Genome-wide DNA Methylation Profiling Reveals Novel Epigenetically Regulated Genes and Non-coding RNAs in Human Testicular Cancer

Overview

Journal Br J Cancer

Specialty Oncology

Date 2010 Jan 7

PMID 20051947

Citations 57

Authors

H H Cheung

T L Lee

A J Davis

D H Taft

O M Rennert

W Y Chan

Affiliations

Soon will be listed here.

Abstract

Background: Testicular germ cell tumour (TGCT) is the most common malignant tumour in young males. Although aberrant DNA methylation is implicated in the pathophysiology of many cancers, only a limited number of genes are known to be epigenetically changed in TGCT. This report documents the genome-wide analysis of differential methylation in an in vitro model culture system. Interesting genes were validated in TGCT patient samples.

Methods: In this study, we used methylated DNA immunoprecipitation (MeDIP) and whole-genome tiling arrays to identify differentially methylated regions (DMRs).

Results: We identified 35 208 DMRs. However, only a small number of DMRs mapped to promoters. A genome-wide analysis of gene expression revealed a group of differentially expressed genes that were regulated by DNA methylation. We identified several candidate genes, including APOLD1, PCDH10 and RGAG1, which were dysregulated in TGCT patient samples. Surprisingly, APOLD1 had previously been mapped to the TGCT susceptibility locus at 12p13.1, suggesting that it may be important in TGCT pathogenesis. We also observed aberrant methylation in the loci of some non-coding RNAs (ncRNAs). One of the ncRNAs, hsa-mir-199a, was downregulated in TGCT patient samples, and also in our in vitro model culture system.

Conclusion: This report is the first application of MeDIP-chip for identifying epigenetically regulated genes and ncRNAs in TGCT. We also demonstrated the function of intergenic and intronic DMRs in the regulation of ncRNAs.

Citing Articles

Genetic determinants of plasma testosterone in male blood donors are associated with altered red blood cell characteristics and survival in cold storage and after transfusion.

Fang F, Roubinian N, Bean S, Kemmler C, Page G, Kanias T Transfus Apher Sci. 2024; 63(6):104017.

PMID: 39427552 PMC: 11641673. DOI: 10.1016/j.transci.2024.104017.

Targeting the chromatin structural changes of antitumor immunity.

Li N, Lun D, Gong N, Meng G, Du X, Wang H J Pharm Anal. 2024; 14(4):100905.

PMID: 38665224 PMC: 11043877. DOI: 10.1016/j.jpha.2023.11.012.

Epigenetic Factors and ncRNAs in Testicular Cancer.

Nunez-Corona D, Contreras-Sanzon E, Puente-Rivera J, Arreola R, Camacho-Nuez M, Cruz Santiago J Int J Mol Sci. 2023; 24(15).

PMID: 37569569 PMC: 10418327. DOI: 10.3390/ijms241512194.

The vascular gene Apold1 is dispensable for normal development but controls angiogenesis under pathological conditions.

Fan Z, Ardicoglu R, Batavia A, Rust R, von Ziegler L, Waag R Angiogenesis. 2023; 26(3):385-407.

PMID: 36933174 PMC: 10328887. DOI: 10.1007/s10456-023-09870-z.

Integrated Microarray-Based Data Analysis of miRNA Expression Profiles: Identification of Novel Biomarkers of Cisplatin-Resistance in Testicular Germ Cell Tumours.

Roska J, Lobo J, Ivovic D, Wachsmannova L, Mueller T, Henrique R Int J Mol Sci. 2023; 24(3).

PMID: 36768818 PMC: 9916636. DOI: 10.3390/ijms24032495.

References

Ma L, Teruya-Feldstein J, Weinberg R . Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature. 2007; 449(7163):682-8. DOI: 10.1038/nature06174. View

Irizarry R, Ladd-Acosta C, Carvalho B, Wu H, Brandenburg S, Jeddeloh J . Comprehensive high-throughput arrays for relative methylation (CHARM). Genome Res. 2008; 18(5):780-90. PMC: 2336799. DOI: 10.1101/gr.7301508. View

Zhang B, Pan X, Cobb G, Anderson T . microRNAs as oncogenes and tumor suppressors. Dev Biol. 2006; 302(1):1-12. DOI: 10.1016/j.ydbio.2006.08.028. View

