Changes

==Cancer Category/Type==

==Cancer Category/Type==

Glioma, astrocytoma, oligodendroglioma, acute myeloid leukaemia, myelodysplastic syndrome, lymphoma, prostate cancer, thyroid cancer

* Glioma

 

 

 

 

 

 

* Acute myeloid leukaemia

 

 

* Myelodysplastic syndrome

 

 

 

 

* Prostate cancer

 

 

* Thyroid cancer

==Gene Overview==

==Gene Overview==

''IDH1'' mutations are most common in certain glioma subtypes, having been identified in approximately 80% of WHO grade II and III astrocytomas and oligodendrogliomas, and secondary glioblastomas [20]. In the context of glioma, ''IDH1'' mutations are associated with an improved outcome and a younger age at diagnosis [21,22]. They are, however, rare in patients younger than 18 years.

''IDH1'' mutations are most common in certain glioma subtypes, having been identified in approximately 80% of WHO grade II and III astrocytomas and oligodendrogliomas, and secondary glioblastomas [20]. In the context of glioma, ''IDH1'' mutations are associated with an improved outcome and a younger age at diagnosis [21,22]. They are, however, rare in patients younger than 18 years.

Up to 40% of chondrosarcomas have been observed with IDH1 mutations, where they predict a shorter survival than in patients without ''IDH1'' mutations. There are no clear associations with ''IDH1'' mutation status and histological grade or age at diagnosis in the context of chondrosarcomas [23,24]. ''IDH1'' mutations are not observed in other mesenchymal tumours. One study found somatic ''IDH1'' mutations in a majority (~80%) of enchondromas and spindle cell hemangiomas from patients with Ollier disease and Maffucci syndrome [25].

Up to 40% of chondrosarcomas have been observed with ''IDH1'' mutations, where they predict a shorter survival than in patients without ''IDH1'' mutations. There are no clear associations with ''IDH1'' mutation status and histological grade or age at diagnosis in the context of chondrosarcomas [23,24]. ''IDH1'' mutations are not observed in other mesenchymal tumours. Somatic ''IDH1'' mutations were reported in a majority (~80%) of enchondromas and spindle cell hemangiomas from patients with Ollier disease and Maffucci syndrome [25].

Although ''IDH1'' mutations are rare in gastrointestinal malignancies, they are found in around 20% of intrahepatic cholangiocarcinomas (ICC). In this context, IDH1 mutations are associated with a longer time to tumour recurrence and a lower probability of recurrence[26–28]. The prognostic outlook for overall survival in these patients is unclear as data in the literature is mixed [26,29,30].

Although ''IDH1'' mutations are rare in gastrointestinal malignancies, they are found in around 20% of intrahepatic cholangiocarcinomas (ICC). In this context, ''IDH1'' mutations are associated with a longer time to tumor recurrence and a lower probability of recurrence [26–28]. The prognostic outlook for overall survival in these patients is unclear as data in the literature is mixed [26,29,30].

Approximately 8% of acute myeloid leukaemias (AML) harbour ''IDH1'' mutations, although the frequency is higher in patients with normal karyotype[31]. Studies have been conflicted regarding the prognostic outlook of ''IDH1'' mutations in AML, but a meta-analysis of published data in 2017 found that overall survival and event-free survival were negatively impacted by IDH1 mutations, particularly in patients with normal karyotype [32]. The cumulative incidence of relapse in patients with intermediate-risk karyotype was improved, however. Interestingly, the synonymous single nucleotide polymorphism rs11554137 in ''IDH1'' was also associated with poorer overall survival. ''IDH1''-mutated AML is not found significantly more frequently in younger patients [31]. ''IDH1'' mutations are seen more often in the M1 French-American-British AML subtype when compared to ''IDH1'' wild-type AML [33].

