Background
Materials and methods
Patients
Training cohort (n = 50) | Validation cohort (n = 34) | |||
---|---|---|---|---|
CCR (n = 28) | Relapse (n = 22) | CCR (n = 25) | Relapse (n = 9) | |
Sex
| ||||
Male/Female | 21/7 | 21/1 | 14/11 | 9/0 |
Age at diag (years)
| ||||
Median (Range) | 13.1 (2.1-16.9) | 12.1 (1.8-17.8) | 7.1 (2.2-18.3)* | 8.8 (1.8-17.5) |
WBC (×10
9
/L)
| ||||
Median (Range) | 171.9 (1.1-791) | 219.2 (4.9-700) | 113.1 (8.2-524.4) | 161.8 (13.4-882) |
BM blast at diag (%)
| ||||
Median (Range) | 94 (70-100) | 91 (74-99) | 90 (35-99) | 95 (70-99) |
Cytogenetics
| ||||
Normal (46 C) | 2 | 3 | 13 | 4 |
Pseudodiploid (46 C) | 12 | 6 | 5 | 2 |
Hyperdiploid (>47 C) | 3 | 2 | 3 | 0 |
Hypodiploid (<46 C) | 0 | 0 | 2 | 1 |
N/A | 11 | 11 | 2 | 2 |
NCI Risk
| ||||
Standard | 0 | 0 | 6 | 1 |
High | 28 | 22 | 19 | 8 |
Induction result
| ||||
M1 | 25 | 19 | 24 | 8 |
M2 | 3 | 0 | 0 | 0 |
M3 | 0 | 0 | 0 | 0 |
N/A | 0 | 3 | 1 | 1 |
Follow-up time (years)
| ||||
Median (Range) | 7.3 (3.3-9.2) | 8.8 (4.3-11.9) | ||
Time to relapse (years)
| ||||
Median (Range) | 1.3 (0.2-3.8) | 1.4 (0.5-3.3) |
Gene expression profiling
Real-time quantitative RT-PCR (qRT-PCR)
Effect of IL7 on cell growth and drug sensitivity
Results
Modeling a multi-gene classifier for outcome prediction
Gene Symbol (Probe ID) | Gene | RF Rank | Mean Expression (Array) | Fold Change (R/CCR) | r | ||
---|---|---|---|---|---|---|---|
R | CCR | Array | qRT-PCR | ||||
ABTB2 (213497_at) | Ankyrin repeat and BTB (POZ) domain-containing 2 | 12 | 119.8 | 89.7 | 1.34 | 3.11 | 0.76 |
IL7R (205798_at) | Interleukin-7 receptor | 43 | 292.0 | 542.7 | 0.54 | 0.47 | 0.92 |
LGALS8 (208936_x_at) | Lectin, galactose binding, (Galectin 8) | 288 | 197.4 | 231.8 | 0.85 | 0.37 | 0.56 |
PLAC8 (219014_at) | Placenta-specific 8 (Onzin) | 297 | 530.4 | 979.5 | 0.54 | 0.22 | 0.90 |
FAM13A1 (217047_s_at) | Family with sequence similarity 13, member A1 | 356 | 70.0 | 84.0 | 0.83 | 0.30 | 0.69 |
Variable | No. of Patients | Hazard Ratio | 95% CIa | p-value |
---|---|---|---|---|
Age at diagnosis
| ||||
<10 years | 17 | 1 b) | ||
≥10 years | 33 | 1.3 | (0.506, 3.32) | 0.59 |
WBC
| ||||
<50/nl | 12 | 1 b) | ||
>50/nl | 38 | 1.15 | (0.425, 3.12) | 0.78 |
Gender
| ||||
Female | 8 | 1 b) | ||
Male | 42 | 5.53 | (0.742, 41.2) | 0.095 |
5-GC score
| 50 | 1.31 | (1.19, 1.44) | <0.0001 |
Validation of the 5-GC in an independent cohort
Model | Cohort | Acc | PPV | NPV | Sens | Spec | P-value |
---|---|---|---|---|---|---|---|
5-GC (5 genes) | Training | 82 | 81 | 83 | 77 | 86 | 9.4 × 10-6 |
Validation | 79 | 100 | 78 | 22 | 100 | 0.064 | |
COG 9404† | 75 | 71 | 76 | 36 | 93 | 0.025 | |
POG 8704† | 68 | 83 | 66 | 29 | 96 | 0.066 | |
Combined
|
76
|
81
|
75
|
47
|
93
|
1.5 × 10
-9
(1.2 × 10
-4
)
| |
Pathway NFκB (7 genes) | Training | 76 | 71 | 81 | 77 | 75 | 4.8 × 10-4 |
Validation | - | - | - | - | - | - | |
COG 9404† | 77 | 83 | 76 | 36 | 97 | 0.009 | |
POG 8704† | 56 | 44 | 59 | 24 | 79 | 1 | |
Combined
|
70
|
67
|
72
|
49
|
84
|
7.2 × 10
-5
(0.073)
| |
Pathway Wnt/Ca2+/cGMP (12 genes) | Training | 76 | 75 | 77 | 68 | 82 | 4.6 × 10-4 |
Validation | - | - | - | - | - | - | |
COG 9404† | 75 | 67 | 77 | 43 | 90 | 0.019 | |
POG 8704† | 68 | 63 | 72 | 59 | 75 | 0.05 | |
Combined
|
73
|
69
|
76
|
58
|
83
|
8.7 × 10
-7
(0.0011)
| |
Pathway Cell Adhesion (14 genes) | Training | 82 | 84 | 81 | 73 | 89 | 8.6 × 10-6 |
Validation | - | - | - | - | - | - | |
COG 9404† | 75 | 62 | 81 | 57 | 83 | 0.012 | |
POG 8704† | 85 | 87 | 85 | 76 | 92 | 1.1 × 10-5 | |
Combined
|
81
|
79
|
82
|
70
|
88
|
8.2 × 10
-12
(4.5 × 10
-7
)
|