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Table 2 Candidate gene resequencing studies of DNMT3A, IDH1, IDH2, TET2 and ASXL1 in acute myeloid leukemia

From: Next Generation Sequencing of Acute Myeloid Leukemia: Influencing Prognosis

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

  1. 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