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→Cancer Category/Type
==Cancer Category/Type==
==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).
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).
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) and Related Precursor Neoplasms]]'''
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).
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 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).
''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).
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]]'''
''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.
''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).
''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).
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).
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).
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).
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).
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).
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).