Background
Methods
Patients and samples
Public datasets
Real-time quantitative reverse transcriptase-PCR (RT-qPCR)
Targeted bisulfite sequencing
Cell culture, 5-aza-dC treatment and real-time methylation-specific polymerase chain reaction (RQ-MSP)
Statistical analysis and bioinformatics
Results
PCDH17 is significantly down-regulated in AML and dynamic expressed during normal hematopoiesis
Repression of PCDH17 is mediated by promoter methylation in AML
PCDH17 expression is associated with clinical characteristics and molecular markers
Patient characteristics | AML (TCGA dataset) | ||
---|---|---|---|
High PCDH17 (n = 86) | Low PCDH17 (n = 87) |
P
| |
Age, years | 0.41 | ||
Median | 59 | 57 | |
Range | 18–88 | 21–82 | |
Sex (male/female) | 54/32 | 38/49 | 0.01 |
WBC count, × 109/L | < 0.0001 | ||
Median | 9.3 | 34 | |
Range | 0.4–116.2 | 0.8–297.4 | |
BM blasts, % | 0.04 | ||
Median | 68.5 | 75 | |
Range | 30–100 | 32–100 | |
PB blasts, % | < 0.001 | ||
Median | 18 | 49 | |
Range | 0–97 | 0–98 | |
Karyotype | 0.343 | ||
Favorable | 16 | 16 | |
Intermediate | 46 | 55 | |
Adverse | 23 | 14 | |
Unknown | 1 | 2 | |
FLT3-ITD | 0.002 | ||
Present | 6 | 21 | |
Absent | 80 | 66 | |
NPM1
| 0.02 | ||
Mutated | 17 | 31 | |
Wild-type | 69 | 56 | |
CEBPA
| 1 | ||
Single mutated | 4 | 4 | |
Double mutated | 2 | 3 | |
Wild-type | 80 | 80 | |
IDH1
| 0.28 | ||
Mutated | 10 | 6 | |
Wild-type | 76 | 81 | |
IDH2
| 0.82 | ||
Mutated | 8 | 9 | |
Wild-type | 78 | 78 | |
RUNX1
| 0.769 | ||
Mutated | 8 | 7 | |
Wild-type | 78 | 80 | |
DNMT3A
| 0.755 | ||
Mutated | 20 | 22 | |
Wild-type | 66 | 65 | |
TP53
| 0.005 | ||
Mutated | 12 | 2 | |
Wild-type | 74 | 85 | |
ERG expressiona | 0.08 | ||
High | 37 | 49 | |
Low | 49 | 38 | |
BAALC expressiona | 0.494 | ||
High | 45 | 41 | |
Low | 41 | 46 | |
MN1 expressiona | 0.704 | ||
High | 44 | 42 | |
Low | 42 | 45 | |
WT1 expressiona | 0.323 | ||
High | 40 | 47 | |
Low | 46 | 40 |
Reduced PCDH17 expression predicts inferior survival in four independent cohorts
Prognostic value of PCDH17 expression in the context of other risk factors in AML
Variables | Overall survival | Disease-free survival | ||
---|---|---|---|---|
Hazard ratio (95% CI) |
P
| Hazard ratio (95% CI) |
P
| |
Full cohort | (n = 173) | (n = 171) | ||
PCDH17
a
| 2.04 (1.37–3.04) | < 0.001 | 1.89 (1.19–2.98) | 0.007 |
Ageb | 2.90 (1.94–4.34) | < 0.0001 | 1.52 (0.96–2.43) | 0.08 |