Approximately 8% of acute myeloid leukemias (AML) harbor ''IDH1'' mutations, although the frequency is higher in patients with normal karyotype [31]. Studies have been conflicted regarding the prognostic outlook of ''IDH1'' mutations in AML, but a meta-analysis of published data in 2017 found that overall survival and event-free survival were negatively impacted by ''IDH1'' mutations, particularly in patients with normal karyotype [32]. In contrast, the cumulative incidence of relapse in patients with intermediate-risk karyotype was improved. Interestingly, the synonymous single nucleotide polymorphism rs11554137 in ''IDH1'' was also associated with poorer overall survival. ''IDH1''-mutated AML is not found significantly more frequently in younger patients [31]. ''IDH1'' mutations are seen more often in the M1 French-American-British AML subtype when compared to ''IDH1'' wild-type AML [33].

''IDH1'' mutations are seen less commonly in other haematological malignancies such as myelodysplastic syndrome [34] and also in cancers of the prostate and thyroid [19], and are less well-studied in these contexts. Mutations of ''IDH1'' have been shown to often be stem or early subclonal events in carcinogenesis in all cancers studied thus far, including AML [25,35–38].

''IDH1'' mutations are seen less commonly in other hematological malignancies such as myelodysplastic syndrome [34] and also in cancers of the prostate and thyroid [19], and are less well-studied in these contexts. Mutations of ''IDH1'' have been shown to often be stem or early subclonal events in carcinogenesis in all cancers studied thus far, including AML [25,35–38].

The precise mechanisms linking ''IDH1'' mutations to various cancers are as yet unknown and are likely to be tissue-specific, but ''IDH1''-mutant cells do exhibit defects in multiple cellular processes. The most commonly seen IDH1 variants across all tumour types are heterozygous missense mutations at Arg132 (R132, NM_005896.2/NP_005887.2) [19]. Consistent with the role of R132 in active site conformation transition, alteration of R132 changes the equilibrium between open and closed conformations [39]. The IDH1 R132 mutation results in decreased enzyme affinity for isocitrate[4] and reduced NADPH production [20]. Most notably, the mutation also leads to IDH1 gaining the ability to reduce αKG to D-2-hydroxyglutarate (2HG) [39]. This neomorphic activity causes accumulation of 2HG and reduction of αKG levels.  

The precise mechanisms linking ''IDH1'' mutations to various cancers are as yet unknown and are likely to be tissue-specific, but ''IDH1''-mutant cells do exhibit defects in multiple cellular processes. The most commonly seen ''IDH1'' variants across all tumor types are heterozygous missense mutations at Arg132 (R132, NM_005896.2/NP_005887.2) [19]. Consistent with the role of R132 in active site conformation transition, alteration of R132 changes the equilibrium between open and closed conformations [39]. The ''IDH1'' R132 mutation results in decreased enzyme affinity for isocitrate [4] and reduced NADPH production [20]. Most notably, the mutation also leads to IDH1 gaining the ability to reduce αKG to D-2-hydroxyglutarate (2HG) [39]. This neomorphic activity causes accumulation of 2HG and reduction of αKG levels.  

Due to this altered enzyme function, ''IDH1'' R132 mutants exhibit complex metabolic perturbations. Like other Warburg-like cancer cells, ''IDH1'' wild-type glioma overexpresses enzymes involved in anaerobic glycolysis[5], as glycolysis and lactate production has the ability to generate both the energy and carbon required for sustained proliferation [41]. IDH1 R132 mutant glioma in contrast downregulates glycolytic enzymes, instead preferring to catabolise glutamate and glucose in the TCA cycle to produce αKG [5]. Genes downstream of isocitrate in the TCA cycle are downregulated in IDH1 R132 mutant glioma while expression of genes functioning upstream of isocitrate is increased [5]. ''IDH1'' R132 mutant cells are therefore more reliant on oxidative phosphorylation compared to ''IDH1'' wild-type cells. The metabolic rewiring in ''IDH1'' R132 mutants is further evidenced by observations of increased mitochondrial gene expression and mitochondrial number in mutant ICC cells [36].

