Background
Methods
Leukemia samples
Mutational analysis of IDH1 and IDH2
Analysis of additional molecular aberrations
Statistical analysis
Results
Frequency and type of IDH1 and IDH2 mutations
Mutation | Nucleotide change | Predicted protein change | No. of patients |
---|---|---|---|
IDH1*
| |||
c.G395A | CGT-CAT | p.R132H | 8 |
c.C394T | CGT-TGT | p.R132C | 6 |
c.C394A | CGT-AGT | p.R132S | 2 |
c.C394G | CGT-GGT | p.R132G | 2 |
c.G395T | CGT-CTT | p.R132L | 1 |
c.A297G | ATA-ATG | p.I99M | 1 |
IDH2**
| |||
c.G419A | CGG-CAG | p.R140Q | 20 |
c.G515A | AGG-AAG | p.R172K | 4 |
Clinical parameters and morphologic subtypes of patients with IDH1 or IDH2 mutations
Variable | All cases |
IDH1
m
|
IDH1
wt
|
P*
|
---|---|---|---|---|
No. of cases
| 230 | 20 | 210 | |
No. of males/females
| 101/129 | 5/15 | 96/114 | .058 |
Age, years
| .860† | |||
Median (range) | 44 (13-86) | 42.5 (15-85) | 45 (13-86) | |
Hemoglobin, g/dL
| .311† | |||
Median (range) | 7.8 (1.4 -14.5) | 7.4 (2.9 - 10.8) | 7.85(1.4-14.5) | |
WBC count, x10
9
/L
| .323† | |||
Median (range) | 27.7 (0.6 -494.4) | 26.9 (1.0 -190.9) | 27.7 (0.6 -494.4) | |
Platelet, x10
9
/L
| .923† | |||
Median (range) | 46 (1.8-965) | 56 (16.9 - 386) | 45.5 (1.8-965) | |
Percentage of blasts
| .738† | |||
Median (range) | 70.19 (6.69-95.44) | 75.8 (13.3-91.4) | 69.77 (6.69-95.44) | |
Patients (%) | Patients (%) | |||
FAB classification
| ||||
M0 | 3 | 1 (5) | 2 (0.9) | |
M1 | 51 | 1 (5) | 50 (23.8) | |
M2 | 76 | 13 (65) | 63 (30) | |
M3 | 36 | 5 (25) | 31 (15) | |
M4 | 34 | 0 (0) | 34 (16) | |
M5 | 21 | 0 (0) | 21 (10) | |
M6 | 8 | 0 (0) | 8 (3.8) | |
M7 | 1 | 0 (0) | 1 (0.5) | |
Patients (%) | Patients (%) | |||
Cytogenetics
| ||||
Abnormal | ||||
t(15;17) | 36 | 5 (25) | 31 (15) | .184 |
t(8;21) | 20 | 0 (0) | 20 (10) | .149 |
inv(16) | 3 | 0 (0) | 3 (1) | .760 |
trisomy 8 | 4 | 1 (5) | 3 (1) | .307 |
Other trisomies | 7 | 0 (0) | 7 (3) | .524 |
All others including monosomies, deletions or combination of these | 22 | 2 (10) | 20 (10) | .594 |
Complex karyotype | 8 | 0 (0) | 8 (4) | .477 |
Normal | 126 | 11 (55) | 115 (55) | .587 |
Variable | All cases |
IDH2
m
|
IDH2
wt
|
P*
|
---|---|---|---|---|
No.of cases
| 230 | 24 | 206 | |
No.of males/females
| 101/129 | 11/13 | 90/116 | .504 |
Age, years
|
.001
†
| |||
Median (range) | 44 (13-86) | 49.5 (38-80) | 43 (13-86) | |
Hemoglobin, g/dL
| .059† | |||
Median (range) | 7.8 (1.4 - 14.5) | 9.25 (4.7-12.6) | 7.7 (1.4 - 14.5) | |
WBC count, × 10
9
/L
| .789† | |||
Median (range) | 27.7 (0.6 - 494.4) | 29.73 (0.89-222) | 26.4 (0.6 - 494.4) | |
Platelet, x10
9
/L
|
.048
†
| |||
Median (range) | 46 (1.8-965) | 59 (11-965) | 45 (1.8-852) | |
Percentage of blasts
| .133 † | |||
Median (range) | 70.19 (6.69-95.44) | 61.79 (32.52-95.03) | 71.66 (6.69-95.44) | |
Patients (%) | Patients (%) | |||
FAB classification
| ||||
M0 | 3 | 0 (0) | 3 (1.5) | |
M1 | 51 | 1 (4) | 50 (24) | |
M2 | 76 | 11 (46) | 65 (31) | |
M3 | 36 | 6 (25) | 30 (15) | |
M4 | 34 | 6 (25) | 28 (14) | |
M5 | 21 | 0 (0) | 20 (10) | |
M6 | 8 | 0 (0) | 8 (4) | |
