Distinguishing epigenetic features of preneoplastic testis tissues adjacent to seminomas and nonseminomas
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Ildar V. Gainetdinov1,*, Sofia A. Kondratieva1,*, Yulia V. Skvortsova1, Marina V. Zinovyeva1, Elena A. Stukacheva1, Alexey Klimov2, Alexey A. Tryakin3, Tatyana L. Azhikina1
1Department of Genetics and Postgenomic Technologies, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
2Department of Oncology, Blokhin Russian Cancer Research Center, Moscow, Russia
3Department of Clinical Pharmacology and Chemotherapy, Blokhin Russian Cancer Research Center, Moscow, Russia
*These authors have contributed equally to this work
Ildar V. Gainetdinov, e-mail: [email protected]
Keywords: PIWI, testicular germ cell tumor, DNA methylation, LINE-1, DDX4
Received: September 24, 2015 Accepted: January 12, 2016 Published: January 29, 2016
PIWI pathway proteins are expressed during spermatogenesis where they play a key role in germ cell development. Epigenetic loss of PIWI proteins expression was previously demonstrated in testicular germ cell tumors (TGCTs), implying their involvement in TGCT development. In this work, apart from studying only normal testis and TGCT samples, we also analyzed an intermediate stage, i.e. preneoplastic testis tissues adjacent to TGCTs. Importantly, in this study, we minimized the contribution of patient-to-patient heterogeneity by using matched preneoplastic/TGCT samples. Surprisingly, expression of germ cell marker DDX4 suggests that spermatogenesis is retained in premalignant testis tissues adjacent to nonseminoma, but not those adjacent to seminoma. Moreover, this pattern is followed by expression of PIWI pathway genes, which impacts one of their functions: DNA methylation level over LINE-1 promoters is higher in preneoplastic testis tissues adjacent to nonseminomas than those adjacent to seminomas. This finding might imply distinct routes for development of the two types of TGCTs and could be used as a novel diagnostic marker, possibly, noninvasively. Finally, we studied the role of CpG island methylation in expression of PIWI genes in patient samples and using in vitro experiments in cell line models: a more complex interrelation between DNA methylation and expression of the corresponding genes was revealed.
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