Due to this altered enzyme function, ''IDH1'' R132 mutants exhibit complex metabolic perturbations. Like other Warburg-like cancer cells, ''IDH1'' wild-type glioma overexpresses enzymes involved in anaerobic glycolysis [5], as glycolysis and lactate production has the ability to generate both the energy and carbon required for sustained proliferation [41]. ''IDH1'' R132 mutant glioma in contrast downregulates glycolytic enzymes, instead preferring to catabolise glutamate and glucose in the TCA cycle to produce αKG [5]. Genes downstream of isocitrate in the TCA cycle are downregulated in ''IDH1'' R132 mutant glioma while expression of genes functioning upstream of isocitrate is increased [5]. ''IDH1'' R132 mutant cells are therefore more reliant on oxidative phosphorylation compared to ''IDH1'' wild-type cells. The metabolic rewiring in ''IDH1'' R132 mutants is further evidenced by observations of increased mitochondrial gene expression and mitochondrial number in mutant ICC cells [36].

Much of the work exploring the role of ''IDH1'' in cancer has revolved around the suggestion that 2HG functions as an ‘onco-metabolite’. 2HG accumulation and the concomitant depletion of αKG has been implicated in the stabilisation of hypoxia-inducible factor 1α (HIF-1α), a transcription factor which modulates apoptosis, cell survival, and angiogenesis and is involved in tumourigenesis [4]. This is through inhibition of the αKG-dependent HIF hydroxylases, negative regulators of HIF-1α, either through competitive binding of 2HG over αKG or by the depletion of αKG [42]. In AML cells 2HG has been shown to inhibit the activity of mitochondrial cytochrome c oxidase, which besides impacting oxidative metabolism also puts ''IDH1'' R132 mutant cells on the brink of BAX/BAK-mediated apoptosis [43], and evidence suggests the case is similar in glioma [44]. The NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (''NAPRT1'') is also inhibited by 2HG in glioma cells [45].

Much of the work exploring the role of ''IDH1'' in cancer has revolved around the suggestion that 2HG functions as an ‘onco-metabolite’. 2HG accumulation and the concomitant depletion of αKG has been implicated in the stabilization of hypoxia-inducible factor 1α (''HIF-1α''), a transcription factor which modulates apoptosis, cell survival, and angiogenesis and is involved in tumorigenesis [4]. This is through inhibition of the αKG-dependent HIF hydroxylases, negative regulators of HIF-1α, either through competitive binding of 2HG over αKG or by the depletion of αKG [42]. In AML cells 2HG has been shown to inhibit the activity of mitochondrial cytochrome c oxidase, which besides impacting oxidative metabolism also puts ''IDH1'' R132 mutant cells on the brink of BAX/BAK-mediated apoptosis [43], and evidence suggests the case is similar in glioma [44]. The NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (''NAPRT1'') is also inhibited by 2HG in glioma cells [45].

2HG production impacts DNA repair by inhibiting the αKG-dependent DNA repair enzyme alkB homolog [46] and DNA damage response proteins lysine-specific methylase 4A and B (''KDM4A/B'') [47]. The altered histone methylation due to KDM4A/B inhibition results in downregulation of the DNA repair protein ATM [48]. This is consistent with the observation that ''IDH1'' R132 mutant cells have increased DNA damage [47,48], although the DNA repair defects only seem to extend to the homologous recombination pathway and not the non-homologous end-joining pathway [47].

2HG production impacts DNA repair by inhibiting the αKG-dependent DNA repair enzyme alkB homolog [46] and DNA damage response proteins lysine-specific methylase 4A and B (''KDM4A/B'') [47]. The altered histone methylation due to KDM4A/B inhibition results in downregulation of the DNA repair protein ATM [48]. This is consistent with the observation that ''IDH1'' R132 mutant cells have increased DNA damage [47,48], although the DNA repair defects only seem to extend to the homologous recombination pathway and not the non-homologous end-joining pathway [47].