M7 | 1 | 0 (0) | 1 (0.5) | |
Patients (%) | Patients (%) | |||
Cytogenetics
| ||||
Abnormal | ||||
t(15;17) | 36 | 6 (25) | 30 (14.6) | .150 |
t(8;21) | 20 | 1 (4.2) | 19 (9.2) | .355 |
inv(16) | 3 | 0 (0) | 3 (1.5) | .717 |
trisomy 8 | 4 | 1 (4.2) | 3 (1.5) | .358 |
Other trisomies | 7 | 2‡ (8.2) | 5 (2.4) | .158 |
All others including monosomies, deletions or combination of these | 22 | 1 (4.2) | 21 (10.2) | .301 |
Complex karyotype | 8 | 0 (0) | 8 (3.8) | .408 |
Normal | 126 | 12 (50) | 114 (55.3) | .388 |
Chromosomal patterns and additional molecular aberrations in patients with IDH1 or IDH2 mutations
Additional gene mutations |
IDH1
m
n = 20 No. | (%) | IDH1
wt
n = 210 No. | % |
P*
| IDH2
m
n = 24 No. | % | IDH2
wt
n = 206 No. | % |
P*
|
---|---|---|---|---|---|---|---|---|---|---|
NPM1
|
<.001
|
<.001
| ||||||||
Wild type | 5 | 26% | 140 | 76% | 8 | 40% | 137 | 75% | ||
Mutated | 14 | 74% | 45 | 24% | 12 | 60% | 47 | 25% | ||
FLT3-
ITD
| .34 | .63 | ||||||||
Absent | 14 | 82% | 108 | 74% | 13 | 76% | 109 | 75% | ||
Present | 3 | 18% | 38 | 16% | 4 | 24% | 37 | 25% | ||
FLT3-
TKD
| .59 | .59 | ||||||||
Absent | 15 | 94% | 133 | 91% | 15 | 94% | 133 | 91% | ||
Present | 1 | 6% | 33 | 9% | 1 | 6% | 33 | 9% | ||
AML1
| .09 | .09 | ||||||||
Wild type | 15 | 100% | 147 | 86% | 17 | 100% | 145 | 86% | ||
Mutated | 0 | 0% | 23 | 14% | 0 | 0% | 23 | 4% | ||
NRAS
| .49 | .42 | ||||||||
Wild type | 8 | 89% | 79 | 81% | 9 | 90% | 78 | 81% | ||
Mutated | 1 | 11% | 18 | 19% | 1 | 10% | 18 | 19% | ||
PML
-RARA
| .43 | .56 | ||||||||
Wild type | 3 | 38% | 12 | 28% | 2 | 25% | 13 | 30% | ||
Mutated | 5 | 62% | 31 | 72% | 6 | 75% | 30 | 70% |
Discussion
Country | No. IDH1m/all cases (%) | No. of IDH1m/CN-AML (%) | No. IDH2m/all cases (%) | No. of IDH2m/CN-AML (%) |
---|---|---|---|---|
ASIA
| ||||
Taiwan
| ||||
Chou W et al.(2010) [18] | 27/493 (5.5) | 20/227 (8.8) | ND | ND |
China
| ||||
Zou Y et al.(2010) [28] | 4/68 (5.9) | ND | 4/48 (8.3) | ND |
Zhang Y et al.(2011) [32] | 23/365 (6.3) | 6/111 (5.4) | ND | ND |
Lin J et al.(2011) [31] | 4/110 (3.6) | ND | ND | ND |
Thailand
| ||||
This study | 20/230 (8.7) | 11/126 (8.7) | 24/230 (10.4) | 12/126 (9.5) |
6.0-10.9 | 9.4-16.0 | 2.0*-10.9 | 3.2*-15.2 | |
NORTH AMERICA
∫
| 2.2-13.7 | 4.9-16.0 | 1.3*-19.2 | 2.4*-19.2 |
Country | No. IDH1m/all cases (%) | No. of IDH1m in APL (%) | No. IDH2m/all cases (%) | No. of IDH2m in APL (%) |
---|---|---|---|---|
ASIA
| ||||
Taiwan
| ||||
Chou W et al.[18] | 27/493 (5.5) | 0/37 (0) | ND | ND |
China
| ||||
Zhang Y et al.[28] | 23/365 (6.3) | 3/77 (3.9) | ND | ND |
Thailand
| ||||
This study | 20/230 (8.7) | 5/36(13.9) | 24/230 (10.4) | 6/36 (16.7) |
EUROPE
| ||||
Germany
| ||||
Schnittger S et al.[27] | 93/1414 (6.6) | 2/88 (2.3) | ND | ND |
The Netherlands
| ||||
Abbas S et al.[24] | 55/893 (6.2) | 0/21 (0) | 97/893 (10.9) | 0/21 (0) |
NORTH AMERICA
| ||||
United States
| ||||
Mardis E et al.[5] | 16/188 (8.5) | 0/16 (0) | ND | ND |
Andersson A et al.[29] | 5/227 (2.2) | 0/7 (0) | 3/227 (1.3) | 0/7 (0) |