XIST-promoter demethylation as tissue biomarker for testicular germ cell tumors and spermatogenesis quality
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.
|Keywords||Methylation, Molecular biomarkers, Spermatogenesis, Testicular germ cell tumors, XIST promoter|
|Persistent URL||dx.doi.org/10.3390/cancers11091385, hdl.handle.net/1765/120323|
Lobo, J. (João), Nunes, S.P. (Sandra P.), Gillis, A.J.M. (Ad J. M.), Barros-Silva, D. (Daniela), Miranda-Gonçalves, V. (Vera), van den Berg, A. (Annette), … Looijenga, L.H.J. (2019). XIST-promoter demethylation as tissue biomarker for testicular germ cell tumors and spermatogenesis quality. Cancers, 11(9). doi:10.3390/cancers11091385