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Open AccessArticle

XIST-Promoter Demethylation as Tissue Biomarker for Testicular Germ Cell Tumors and Spermatogenesis Quality

1
Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands
2
Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
3
Cancer Biology and Epigenetics Group, Research Center of Portuguese Oncology Institute of Porto (GEBC CI-IPOP) and Porto Comprehensive Cancer Center (P.CCC), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
4
Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal
5
Department of Pathology, Lab. for Exp. Patho-Oncology (LEPO), Erasmus MC-University Medical Center Rotterdam, Cancer Institute, Be-432A, PO Box 2040, 3000 CA Rotterdam, The Netherlands
*
Author to whom correspondence should be addressed.
Contributed equally to the work.
Cancers 2019, 11(9), 1385; https://doi.org/10.3390/cancers11091385
Received: 29 August 2019 / Revised: 13 September 2019 / Accepted: 14 September 2019 / Published: 17 September 2019
(This article belongs to the Collection Germ Cell Tumors)
Background: The event of X chromosome inactivation induced by XIST, which is physiologically observed in females, is retained in testicular germ cell tumors (TGCTs), as a result of a supernumerary X chromosome constitution. X chromosome inactivation also occurs in male germline, specifically during spermatogenesis. We aimed to analyze the promoter methylation status of XIST in a series of TGCT tissues, representative cell lines, and testicular parenchyma. Methods: Two independent cohorts were included, comprising a total of 413 TGCT samples, four (T)GCT cell lines, and 86 testicular parenchyma samples. The relative amount of methylated and demethylated XIST promoter fragments was assessed by quantitative methylation-specific PCR (qMSP) and more sensitive high-resolution melting (HRM) methylation analyses. Results: Seminomas showed a lower amount of methylated XIST fragments as compared to non-seminomas or normal testis (p < 0.0001), allowing for a good discrimination among these groups (area under the curve 0.83 and 0.81, respectively). Seminomas showed a significantly higher content of demethylated XIST as compared to non-seminomas. The percentage of demethylated XIST fragment in cell lines reflected their chromosomal constitution (number of extra X chromosomes). A novel and strong positive correlation between the Johnsen’s score and XIST demethylation was identified (r = 0.75, p < 0.0001). Conclusions: The X chromosome inactivation event and demethylated XIST promoter are promising biomarkers for TGCTs and for assessing spermatogenesis quality. View Full-Text
Keywords: molecular biomarkers; testicular germ cell tumors; spermatogenesis; methylation; XIST promoter molecular biomarkers; testicular germ cell tumors; spermatogenesis; methylation; XIST promoter
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MDPI and ACS Style

Lobo, J.; Nunes, S.P.; Gillis, A.J.M.; Barros-Silva, D.; Miranda-Gonçalves, V.; Berg, A.v.d.; Cantante, M.; Guimarães, R.; Henrique, R.; Jerónimo, C.; Looijenga, L.H.J. XIST-Promoter Demethylation as Tissue Biomarker for Testicular Germ Cell Tumors and Spermatogenesis Quality. Cancers 2019, 11, 1385.

AMA Style

Lobo J, Nunes SP, Gillis AJM, Barros-Silva D, Miranda-Gonçalves V, Berg Avd, Cantante M, Guimarães R, Henrique R, Jerónimo C, Looijenga LHJ. XIST-Promoter Demethylation as Tissue Biomarker for Testicular Germ Cell Tumors and Spermatogenesis Quality. Cancers. 2019; 11(9):1385.

Chicago/Turabian Style

Lobo, João; Nunes, Sandra P.; Gillis, Ad J. M.; Barros-Silva, Daniela; Miranda-Gonçalves, Vera; Berg, Annette van den; Cantante, Mariana; Guimarães, Rita; Henrique, Rui; Jerónimo, Carmen; Looijenga, Leendert H. J. 2019. "XIST-Promoter Demethylation as Tissue Biomarker for Testicular Germ Cell Tumors and Spermatogenesis Quality" Cancers 11, no. 9: 1385.

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