FFLs, and TF-miRNA mediated regulatory networks in two major types of testicular germ cell tumors (TGCT): seminoma (SE) and non-seminoma (NSE). Specifically, we identified differentially expressed mRNA genes and miRNAs in 103 tumors using the transcriptomic data from The Cancer Genome Atlas. Next, we determined significantly correlated TFgene/miRNA and miRNA-gene/TF pairs with regulation direction. Subsequently, we determined 288 and 664 dysregulated TF-miRNA-gene FFLs in SE and NSE, respectively. By constructing dysregulated FFL networks, we found that many hub nodes (12 out of 30 for SE and 8 out of 32 for NSE) in the top ranked FFLs could predict subtype-classification (Random Forest classifier, average accuracy ≥90%). These hub molecules were validated by an independent dataset. Our network analysis pinpointed several SE-specific dysregulated miRNAs (miR-200c-3p, miR-25-3p, and miR-302a-3p) and genes (EPHA2, JUN, KLF4, PLXDC2, RND3, SPI1, and TIMP3) and NSE-specific dysregulated miRNAs (miR-367-3p, miR-519d-3p, and miR-96-5p) and genes (NR2F1 and NR2F2). This study is the first systematic investigation of TF and miRNA regulation and their co-regulation in two major TGCT subtypes. Testicular germ cell tumors (TGCT) occur most frequently in men between ages of 20 and 40 1,2. Accordingly to histology, TGCT can be separated into two major types: seminoma (SE) and non-seminoma (NSE) 1-4 , and NSE has several subtypes. While the etiology of the two TGCT subtypes is well studied, their molecular profiles, signature genetic markers, and regulatory mechanisms have not been systematically investigated, unlike other common cancers. Such an investigation is much needed now to identify molecular signatures either common in two subtypes, or unique in subtype. The molecular signatures may be further useful for clinical implications, such as patient stratification and subtype-based or personalized treatment. Currently, there are several challenges in TGCT treatment. First, TGCT patients have a high risk of relapse with poor prognosis. Second, there are severe side effects for current chemotherapy and radiotherapy that lead to development of other pathologies. Third, since most of the patients are adolescent or young men, there is a heavy burden for the patients and families in the long run 2,3. During the last decade, a number of studies have been conducted to explore insights into the genetic, epigenetic, and molecular mechanisms of TGCT. For example, after collecting TGCT related genes from previous

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Section: Common and Subtype-specific Regulatory Network Topologicalmentioning

confidence: 97%

MicroRNA and transcription factor co-regulatory networks and subtype classification of seminoma and non-seminoma in testicular germ cell tumors

Qin

Mallik

Mitra

et al. 2020

Sci Rep

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“…The different GCT subtypes reflect distinct developmental stages of embryonic development with seminomas being phenotypically the closest related to the PGC/GCNIS and embryonal carcinomas as a malignant counterpart to embryonic stem cells, with both subtypes expressing markers of pluripotency, for example, OCT3/4, NANOG, LIN28, and SOX17 (seminoma) or SOX2 (embryonal carcinoma), respectively. As during embryonic development, epigenetics play a pivotal role in both, normal germ cell and GCT development as well as in GCT treatment response (Glasspool et al, 2006;Buljubasic et al, 2018). Importantly, GCTs usually harbor an overall low mutational burden and no exceptional driver mutation for GCT development has been identified (Oosterhuis & Looijenga, 2005;Yarchoan et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, regulatory mechanisms other than genomic aberrations seem to decide upon the GCT cell fate and subtype composition. As during embryonic development, epigenetics play a pivotal role in both, normal germ cell and GCT development as well as in GCT treatment response (Glasspool et al, 2006;Buljubasic et al, 2018). As such, the promotor of the pluripotency factor NANOG is hypomethylated in fetal gonocytes, seminomas, and ECs as well as in corresponding cells lines, but hypermethylated in teratomas, yolk-sac tumors, and choriocarcinomas (Nettersheim et al, 2011a).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic treatment combinations to effectively target cisplatin‐resistant germ cell tumors: past, present, and future considerations

