TET2

Primary Author(s)*

Paul De Fazio, MSc, Monash Health

Synonyms

• Tet Methylcytosine Dioxygenase 2

• KIAA1546

Genomic Location

Cytoband: 4q24

Genomic Coordinates:

chr4:106,067,032-106,200,973 [hg19]

chr4:105,145,875-105,279,816 [hg38]

Cancer Category/Type

• Clonal Hematopoiesis of Indeterminate Potential (CHIP; premalignant)

• Myelodysplastic Syndrome (MDS)

Recurrent TET2 mutation was first reported in myelodysplastic syndrome (MDS) patients with chromosome 4q24 abnormalities. In this cohort TET2 mutations have been observed in 19-26% of patients and are among the most common genetic lesions (Delhommeau et al., 2009; Langemeijer et al., 2009). Cell lineage evidence supports the notion that TET2 mutations occur very early during disease evolution (Itzykson et al., 2013a; Langemeijer et al., 2009). TET2 mutations are overrepresented in samples with normal cytogenetics (Bejar et al., 2011). Mutations in EZH2 occur in as many as 35% of TET2-mutated MDS (Muto et al., 2013). There is no impact of TET2 mutations on overall survival, but their presence may predict response to hypomethylating agents (Bejar et al., 2011; Itzykson et al., 2011).

• Chronic Myelomonocytic Leukemia (CMML)

Approximately 60% of chronic myelomonocytic leukemia (CMML) is TET2 mutated (Itzykson et al., 2013b). In CMML TET2 mutations are associated with low-risk cytogenetics and a lower platelet count, typically co-occur with mutations in the splicing gene SRSF2, and are mutually exclusive with IDH1 and IDH2 mutations. TET2 mutation has not previously been found to confer an overall survival advantage (Itzykson et al., 2013b), although a more recent study suggests there is enhanced overall survival in TET2-mutated CMML in the absence of ASXL1 mutations (Patnaik et al., 2016).

• Acute Myeloid Leukemia (AML)

In acute myeloid leukemia (AML) TET2 mutations occur in around 28% of patients, of which half have mutations in both alleles (Weissmann et al., 2012). They occur more frequently in patients with normal karyotype and are associated with higher white blood cell counts, lower platelet counts, and a higher age at diagnosis. TET2 mutations predict lower event-free survival, particularly in patients younger than 65 years old and those in the European LeukemiaNet (ELN) favourable-risk subgroup. Overall survival does not seem to be impacted except for in patients with TET2 mutation and intermediate-risk AML, where overall survival is reduced (Patel et al., 2012; Weissmann et al., 2012). There is a strong correlation with JAK2 mutations occurring in patients with TET2-mutated secondary AML after myeloproliferative neoplasm, and there is a highly inverse association between TET2 mutations and mutations in IDH1 and IDH2 (Weissmann et al., 2012). This inverse association is also observed for TET2 and WT1 mutations, and TET2 and WT1 physically interact, suggesting overlapping pathways for these genes in AML (Wang et al., 2015). TET2 mutations increase the response of low blast count AML patients to the hypomethylating agent azacitidine (Itzykson et al., 2011).

• Angioimmunoblastic T-cell Lymphoma (AITL) and Other Nodal Lymphoma of T-follicular Helper (TFH) Cell Origin

TET2 mutations are observed frequently in angioimmunoblastic lymphoma (AITL), with mutation rates of 30-80% depending on study (Odejide et al., 2014; Quivoron et al., 2011). Many TET2-mutated AITLs harbour multiple TET2 mutations. There is a strong positive correlation with DNMT3A mutation, a trend towards older age at diagnosis, and an increased association with elevated lactate dehydrogenase (LDH) (Odejide et al., 2014). Around 20% of TET2-mutated AITL also carry an IDH2 mutation, which is in stark contrast with the strong negative correlation between these two genes in other haematological malignancies (Odejide et al., 2014). No difference in overall survival is evident for TET2-mutated AITL compared to wild-type.

