Abstract
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.
Highlights
Germ cell tumors (GCTs) are remarkable developmental cancers, meaning that they recapitulate the various steps of embryonic and germ cell development, reflecting the main characteristics of their cells of origin [1]
We first focused on the methylated XIST promoter fragment, in our discovery cohort
GCTs are remarkable for their intimate connection with developmental biology
Summary
Germ cell tumors (GCTs) are remarkable developmental cancers, meaning that they recapitulate the various steps of embryonic and germ cell development, reflecting the main characteristics of their cells of origin [1]. The type II tumors are the most frequent and clinically relevant [6] They derive from a common precursor lesion, germ cell neoplasia in situ (GCNIS), and are divided into the following two major and relevant categories, with distinct clinical behavior: the seminomas (SEs) and the various non-seminoma (NS) subtypes, including embryonal carcinoma (EC), (postpubertal-type) yolk sac tumor (YST), choriocarcinoma (CH), and (postpubertal-type) teratoma (TE) [7]. For these tumors, developmental biology has an invaluable impact by driving the identification of relevant disease biomarkers. We aimed to analyze the promoter methylation status of XIST in a series of TGCT tissues, representative cell lines, and testicular parenchyma
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