Increasingly, αKG and 2HG have been implicated in epigenetic regulation of gene expression, and widespread hypermethylation has been reported in ''IDH1'' R132 mutant glioma and leukemia [49,50]. This phenotype has been referred to as the CpG island methylator phenotype (CIMP) [51]. 2HG has been established as an inhibitor of αKG-dependent deoxygenases involved in histone demethylation, including lysine-specific methylases as mentioned above as well as the myeloid tumour suppressor ''TET2'' [52]. Downstream effects include the downregulation of ''ATM'', as already described, and likely also the expression of branched-chain amino acid transaminase 1 (''BCAT1''), which metabolises branched chain amino acids as a nitrogen source for neurotransmitter glutamate synthesis [53].

Increasingly, αKG and 2HG have been implicated in epigenetic regulation of gene expression, and widespread hypermethylation has been reported in ''IDH1'' R132 mutant glioma and leukemia [49,50]. This phenotype has been referred to as the CpG island methylator phenotype (CIMP) [51]. 2HG has been established as an inhibitor of αKG-dependent deoxygenases involved in histone demethylation, including lysine-specific methylases as mentioned above as well as the myeloid tumor suppressor ''TET2'' [52]. Downstream effects include the downregulation of ''ATM'', as already described, and likely also the expression of branched-chain amino acid transaminase 1 (''BCAT1''), which metabolizes branched chain amino acids as a nitrogen source for neurotransmitter glutamate synthesis [53].

NADPH is required to recharge, activate, or generate reduced glutathione (GSH), thioredoxin, catalase tetramers, and cytochrome p450, which are all involved in cellular protection against oxidative stress. NADPH production in ''IDH1'' R132-mutants is hampered and, moreover, the conversion of αKG to 2HG by these mutants is NADPH-dependent which reduces NADPH levels even further [6]. NADPH has shown to be depleted in colorectal cancer and glioma cells [54,55], although glucose-6-phosphate dehydrogenase (G6PDH) is the major source of NADPH in myeloid cells [56]. 2HG accumulation can also induce oxidative stress independently of ''IDH1'' mutations [57].

NADPH is required to recharge, activate, or generate reduced glutathione (GSH), thioredoxin, catalase tetramers, and cytochrome p450, which are all involved in cellular protection against oxidative stress. NADPH production in ''IDH1'' R132-mutants is hampered and, moreover, the conversion of αKG to 2HG by these mutants is NADPH-dependent which reduces NADPH levels even further [6]. NADPH has shown to be depleted in colorectal cancer and glioma cells [54,55], although glucose-6-phosphate dehydrogenase (G6PDH) is the major source of NADPH in myeloid cells [56]. 2HG accumulation can also induce oxidative stress independently of ''IDH1'' mutations [57].

''TP53'' mutations have been associated with ''IDH1''-mutated astrocytoma and glioblastoma more than with other glioma subtypes [20,59], and astrocytomas are thought to develop via ''TP53'' and ''ATRX'' mutations subsequent to ''IDH1'' mutations. Astrocytomas associated with germline ''TP53'' mutations were found to have somatic ''IDH1'' Arg123Cys (NM_005896.2/NP_005887.2) mutations which are otherwise rare in this malignancy, suggesting the preferential occurrence of this specific mutation in cells that already contain a ''TP53'' mutation [60].

''TP53'' mutations have been associated with ''IDH1''-mutated astrocytoma and glioblastoma more than with other glioma subtypes [20,59], and astrocytomas are thought to develop via ''TP53'' and ''ATRX'' mutations subsequent to ''IDH1'' mutations. Astrocytomas associated with germline ''TP53'' mutations were found to have somatic ''IDH1'' Arg123Cys (NM_005896.2/NP_005887.2) mutations which are otherwise rare in this malignancy, suggesting the preferential occurrence of this specific mutation in cells that already contain a ''TP53'' mutation [60].

Loss of chromosome arms 1p and 19q is observed more frequently in oligodendroglial tumours with ''IDH1'' mutations compared to other ''IDH1''-mutated or ''IDH1'' wild-type gliomas [20]. Oligodendrogliomas often develop mutations in the ''TERT'' promoter in addition to 1p/19q deletions after ''IDH1'' mutation[61], and these are thought to be important events in their developmental pathway.  

