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Hypermethylation of genes in testicular embryonal carcinomas.

ABSTRACT: Testicular embryonal carcinoma (EC) is a major subtype of non-seminomatous germ cell tumours in males. Embryonal carcinomas are pluripotent, undifferentiated germ cell tumours believed to originate from primordial germ cells. Epigenetic changes during testicular EC tumorigenesis require better elucidation.To identify epigenetic changes during testicular neoplastic transformation, we profiled DNA methylation of six ECs. These samples represent different stages (stage I and stage III) of divergent invasiveness. Non-cancerous testicular tissues were included. Expression of a number of hypermethylated genes were examined by quantitative RT-PCR and immunohistochemistry (IHC).A total of 1167 tumour-hypermethylated differentially methylated regions (DMRs) were identified across the genome. Among them, 40 genes/ncRNAs were found to have hypermethylated promoters. Quantitative RT-PCR confirmed downregulation of 8 out of 9 of the genes. Among the confirmed genes, five were sex-linked genes, including X-linked genes STAG2, SPANXD/E and MIR1184, and Y-linked genes RBMY1A1/1B/1D and FAM197Y2P. RBMY1A is a testis-specific gene for spermatogenesis. RNF168 and USP13 are potential tumour suppressors. Expression of RBMY1A was lost in EC and seminoma as documented in the Protein Atlas. We confirmed downregulation of USP13 in EC by IHC.Our genome-wide analysis of testicular EC identified methylation changes in several previously unknown genes. This may provide insight of crosstalk between normal germ cell development and carcinogenesis.

SUBMITTER: Cheung HH

PROVIDER: S-EPMC4815804 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Hypermethylation of genes in testicular embryonal carcinomas.

Cheung Hoi-Hung HH Yang Yanzhou Y Lee Tin-Lap TL Rennert Owen O Chan Wai-Yee WY

British journal of cancer 20151201 2

<h4>Background</h4>Testicular embryonal carcinoma (EC) is a major subtype of non-seminomatous germ cell tumours in males. Embryonal carcinomas are pluripotent, undifferentiated germ cell tumours believed to originate from primordial germ cells. Epigenetic changes during testicular EC tumorigenesis require better elucidation.<h4>Methods</h4>To identify epigenetic changes during testicular neoplastic transformation, we profiled DNA methylation of six ECs. These samples represent different stages ( ...[more]

PMID: 26625006

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Project description:Many cancers may originate in stem or early progenitor cells 1-4 which depend on epigenetic modulation of gene expression for normal function (ref). We have studied whether epigenetic states in cancers, and particularly abnormal gene silencing associated with promoter DNA hypermethylation in CpG rich regions (refs), may represent links between cancer and stem cell epigenetic patterns. We studied embryonal carcinomas (EC) which are malignancies of embryonic stem (ES) cells, but retain high potential for multi-lineage differentiation 5-8. Surprisingly, genes DNA hypermethylated and silenced in adult cancers are unmethylated in ES and EC cells. Remarkably, the promoter chromatin of the genes in EC cells is virtually identical to the same genes in adult cancers when the latter are induced to de-methylate. This chromatin, as recently reported for CpG island promoters of low expression, developmentally related, genes in ES cells (refs), is âbivalentâ and contains both active and repressive histone modifications. The latter includes trimethyl lysine 27 of histone H3 (H3K27me3), which may recruit DNA methylation (refs), and the promoter regions are enriched for polycomb group (PcG) proteins which place this H3K27me3 mark. Thus, many genes which undergo abnormal DNA methylation and permanent silencing in adult cancers may be programmed to do so by a pre-existent stem cell-like chromatin pattern inherent to the cells in which they arise. Experiment Overall Design: Data analysis. All arrays were subject to quality checks recommended by the manufacturer. Images were visually inspected for artifacts and distributions of signal and background intensity of both red and green channels are examined to identify anomalous arrays. No irregularities were observed, and all arrays were retained and used. Experiment Overall Design: All calculations were performed using the R statistical computing platform, (cite R) and packages from Bioconductor bioinformatics software project (cite Bioconductor). The log ratio of red median signal to green median signal was calculated after background-subtraction and loess normalzation as implemented in the limma package from Bioconductor. ( cite Smyth) Individual arrays were scaled to have the same inter-quartile range (75th percentile -25th percentile) Log fold changes were averaged over dye-swap replicate microarrays to produce a single set of expression values for each condition.

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Hypermethylation of genes in testicular embryonal carcinomas.

Publications

Hypermethylation of genes in testicular embryonal carcinomas.

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