Meta-analysis of IDH-mutant Cancers Identifies EBF1 As an Interaction Partner for TET2

Overview

Journal Nat Commun

Specialty Biology

Date 2013 Jul 19

PMID 23863747

Citations 93

Authors

Paul Guilhamon

Malihe Eskandarpour

Dina Halai

Gareth A Wilson

Andrew Feber

Andrew E Teschendorff

Valenti Gomez

Alexander Hergovich

Roberto Tirabosco

M Fernanda Amary

Daniel Baumhoer

Gernot Jundt

Mark T Ross

Adrienne M Flanagan

Stephan Beck

Affiliations

Soon will be listed here.

Abstract

Isocitrate dehydrogenase (IDH) genes 1 and 2 are frequently mutated in acute myeloid leukaemia (AML), low-grade glioma, cholangiocarcinoma (CC) and chondrosarcoma (CS). For AML, low-grade glioma and CC, mutant IDH status is associated with a DNA hypermethylation phenotype, implicating altered epigenome dynamics in the aetiology of these cancers. Here we show that the IDH variants in CS are also associated with a hypermethylation phenotype and display increased production of the oncometabolite 2-hydroxyglutarate, supporting the role of mutant IDH-produced 2-hydroxyglutarate as an inhibitor of TET-mediated DNA demethylation. Meta-analysis of the acute myeloid leukaemia, low-grade glioma, cholangiocarcinoma and CS methylation data identifies cancer-specific effectors within the retinoic acid receptor activation pathway among the hypermethylated targets. By analysing sequence motifs surrounding hypermethylated sites across the four cancer types, and using chromatin immunoprecipitation and western blotting, we identify the transcription factor EBF1 (early B-cell factor 1) as an interaction partner for TET2, suggesting a sequence-specific mechanism for regulating DNA methylation.

Citing Articles

Selective Estrogen Receptor Modulators' (SERMs) Influence on Expression in Breast Cancer Cell Lines with Distinct Biological Subtypes.

Linowiecka K, Szpotan J, Godlewska M, Gawel D, Zarakowska E, Gackowski D Int J Mol Sci. 2024; 25(16).

PMID: 39201247 PMC: 11354732. DOI: 10.3390/ijms25168561.

Clinico-Genomic Profiling of Conventional and Dedifferentiated Chondrosarcomas Reveals TP53 Mutation to Be Associated with Worse Outcomes.

Denu R, Yang R, Lazar A, Patel S, Lewis V, Roszik J Clin Cancer Res. 2023; 29(23):4844-4852.

PMID: 37747813 PMC: 10835757. DOI: 10.1158/1078-0432.CCR-23-1703.

TET (Ten-eleven translocation) family proteins: structure, biological functions and applications.

Zhang X, Zhang Y, Wang C, Wang X Signal Transduct Target Ther. 2023; 8(1):297.

PMID: 37563110 PMC: 10415333. DOI: 10.1038/s41392-023-01537-x.

Genetic impacts on DNA methylation help elucidate regulatory genomic processes.

Villicana S, Castillo-Fernandez J, Hannon E, Christiansen C, Tsai P, Maddock J Genome Biol. 2023; 24(1):176.

PMID: 37525248 PMC: 10391992. DOI: 10.1186/s13059-023-03011-x.

Mutations in Chondrosarcoma: Case Closed or Not?.

Venneker S, Bovee J Cancers (Basel). 2023; 15(14).

PMID: 37509266 PMC: 10377514. DOI: 10.3390/cancers15143603.