Weber M, Davies J, Wittig D, Oakeley E, Haase M, Lam W . Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet. 2005; 37(8):853-62. DOI: 10.1038/ng1598. View

Oka M, Rodic N, Graddy J, Chang L, Terada N . CpG sites preferentially methylated by Dnmt3a in vivo. J Biol Chem. 2006; 281(15):9901-8. DOI: 10.1074/jbc.M511100200. View

Brandt J, Veith A, Volff J . A family of neofunctionalized Ty3/gypsy retrotransposon genes in mammalian genomes. Cytogenet Genome Res. 2005; 110(1-4):307-17. DOI: 10.1159/000084963. View

Koch S, Mayer F, Honecker F, Schittenhelm M, Bokemeyer C . Efficacy of cytotoxic agents used in the treatment of testicular germ cell tumours under normoxic and hypoxic conditions in vitro. Br J Cancer. 2003; 89(11):2133-9. PMC: 2376846. DOI: 10.1038/sj.bjc.6601375. View

Burger H, Nooter K, Boersma A, Kortland C, Stoter G . Expression of p53, Bcl-2 and Bax in cisplatin-induced apoptosis in testicular germ cell tumour cell lines. Br J Cancer. 1998; 77(10):1562-7. PMC: 2150079. DOI: 10.1038/bjc.1998.257. View

Horwich A, Shipley J, Huddart R . Testicular germ-cell cancer. Lancet. 2006; 367(9512):754-65. DOI: 10.1016/S0140-6736(06)68305-0. View

10.

Bibikova M, Lin Z, Zhou L, Chudin E, Garcia E, Wu B . High-throughput DNA methylation profiling using universal bead arrays. Genome Res. 2006; 16(3):383-93. PMC: 1415217. DOI: 10.1101/gr.4410706. View

11.

Migliore C, Petrelli A, Ghiso E, Corso S, Capparuccia L, Eramo A . MicroRNAs impair MET-mediated invasive growth. Cancer Res. 2008; 68(24):10128-36. DOI: 10.1158/0008-5472.CAN-08-2148. View

12.

Huang Q, Gumireddy K, Schrier M, le Sage C, Nagel R, Nair S . The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nat Cell Biol. 2008; 10(2):202-10. DOI: 10.1038/ncb1681. View

13.

Morrow E, Yoo S, Flavell S, Kim T, Lin Y, Hill R . Identifying autism loci and genes by tracing recent shared ancestry. Science. 2008; 321(5886):218-23. PMC: 2586171. DOI: 10.1126/science.1157657. View

14.

Crockford G, Linger R, Hockley S, Dudakia D, Johnson L, Huddart R . Genome-wide linkage screen for testicular germ cell tumour susceptibility loci. Hum Mol Genet. 2006; 15(3):443-51. DOI: 10.1093/hmg/ddi459. View

15.

Andrews P, Matin M, Bahrami A, Damjanov I, Gokhale P, Draper J . Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin. Biochem Soc Trans. 2005; 33(Pt 6):1526-30. DOI: 10.1042/BST0331526. View

16.

Larsen F, Gundersen G, Lopez R, Prydz H . CpG islands as gene markers in the human genome. Genomics. 1992; 13(4):1095-107. DOI: 10.1016/0888-7543(92)90024-m. View

17.

Mares J, Kriz V, Weinhausel A, Vodickova S, Kodet R, Haas O . Methylation changes in promoter and enhancer regions of the WT1 gene in Wilms' tumours. Cancer Lett. 2001; 166(2):165-71. DOI: 10.1016/s0304-3835(01)00402-5. View

18.

Han L, Witmer P, Casey E, Valle D, Sukumar S . DNA methylation regulates MicroRNA expression. Cancer Biol Ther. 2007; 6(8):1284-8. DOI: 10.4161/cbt.6.8.4486. View

19.

Toyota M, Suzuki H, Sasaki Y, Maruyama R, Imai K, Shinomura Y . Epigenetic silencing of microRNA-34b/c and B-cell translocation gene 4 is associated with CpG island methylation in colorectal cancer. Cancer Res. 2008; 68(11):4123-32. DOI: 10.1158/0008-5472.CAN-08-0325. View

20.

Esteller M . Epigenetic gene silencing in cancer: the DNA hypermethylome. Hum Mol Genet. 2007; 16 Spec No 1:R50-9. DOI: 10.1093/hmg/ddm018. View