Oing

Skowron²,

Bokemeyer

et al. 2019

Andrology

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Background: Type II germ cell tumors represent the most common solid malignancy in men aged 15-45 years. Despite high cure rates of >90% over all stages, 10-15% of advanced patients develop treatment resistance and potentially succumb to their disease. Treatment of refractory germ cell tumors remains unsatisfactory, and new approaches are needed to further improve outcomes. Objectives: With this narrative review, we highlight epigenetic mechanisms related to resistance to standard systemic treatment, which may act as promising targets for novel combined epigenetic treatment approaches. Materials and methods: A comprehensive literature search of PubMed and MEDLINE was conducted to identify original and review articles on resistance mechanisms and/or epigenetic treatment of germ cell tumors in vitro and in vivo. Review articles were hand-searched to identify additional articles. Results: Distinct epigenetic phenomena have been linked to chemotherapy resistance in germ cell tumors, among which DNA hypermethylation, histone acetylation, and bromodomain proteins appear as promising targets for therapeutic exploitation. Inhibitors of key regulators, for example DNA methyltransferases (e.g. decitabine, guadecitabine), histone deacetylases (e.g. romidepsin), and bromodomain proteins (e.g. JQ1) decreased cell viability, triggered apoptosis, and growth arrest. Additionally, these epigenetic drugs induced differentiation and led to loss of pluripotency and re-sensitization towards cisplatin in cell lines and animal models. Discussion: Epigenetic treatments hold promise to (i) reduce the treatment burden of and (ii) overcome resistance to standard cisplatin-based chemotherapy. Combined approaches may enhance activity, while the ideal target and treatment combination of epigenetic drugs, either with another epigenetic agent or conventional cytotoxic agents need to be defined. Conclusion: Epigenetic (combination) treatment for germ cell tumors should be further explored in pre-clinical and clinical research for its potential to further improve germ cell tumor treatment.

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“…Aside from genetic anomalies, epigenetic changes seem to play an important role in the development of TGCTs [ 18 ]. Indeed, epigenetic mechanisms, i.e., DNA methylation, chromatin remodeling, and microRNAs (miRNAs), are the focus of contemporary TGCT research [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

In Search of TGCT Biomarkers: A Comprehensive In Silico and Histopathological Analysis

et al. 2020

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Testicular germ cell tumors (TGCTs) are ever more affecting the young male population. Germ cell neoplasia in situ (GCNIS) is the origin of TGCTs, namely, seminomas (SE) and a heterogeneous group of nonseminomas (NS) comprising embryonal carcinoma, teratoma, yolk sac tumor, and choriocarcinoma. Response to the treatment and prognosis, especially of NS, depend on precise diagnosis with a necessity for discovery of new biomarkers. We aimed to perform comprehensive in silico analysis at the DNA, RNA, and protein levels of six prospective (HOXA9, MGMT, CFC1, PRSS21, RASSF1A, and MAGEC2) and six known TGCT biomarkers (OCT4, SOX17, SOX2, SALL4, NANOG, and KIT) and assess its congruence with histopathological analysis in all forms of TGCTs. Cancer Hallmarks Analytics Tool, the Search Tool for the Retrieval of Interacting Genes/Proteins database, and UALCAN, an interactive web resource for analyzing cancer OMICS data, were used. In 108 TGCT and 48 tumor-free testicular samples, the immunoreactivity score (IRS) was calculated. SE showed higher frequency in DNA alteration, while DNA methylation was significantly higher for all prospective biomarkers in NS. In GCNIS, we assessed the clinical positivity of RASSF1 and PRSS21 in 52% and 62% of samples, respectively, in contrast to low or nil positivity in healthy seminiferous tubules, TGTCs as a group, SE, NS, or all NS components. Although present in approximately 80% of healthy seminiferous tubules (HT) and GCNIS, HOXA9 was diagnostically positive in 64% of TGCTs, while it was positive in 82% of NS versus 29% of SE. Results at the DNA, mRNA, and protein levels on putative and already known biomarkers were included in the suggested panels that may prove to be important for better diagnostics of various forms of TGCTs.

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Epigenetics and testicular germ cell tumors

Cited by 38 publications

References 144 publications

MicroRNA and transcription factor co-regulatory networks and subtype classification of seminoma and non-seminoma in testicular germ cell tumors

MicroRNA and transcription factor co-regulatory networks and subtype classification of seminoma and non-seminoma in testicular germ cell tumors

Epigenetic treatment combinations to effectively target cisplatin‐resistant germ cell tumors: past, present, and future considerations

In Search of TGCT Biomarkers: A Comprehensive In Silico and Histopathological Analysis

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