Loss of chromosome arms 1p and 19q is observed more frequently in oligodendroglial tumours with ''IDH1'' mutations compared to other ''IDH1''-mutated or ''IDH1'' wild-type gliomas [20]. Oligodendrogliomas often develop mutations in the ''TERT'' promoter in addition to 1p/19q deletions after ''IDH1'' mutation [61], and these are thought to be important events in their developmental pathway.  

Other genetic changes common to glioma such as epidermal growth factor receptor (''EGFR'') amplification, cyclin-dependent kinase inhibitor 2A or 2B (''CDKN2A/2B'') deletion, and phosphatase or tensin homolog (''PTEN'') mutations occur less frequently in IDH1-mutated malignancies compared to those with wild-type IDH1 [20].

Other genetic changes common to glioma such as epidermal growth factor receptor (''EGFR'') amplification, cyclin-dependent kinase inhibitor 2A or 2B (''CDKN2A/2B'') deletion, and phosphatase or tensin homolog (''PTEN'') mutations occur less frequently in ''IDH1''-mutated malignancies compared to those with wild-type ''IDH1'' [20].

In AML, ''IDH1'' mutations are associated with ''NPM1'' mutations but show negative association with ''CEBPA'' and ''WT1'' mutations[62]. Patients with ''IDH1'' mutations also have a lower frequency of FLT3-ITD mutations and are generally associated with a molecular low-risk group (''NPM1''-mutated and FLT3-ITD-negative)63 and normal cytogenetics [64].

In AML, ''IDH1'' mutations are associated with ''NPM1'' mutations but show negative association with ''CEBPA'' and ''WT1'' mutations [62]. Patients with ''IDH1'' mutations also have a lower frequency of ''FLT3''-ITD mutations and are generally associated with a molecular low-risk group (''NPM1''-mutated and ''FLT3''-ITD-negative) [63] and normal cytogenetics [64].

===Therapeutic Implications===

===Therapeutic Implications===

Due to their reliance on oxidative phosphorylation ''IDH1''-mutated cancer cells are vulnerable to inhibitors of this metabolic process. The biguanides metformin and phenformin inhibit NADH dehydrogenase (complex I of the electron transport chain (ETC)), and ''IDH1'' mutations confer sensitivity to these agents[65]; metformin is currently undergoing clinical trial for use in patients with ''IDH1/2''-mutant solid tumours [66].  

Due to their reliance on oxidative phosphorylation ''IDH1''-mutated cancer cells are vulnerable to inhibitors of this metabolic process. The biguanides metformin and phenformin inhibit NADH dehydrogenase (complex I of the electron transport chain (ETC)), and ''IDH1'' mutations confer sensitivity to these agents [65]; metformin is currently undergoing clinical trial for use in patients with ''IDH1/2''-mutant solid tumors [66].  

''IDH1''-mutated cells also have a dependence on the glutaminolysis pathway. Although ''IDH1''-mutated cells need αKG to produce 2HG, they also restrict αKG production[5]. Producing αKG from glutamine allows for an alternative source of αKG in ''IDH''-mutated cells, but makes the cells vulnerable to inhibition of glutaminolysis with agents such as aminooxyacetic acid, BPTES, zaprinast, and chloroquinine in various cell types [67–70].  

''IDH1''-mutated cells also have a dependence on the glutaminolysis pathway. Although ''IDH1''-mutated cells need αKG to produce 2HG, they also restrict αKG production [5]. Producing αKG from glutamine allows for an alternative source of αKG in ''IDH''-mutated cells, but makes the cells vulnerable to inhibition of glutaminolysis with agents such as aminooxyacetic acid, BPTES, zaprinast, and chloroquinine in various cell types [67–70].  

''IDH1'' mutation disables the decarboxylation reaction that converts αKG to isocitrate, a reaction important in hypoxic conditions where pyruvate influx from the TCA cycle is compromised and cells must use citrate and acetyl-CoA generated from glutamine and glutamate in order to maintain the ability to synthesise lipids [71]. In primary glioblastoma, where ''IDH1'' is overexpressed, knockdown of ''IDH1'' sensitises glioma-initiating cells with EGFR amplifications to erlotinib through decreased fatty acid and cholesterol synthesis [72].