TET2 mutations are associated with a T-follicular like cellular phenotype and may be associated with non-AITL TFH subtypes, as defined by the World Health Organisation (Swerdlow et al., 2017).

• Peripheral T-cell Lymphoma (PTCL)

Peripheral T-cell lymphoma (PTCL) is TET2-mutated at a frequency of ~20-40% (Lemonnier et al., 2012; Quivoron et al., 2011). TET2 mutations in this disease correlate with T follicular helper cell features or features similar to AITL in addition to advanced-stage disease and shorter progression-free survival (Lemonnier et al., 2012).

• Diffuse Large B-Cell Lymphoma (DLBCL)

TET2 mutations are observed in diffuse large B-cell lymphoma (DLBCL) at a rate of 6-15% (Asmar et al., 2011; Quivoron et al., 2011). They do not appear to confer prognostic value in DLBCL, and are not observed in other B-cell neoplasms.

• Glioma

IDH1/2 mutations are observed frequently in grades II and III gliomas and secondary glioblastomas (Yan et al., 2009), but despite the overlapping pathways between the IDH1/2 and TET2 genes mutations in the latter are rarely observed in glioma and do not appear to have pathogenic effect (Kraus et al., 2015). However, TET2 promoter methylation has been observed in IDH1/2 wild-type but not mutant glioma suggesting that methylation of the TET2 promoter and not coding region mutations are biologically relevant in this disease (Kim et al., 2011).

• Prostate Cancer

In prostate cancer TET2 is downregulated, possibly through androgen receptor-mediated induction of the miR-29 microRNA family, and loss of TET2 expression is associated with cancer progression (Takayama et al., 2015). Germline TET2 variants may also be a risk factor for prostate cancer (Koutros et al., 2013).

• Ovarian Cancer

Exome sequencing of ovarian clear cell carcinoma revealed frequent (73%) copy number losses affecting TET2 (Kim et al., 2018). DNA demethylation, measured by 5-hmC levels, and TET2 expression appear to hold prognostic value in epithelial ovarian cancer, with higher values significantly associated with improved overall survival (Zhang et al., 2015).

• Breast Cancer

Reduction of 5hmC and TET2 expression is associated with disease progression in breast cancer and may predict a poorer overall survival (Tsai et al., 2015; Yang et al., 2015). Germline variants in the TET2 promoter and enhancer regions may correlate with increased breast cancer risk (Guo et al., 2015).

• Colorectal Cancer

Loss of TET2 nuclear localisation has been observed in colorectal cancer cells in association with metastasis (Huang et al., 2016). Colorectal cancer cells exhibit reduced TET2 transcript levels, while patients with high TET2 mRNA levels in cells from histologically unchanged tissue have higher overall survival (Rawłuszko-Wieczorek et al., 2015).

• Gastric Cancer

5-hmC and TET2 expression levels in gastric cancer are also decreased (Du et al., 2015), and reduced 5-hmC levels may be an independent poor prognostic factor in these patients (Deng et al., 2016; Yang et al., 2013). TET2 may have protective effects against DNA methylation in gastric epithelial cells following Epstein-Barr virus (EBV) infection (Namba-Fukuyo et al., 2016).

• Endometrial Cancer

Increased metastasis and disease stage in endometrial cancer is correlated with decreased TET2 expression levels (Ciesielski et al., 2017). In contrast with breast and prostate cancer, at least one germline TET2 variant (rs7679673) may predict decreased risk for this disease (Setiawan et al., 2014).

Gene Overview

TET2 is a member of the ten-eleven translocation (TET) family along with TET1 and TET3 (Lorsbach et al., 2003). The TET family proteins play key roles in DNA cytosine demethylation. All family members share a C-terminal catalytic double-stranded β-helix dioxygenase domain which has oxidating activity against 5-methylcytosine (5-mC). This domain also has binding sites for α-ketoglutarate (αKG) and Fe(II) which are required for its catalytic function. The middle portion of the TET protein is a cysteine-rich domain with unknown function.