WBC countc | – | – | 2.14 (1.36–3.39) | 0.001 |
Cytogenetic riskd | 1.84 (1.28–2.65) | 0.001 | 1.39 (0.95–2.04) | 0.09 |
TP53
e
| 2.76 (1.37–5.55) | 0.004 | 2.64 (0.93–7.47) | 0.07 |
DNMT3A
e
| 1.61 (1.05–2.48) | 0.03 | 1.41 (0.85–2.33) | 0.18 |
RUNX1
e
| 1.75 (0.94–3.26) | 0.08 | – | – |
CN-AML | (n = 80) | (n = 80) | ||
---|---|---|---|---|
PCDH17
a
| 2.02 (1.13–3.62) | 0.02 | 1.79 (0.93–3.44) | 0.08 |
Ageb | 2.38 (1.35–4.19) | 0.003 | 2.19 (1.10–4.36) | 0.03 |
WBC countc | 1.42 (0.81–2.48) | 0.22 | 1.65 (0.89–3.04) | 0.11 |
FLT3-ITDf | – | – | 1.34 (0.60–2.99) | 0.47 |
TP53
e
| – | – | 4.09 (0.46–36.02) | 0.20 |
DNMT3A
e
| 1.99 (1.13–3.52) | 0.02 | 2.15 (1.15–4.03) | 0.02 |
IDH1
e
| 0.61 (0.21–1.78) | 0.36 | 0.68 (0.22–2.08) | 0.49 |
Variables | Univariate analysis | Multivariate analysis | ||
---|---|---|---|---|
Hazard Ratio (95% CI) |
P
| Hazard Ratio (95% CI) |
P
| |
Full cohort | (n = 97) | (n = 97) | ||
PCDH17
a
| 1.65 (1–2.72) | 0.05 | 2.01 (1.19–2.98) | 0.01 |
Ageb | 3.07 (1.87–5.04) | < 0.0001 | 2.10 (1.18–3.61) | 0.02 |
WBC countc | 3.14 (1.92–5.14) | < 0.0001 | 2.06 (1.16–3.64) | 0.01 |
Cytogenetic riskd | 2.04 (1.49–2.78) | < 0.0001 | 1.60 (1.05–2.43) | 0.03 |
FLT3-ITDe | 0.80 (0.36–1.77) | 0.58 | – | – |
NPM1
f
| 0.97 (0.39–2.43) | 0.95 | – | – |
CEBPA
f
| 1.18 (0.53–2.62) | 0.69 | – | – |
DNMT3A
f
| 1.66 (0.71–3.89) | 0.24 | – | – |
IDH2
f
| 6.13 (0.8–47) | 0.08 | 5.35 (0.63–45.16) | 0.12 |
NRAS
f
| 1.18 (0.37–3.81) | 0.78 | – | – |
KRAS
f
| 8.80 (2.53–30.55) | < 0.001 | 5.16 (1.13–23.59) | 0.03 |
U2AF1
f
| 14.43 (1.81–115.4) | 0.01 | 4.99 (0.37–67.94) | 0.23 |
SRSF2
f
| 3.28 (0.78–13.85) | 0.11 | 0.95 (0.12–7.46) | 0.96 |
SETBP1
f
| 0.82 (0.11–5.96) | 0.85 | – | – |
KIT
f
| 0.64 (0.16–2.64) | 0.54 | – | – |
CN-AML | (n = 36) | (n = 36) | ||
---|---|---|---|---|
PCDH17
a
| 2.58 (1.02–6.52) | 0.04 | 2.95 (1.04–8.32) | 0.04 |
Ageb | 1.39 (0.61–3.14) | 0.43 | – | – |
WBC countc | 3.05 (1.34–6.93) | 0.008 | 3.26 (1.35–7.87) | 0.009 |
FLT3-ITDe | 0.48 (0.14–1.63) | 0.24 | – | – |
NPM1
f
| 0.50 (0.15–1.69) | 0.27 | – | – |
CEBPA
f
| 1.19 (0.40–3.50) | 0.76 | – | – |
DNMT3A
f
| 1.25 (0.42–3.68) | 0.69 | – | – |
IDH2
f
| 6.37 (0.76–53.48) | 0.09 | 13.30 (1.23–143.32) | 0.03 |
NRAS
f
| 3.55 (0.45–27.94) | 0.23 | – | – |
KRAS
f
| 6.46 (1.37–30.46) | 0.02 | 9.17 (1.72–48.86) | 0.009 |
SETBP1
f
| 6.37 (0.76–53.48) | 0.09 | 4.52 (0.48–42.10) | 0.19 |