''IDH1'' mutation disables the decarboxylation reaction that converts αKG to isocitrate, a reaction important in hypoxic conditions where pyruvate influx from the TCA cycle is compromised and cells must use citrate and acetyl-CoA generated from glutamine and glutamate in order to maintain the ability to synthesize lipids [71]. In primary glioblastoma, where ''IDH1'' is overexpressed, knockdown of ''IDH1'' sensitizes glioma-initiating cells with ''EGFR'' amplifications to erlotinib through decreased fatty acid and cholesterol synthesis [72].

2HG inhibits cytochrome c oxidase (complex IV of the ETC), preventing cytochrome c release into the mitochondrial matrix. This makes IDH mutated cells vulnerable to apoptosis through BAX/BAK mediated permeabilisation of the outer mitochondrial membrane, although normally this is prevented by BCL-2 binding to the BAX/BAK proapoptotic proteins [43,44]. Disrupting BCL-2 binding with venetoclax, a BH3 mimetic, results in apoptosis of IDH mutated cells but unmutated cells are relatively insensitive [73]. This has been observed in AML patients and glioblastoma models, though in the latter case BCL-xL appeared to be the primary target of the BH3 mimetic rather than BCL-2 [44].

2HG inhibits cytochrome c oxidase (complex IV of the ETC), preventing cytochrome c release into the mitochondrial matrix. This makes ''IDH'' mutated cells vulnerable to apoptosis through BAX/BAK mediated permeabilisation of the outer mitochondrial membrane, although normally this is prevented by BCL-2 binding to the BAX/BAK proapoptotic proteins [43,44]. Disrupting BCL-2 binding with venetoclax, a BH3 mimetic, results in apoptosis of ''IDH'' mutated cells but unmutated cells are relatively insensitive [73]. This has been observed in AML patients and glioblastoma models, though in the latter case BCL-xL appeared to be the primary target of the BH3 mimetic rather than BCL-2 [44].

2HG downregulates nicotinate phosphoribosyltransferase (NAPRT1), which is an enzyme in the NAD+ salvage pathway. This leads to sensitivity to depletion of NAD+ in ''IDH1''-mutated cells by inhibition of nicotinamide phosphoribosyltransferase (NAMPT), another member of the pathway, with the preclinical compounds FK866 and GMX1778 leading to AMP kinase-initiated autophagy and cell death [45].

2HG downregulates nicotinate phosphoribosyltransferase (NAPRT1), which is an enzyme in the NAD+ salvage pathway. This leads to sensitivity to depletion of NAD+ in ''IDH1''-mutated cells by inhibition of nicotinamide phosphoribosyltransferase (NAMPT), another member of the pathway, with the preclinical compounds FK866 and GMX1778 leading to AMP kinase-initiated autophagy and cell death [45].

In AML, the ''IDH1'' Arg132His (NM_005896.2/NP_005887.2) mutant gene expression signature is indicative of a cellular phenotype that is responsive to treatment with small molecules targeting ROS and NAP+/NADPH signalling and metabolism [75].  

In AML, the ''IDH1'' Arg132His (NM_005896.2/NP_005887.2) mutant gene expression signature is indicative of a cellular phenotype that is responsive to treatment with small molecules targeting ROS and NAP+/NADPH signalling and metabolism [75].  

In pancreatic cancer cells, IDH1 has been linked to antioxidant defence as an adaptive strategy to cope with stress. Expression of ''IDH1'' is induced by HuR (Hu-Antigen R) after nutrient withdrawal or gemcitabine treatment. It has been suggested that this regulation is critical for pancreatic cancer cell survival under stress [76]. IDH1 mutations are rare in pancreatic cancer, however, probably owing to the importance of wild-type IDH1 function to pancreatic cancer cell survival.