The N-terminal region of TET1 and TET3 contain a conserved CXXC-type domain that is critical for binding to unmethylated cytosine residues, but TET2 lacks this domain. It is hypothesised that the CXXC-type domain of TET2 separated during evolution to become the CXXC-containing gene IDAX, which is located at the 5’ end of TET2 in the opposite orientation. IDAX can apparently negatively regulate TET2 (Ko et al., 2013).

Cytosine residue methylation mediated by DNA methyltransferase (DNMT) is an important mechanism for gene expression regulation (Wu and Zhang, 2014). TET family proteins demethylate cytosine residues by converting 5-mC to 5-hydroxymetylcytosine (5-hmC). Methylation is then removed either by “passive dilution”, whereby methylation status is not replicated onto the newly synthesised DNA strand after DNA replication, or after further processing by TET proteins or other enzymes which allow base excision DNA repair to convert the residue back into cytosine (Wu and Zhang, 2014).

TET family proteins also interact with O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) to facilitate chromatin modification, another important regulator of gene transcription (Chen et al., 2013). The TET-OGT interaction augments OGT activity resulting in enhanced O-GlcNAcylation of target proteins such as histone 2B (H2B) and host cell factor 1 (HCF1), and also recruits OGT directly to the transcriptional start sites of certain target genes (Deplus et al., 2013; Vella et al., 2013).

Mouse studies demonstrate that TET2 plays a critical role in the regulation of haematopoiesis by controlling stem and progenitor cell homeostasis (Quivoron et al., 2011). Evidence suggests that TET2 functions as a tumour suppressor in mice and humans (Quivoron et al., 2011).

Most TET2 mutations in human cancers are missense mutations in the C-terminal catalytic domain or nonsense/frameshift mutations that cause truncation of the protein upstream of the catalytic domain (Cimmino et al., 2011). This mutational pattern is consistent with the role of TET2 as a tumour suppressor.

In mouse models TET2 homozygous mutations result in multipotent progenitor cell and myeloid progenitor cell expansion, enhanced haematopoietic stem cell (HSC) self-renewal, and disruption of myeloid differentiation (Kunimoto et al., 2012). These phenotypes are recapitulated by TET2 haploinsufficiency, suggesting that heterozygous mutations are sufficient to impair haematopoiesis (Moran-Crusio et al., 2011). There is interplay between TET2 and the TCA cycle genes IDH1 and IDH2 (Figueroa et al., 2010). IDH1 and IDH2 produce αKG which is required for TET2 function.

TET2 mutations are found most often in haematological malignancies, where they appear to be early genetic events (Pan et al., 2015). Somatic TET2 mutations are recurrent in otherwise healthy elderly individuals as part of a process called clonal haematopoiesis of indeterminate potential, or CHIP (Busque et al., 2012; Solary et al., 2014; Steensma et al., 2015). TET2 also appears to play roles in other cancers, but evidence is more limited.

Common Alteration Types

The most common alterations appearing in the COSMIC database of somatic mutations are missense mutations in the C-terminal catalytic domain (e.g. c.5284A>G p.I1762V, c.5162T>G p.L1721W, c.5618T>C p.I1873T; all NM_001127208.2 ) or nonsense mutations which truncate the catalytic domain (e.g. c.1648C>T p.R550*, c.4393C>T p.R1465*, c.2746C>T p.Q916*; all NM_001127208.2) (source: COSMIC). The catalytic domain lies between residues 1290 and 1905 (NM_001127208.2) based on alignment similarity (source: Pfam).

