Table 2.
Candidate gene resequencing studies of DNMT3A, IDH1, IDH2, TET2 and ASXL1 in acute myeloid leukemia
| Gene | Reference Study | AML Group | Mutation frequency | Clinical characteristics | Cytogenetics | Association with other mutations | Outcome |
|---|---|---|---|---|---|---|---|
| DNMT3A | Roller et al[50] | 194 CN-AML | 36.10% | Associated with female gender and younger age | All cases are CN-AML | NPM1, FLT3-ITD and IDH1. | NO effect on OS |
| Ostronoff et al[48] | 191 selected AML | 19% | Significant association with age, gender, WBC count | 75% DNMT3Amut cases are CN-AML | NPM1 | In CN-AML cases, DNMT3A mut has worse OS, EFS and RFS | |
| Ribeiro et al[49] | 415 AML | 23.10% | Associated with higher age, higher WBC and platelet counts | Significant in CN-AML | FLT3-ITD, NPM1 and IDH1. | No effect on CR. DNMT3A mut cases have worse OS and RFS | |
| Marcucci et al[89] | 415 CN-AML | 34.20% | Associated with higher WBC count, BM blast percentage | All cases are CN-AML | NPM1, FLT3-ITD | No effect on CR, DNMT3A mut associated with shorter DFS. | |
| Renneville et al[90] | 123 younger CN-AML | 29.30% | No significant association with age, sex and WBC count | FAB M4/M5 | NPM1. Inverse association with CEBPA. | Lower CR, shorter EFS and OS. DNMT3A mut with NPM1 have inferior EFS and OS | |
| Thol et al[89] | 489 AML younger than 60yrs | 17.80% | Associated with old age, high WBC and platelet counts | Significantly associated with normal karyotype | NPM1, FLT3 and IDH1 | Shorter OS. In CN-AML shorter OS and lower CR rate | |
| IDH | Yamaguchi et al[91] | 233 Adult AML | 8.6% (IDH1), 8.2% (IDH2) | Associated with older age, high platelet counts and blast percentage | 59% of IDH mut cases have normal karyotype | NPM1. Not a single IDH mut case has CEBPA mutation | Low CR rate and no difference in RFS |
| Koszarska et al[37] | 376 AML | 8.5% (IDH1), 7.5% (IDH2) | Associated with older age, high platelet counts | Associated with intermediate karyotype | NPM1 | No significant difference in OS, remission and relapse rates | |
| Patel et al[38] | 199 AML | 6.0% (IDH1), 2.0% (IDH2) | No significant association with age, gender and WBC count | Strongly associated with normal cytogenetics | No significant association | No analysis | |
| Nomdedéu et al[63] | 275 AML | 13.1% (IDH1), 10.2% (IDH2) | No significant association with age, gender and WBC count | 45.2% IDH mut cases have normal karyotype.73.4% IDH mut belongs to FAB M4/5 | No association | No difference in survival and relapse. CN-AML with IDH mut have adverse OS and DFS | |
| Chotirat et al[92] | 230 AML | 8.7% (IDH1), 10.4% (IDH2) | Associated with older age, high platelet counts | 55% IDH mut cases have normal karyotype, FAB M2 | NPM1 | No effect | |
| Chao et al[93] | 195 AML | 4.6% (IDH1), 11.28% (IDH2) | Associated with age but not significant in gender and WBC count | Associated with normal cytogenetics. 68%-FAB M5 | NPM1 | No analysis | |
| TET2 | Grossmann et al[94] | 95 CEBPA dm AML | 34% | ASXL1, TET2 and DNMT3A mutations are associated with older age and FLT3 associated with younger age | GATA2, ASXL1, DNMT3A | Shorter OS and EFS. Additional mutation with TET2 put worse OS | |
| Weissmann et al[95] | 318 AML patients | 27.40% | Associated with older age and high WBC count | 75% of TET2 mut cases are normal karyotype | Inversely associated with IDH | Inferior OS and significant shorter EFS. | |
| Chou et al[73] | 486 pAML | 13.20% | Significant with older age, high WBC count and blast percentage | Significantly associated with normal karyotype | NPM1 and ASXL1 are less associated with TET2 mutation. IDH1 is mutually exclusive | Shorter OS in CN-AML. No difference in CR rate and relapse-free survival | |
| Metzeler et al[72] | 427 CN-AML | 23% | Associated with older age, high WBC count | ALL cases are CN | IDH mutations less frequent with TET2 mutations, CEBPA is more frequent with TET2 | Shorter EFS and DFS, low CR and shorter OS | |
| Kosmider et al[96] | 247sAML | 19.80% | Associated with male gender, old age and platelet counts | 51% TET2 mut cases are normal karyotype. | No significant association | No effect on OS | |
| ASXL1 | Pratcorona et al[97] | 886 AML (775 denovo AML, 24 MDS, 37 tAML) | 5.30% | Associated with old age and low WBC count | Associated with FAB M0 type, inversely related to M4 type | Inversely related to NPM1 and FLT3-ITD | Independent poor risk factor for OS |
| Chou et al[40] | 501 denovo AML | 10.80% | Associated with old age and male sex | Associated with FAB M0 type and isolated trisomy 8 | RUNX1. Inversely related to NPM1 and FLT3-ITD | Shorter OS | |
| Schnittger et al[80] | 740 AML with intermediate risk karyotype | 17.20% | Associated with old age and low WBC count and male gender | Significantly associated with trisomy 8 | RUNX1.Inversely correlated with NPM1 and FLT3-ITD | Shorter OS and EFS | |
| Metzeler et al[41] | 423 primary CN-AML | 10.40% | Associated with old age and male sex, low WBC and Blast percentage | ELN category of CN-AML: Favorable(ASXL1 mutation in old patients) | Inversly related to NPM1 and FLT3-ITD | Shorter OS | |
Abbreviations: AML: Acute Myeloid Leukemia; CN-AML: cytogenetically normal acute myeloid leukemia; pAML: primary AML; sAML: secondary AML; tAML: therapy related AML; WBC: White blood cell; FAB: French American British; CR: complete remission; OS: overall survival; EFS: Event-free survival; DFS: Disease-free survival; RFS: relapse free survival; mut: mutant; dm: double mutant