In pancreatic cancer cells, ''IDH1'' has been linked to antioxidant defense as an adaptive strategy to cope with stress. Expression of ''IDH1'' is induced by HuR (Hu-Antigen R) after nutrient withdrawal or gemcitabine treatment. It has been suggested that this regulation is critical for pancreatic cancer cell survival under stress [76]. ''IDH1'' mutations are rare in pancreatic cancer, however, probably owing to the importance of wild-type IDH1 function to pancreatic cancer cell survival.

Mutant ''IDH1'' or ''IDH1'' knockdown radiosensitises cancerous and noncancerous cells[54,77], while ''IDH1'' overexpression is chemoprotective[78]. The radiosensitive phenotype of ''IDH1'' mutants is caused by both antioxidant depletion and impaired DNA damage response [54], the latter of which is associated with 2HG accumulation. The inhibition of ALKBH by 2HG also results in sensitisation of ''IDH1''-mutant cells to alkylating agents such as busulfan and CCNU [79], which provides an explanation for the sensitivity of ''IDH1''-mutated glioma to treatment with radiotherapy in the presence or absence of procarbazine, CCNU, and vincristine (the first two of which are alkylating agents) [80]. ''IDH1'' mutations also predict the response of glioblastoma to treatment with the DNA-alkylating agent temozolomide [81].

Mutant ''IDH1'' or ''IDH1'' knockdown radiosensitizes cancerous and noncancerous cells [54,77], while ''IDH1'' overexpression is chemoprotective [78]. The radiosensitive phenotype of ''IDH1'' mutants is caused by both antioxidant depletion and impaired DNA damage response [54], the latter of which is associated with 2HG accumulation. The inhibition of ALKBH by 2HG also results in sensitization of ''IDH1''-mutant cells to alkylating agents such as busulfan and CCNU [79], which provides an explanation for the sensitivity of ''IDH1''-mutated glioma to treatment with radiotherapy in the presence or absence of procarbazine, CCNU, and vincristine (the first two of which are alkylating agents) [80]. ''IDH1'' mutations also predict the response of glioblastoma to treatment with the DNA-alkylating agent temozolomide [81].

''IDH1''-mutated cancers are sensitive to PARP inhibitors, a phenotype that has been observed in AML and glioma [82,83], although the mechanism is unknown. Inhibition of the PARP-associated DNA repair pathway synergises with temozolomide in mutant glioma cells, and with daunorubicin in mutant AML, which suggests a treatment strategy that exploits the impaired DNA-repair pathway in ''IDH1''-mutants rather than using IDH1-mutant inhibitors may be beneficial [82]. In human cell models, a combination of ''IDH1'' mutation and ''ATM'' suppression caused sensitivity to irradiation and daunorubicin [82].

''IDH1''-mutated cancers are sensitive to PARP inhibitors, a phenotype that has been observed in AML and glioma [82,83], although the mechanism is unknown. Inhibition of the PARP-associated DNA repair pathway synergizes with temozolomide in mutant glioma cells, and with daunorubicin in mutant AML, which suggests a treatment strategy that exploits the impaired DNA-repair pathway in ''IDH1''-mutants rather than using ''IDH1''-mutant inhibitors may be beneficial [82]. In human cell models, a combination of ''IDH1'' mutation and ''ATM'' suppression caused sensitivity to irradiation and daunorubicin [82].

The fact that ''IDH1'' mutations arise very early in many cancers makes it an attractive therapeutic target, as the resulting tumour homogeneity decreases the risk of therapy resistance arising. IDH1-mutant inhibitors have been developed and show therapeutic promise in glioma, AML, and chondrosarcoma [84–87], although in AML these inhibitors may induce differentiation syndrome in some patients [88].

The fact that ''IDH1'' mutations arise very early in many cancers makes it an attractive therapeutic target, as the resulting tumor homogeneity decreases the risk of therapy resistance arising. ''IDH1''-mutant inhibitors have been developed and show therapeutic promise in glioma, AML, and chondrosarcoma [84–87], although in AML these inhibitors may induce differentiation syndrome in some patients [88].

==Common Alteration Types==

==Common Alteration Types==