Copy Number Loss	Copy Number Gain	LOH	Loss-of-Function Mutation	Gain-of-Function Mutation	Translocation/Fusion
EXAMPLE: X	EXAMPLE: X	EXAMPLE: X	EXAMPLE: X	EXAMPLE: X	EXAMPLE: X

Internal Pages

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External Links

TET2 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information

TET2 by COSMIC - sequence information, expression, catalogue of mutations

TET2 by CIViC - general knowledge and evidence-based variant specific information

TET2 by St. Jude ProteinPaint - mutational landscape and matched expression data

TET2 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs

TET2 by Cancer Index - gene, pathway, publication information matched to cancer type

TET2 by OncoKB - mutational landscape, mutation effect, variant classification

TET2 by My Cancer Genome - brief gene overview

TET2 by UniProt - protein and molecular structure and function

TET2 by Pfam - gene and protein structure and function information

TET2 by GeneCards - general gene information and summaries

References

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• Bejar, R., Stevenson, K., Abdel-Wahab, O., Galili, N., Nilsson, B., Garcia-Manero, G., Kantarjian, H., Raza, A., Levine, R.L., Neuberg, D., et al. (2011). Clinical effect of point mutations in myelodysplastic syndromes. N. Engl. J. Med. 364, 2496–2506. PMID: 21714648

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• Chen, Q., Chen, Y., Bian, C., Fujiki, R., and Yu, X. (2013). TET2 promotes histone O-GlcNAcylation during gene transcription. Nature 493, 561–564. PMID: 23222540

• Ciesielski, P., Jóźwiak, P., Wójcik-Krowiranda, K., Forma, E., Cwonda, Ł., Szczepaniec, S., Bieńkiewicz, A., Bryś, M., and Krześlak, A. (2017). Differential expression of ten-eleven translocation genes in endometrial cancers. Tumour Biol. 39, 1010428317695017. PMID: 28349832

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• Moran-Crusio, K., Reavie, L., Shih, A., Abdel-Wahab, O., Ndiaye-Lobry, D., Lobry, C., Figueroa, M.E., Vasanthakumar, A., Patel, J., Zhao, X., et al. (2011). Tet2 Loss Leads to Increased Hematopoietic Stem Cell Self-Renewal and Myeloid Transformation. Cancer Cell 20, 11–24. PMID: 21723200

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• Namba-Fukuyo, H., Funata, S., Matsusaka, K., Fukuyo, M., Rahmutulla, B., Mano, Y., Fukayama, M., Aburatani, H., and Kaneda, A. (2016). TET2 functions as a resistance factor against DNA methylation acquisition during Epstein-Barr virus infection. Oncotarget 7, 81512–81526. PMID: 27829228

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• Quivoron, C., Couronné, L., Della Valle, V., Lopez, C.K., Plo, I., Wagner-Ballon, O., Do Cruzeiro, M., Delhommeau, F., Arnulf, B., Stern, M.-H., et al. (2011). TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 20, 25–38. PMID: 21723201

• Rawłuszko-Wieczorek, A.A., Siera, A., Horbacka, K., Horst, N., Krokowicz, P., and Jagodziński, P.P. (2015). Clinical significance of DNA methylation mRNA levels of TET family members in colorectal cancer. J. Cancer Res. Clin. Oncol. 141, 1379–1392. PMID: 25557833

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• Takayama, K., Misawa, A., Suzuki, T., Takagi, K., Hayashizaki, Y., Fujimura, T., Homma, Y., Takahashi, S., Urano, T., and Inoue, S. (2015). TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression. Nat Commun 6, 8219. PMID: 26404510

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• Yang, L., Yu, S.-J., Hong, Q., Yang, Y., and Shao, Z.-M. (2015). Reduced Expression of TET1, TET2, TET3 and TDG mRNAs Are Associated with Poor Prognosis of Patients with Early Breast Cancer. PLoS ONE 10, e0133896. PMID: 26207381

• Yang, Q., Wu, K., Ji, M., Jin, W., He, N., Shi, B., and Hou, P. (2013). Decreased 5-hydroxymethylcytosine (5-hmC) is an independent poor prognostic factor in gastric cancer patients. J Biomed Nanotechnol 9, 1607–1616. PMID: 23980508

• Zhang, L.-Y., Li, P.-L., Wang, T.-Z., and Zhang, X.-C. (2015). Prognostic values of 5-hmC, 5-mC and TET2 in epithelial ovarian cancer. Arch. Gynecol. Obstet. 292, 891–897. PMID: 25827305

Notes

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