References

Soprano K, Soprano D . Retinoic acid receptors and cancer. J Nutr. 2002; 132(12):3809S-3813S. DOI: 10.1093/jn/132.12.3809S. View

Kim Y, Pierscianek D, Mittelbronn M, Vital A, Mariani L, Hasselblatt M . TET2 promoter methylation in low-grade diffuse gliomas lacking IDH1/2 mutations. J Clin Pathol. 2011; 64(10):850-2. DOI: 10.1136/jclinpath-2011-200133. View

Thirlwell C, Eymard M, Feber A, Teschendorff A, Pearce K, Lechner M . Genome-wide DNA methylation analysis of archival formalin-fixed paraffin-embedded tissue using the Illumina Infinium HumanMethylation27 BeadChip. Methods. 2010; 52(3):248-54. DOI: 10.1016/j.ymeth.2010.04.012. View

Amary M, Damato S, Halai D, Eskandarpour M, Berisha F, Bonar F . Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat Genet. 2011; 43(12):1262-5. DOI: 10.1038/ng.994. View

Portela A, Esteller M . Epigenetic modifications and human disease. Nat Biotechnol. 2010; 28(10):1057-68. DOI: 10.1038/nbt.1685. View

Teschendorff A, Menon U, Gentry-Maharaj A, Ramus S, Gayther S, Apostolidou S . An epigenetic signature in peripheral blood predicts active ovarian cancer. PLoS One. 2009; 4(12):e8274. PMC: 2793425. DOI: 10.1371/journal.pone.0008274. View

Rakyan V, Down T, Balding D, Beck S . Epigenome-wide association studies for common human diseases. Nat Rev Genet. 2011; 12(8):529-41. PMC: 3508712. DOI: 10.1038/nrg3000. View

Figueroa M, Abdel-Wahab O, Lu C, Ward P, Patel J, Shih A . Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010; 18(6):553-67. PMC: 4105845. DOI: 10.1016/j.ccr.2010.11.015. View

Bibikova M, Barnes B, Tsan C, Ho V, Klotzle B, Le J . High density DNA methylation array with single CpG site resolution. Genomics. 2011; 98(4):288-95. DOI: 10.1016/j.ygeno.2011.07.007. View

10.

Wang P, Dong Q, Zhang C, Kuan P, Liu Y, Jeck W . Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene. 2012; 32(25):3091-100. PMC: 3500578. DOI: 10.1038/onc.2012.315. View

11.

Krueger F, Kreck B, Franke A, Andrews S . DNA methylome analysis using short bisulfite sequencing data. Nat Methods. 2012; 9(2):145-51. DOI: 10.1038/nmeth.1828. View

12.

Ye D, Xiong Y, Guan K . The mechanisms of IDH mutations in tumorigenesis. Cell Res. 2012; 22(7):1102-4. PMC: 3391014. DOI: 10.1038/cr.2012.51. View

13.

Krueger F, Andrews S . Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics. 2011; 27(11):1571-2. PMC: 3102221. DOI: 10.1093/bioinformatics/btr167. View

14.

Li Y, Zhu J, Tian G, Li N, Li Q, Ye M . The DNA methylome of human peripheral blood mononuclear cells. PLoS Biol. 2010; 8(11):e1000533. PMC: 2976721. DOI: 10.1371/journal.pbio.1000533. View

15.

He Y, Li B, Li Z, Liu P, Wang Y, Tang Q . Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. 2011; 333(6047):1303-7. PMC: 3462231. DOI: 10.1126/science.1210944. View

16.

Tahiliani M, Koh K, Shen Y, Pastor W, Bandukwala H, Brudno Y . Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009; 324(5929):930-5. PMC: 2715015. DOI: 10.1126/science.1170116. View

17.

Tang X, Gudas L . Retinoids, retinoic acid receptors, and cancer. Annu Rev Pathol. 2010; 6:345-64. DOI: 10.1146/annurev-pathol-011110-130303. View

18.

Turcan S, Rohle D, Goenka A, Walsh L, Fang F, Yilmaz E . IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012; 483(7390):479-83. PMC: 3351699. DOI: 10.1038/nature10866. View

19.

Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim S . Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011; 19(1):17-30. PMC: 3229304. DOI: 10.1016/j.ccr.2010.12.014. View

20.

Weissmann S, Alpermann T, Grossmann V, Kowarsch A, Nadarajah N, Eder C . Landscape of TET2 mutations in acute myeloid leukemia. Leukemia. 2011; 26(5):934-42. DOI: 10.1038/leu.2011.326. View