Introduction
Methods
Tumor material and patient characteristics
All patients | M0, age at diagnosis >4 | M1–M4 or M0, age at diagnosis <4 | |
---|---|---|---|
Number of patients | 184a
| 88 | 95 |
Number of events/deaths | 42/23 | 11/9 | 31/14 |
Median follow-up time (95 %CI) | 1.78 (1.37; 2.19) | 1.78 (1.21; 2.35) | 1.82 (1.40; 2.24) |
Gender | |||
Male | 121 | 58 | 62 |
Female | 63 | 30 | 33 |
Age at diagnosis | |||
Median | 7.64 | 9.03 | 6.66 |
Range | 0.29–38.88 | 4.56–38.88 | 0.29–21.87 |
M stagea age at diagnosis | |||
M0 and <4 | 23 | – | – |
M0 and >4 | 88 | – | – |
M1–M4 and <4 | 14 | – | – |
M1–M4 and >4 | 58 | – | – |
N/A | 1 | – | – |
Treatment stratum | |||
HIT 2000 BIS 4 | 22 | – | 22 |
HIT 2000 AB 4 | 96 | 84 | 11 |
MET-HIT 2000 AB 4 | 48 | 1 | 47 |
MET-HIT 2000 BIS 4 before Am. | 2 | – | 2 |
MET-HIT 2000 BIS 4 after Am. | 11 | – | 11 |
N/A | 5 | 3 | 2 |
Reference histology | |||
CMB | 132 | 66 | 65 |
DMB | 37 | 19 | 18 |
MBEN | 6 | – | 6 |
LCMB | 1 | – | 1 |
AMB | 8 | 3 | 5 |
Residual tumor | |||
<1.5 cm2
| 145 | 76 | 68 |
>1.5 cm2
| 23 | 6 | 17 |
N/A | 16 | 6 | 10 |
PNET5 risk group | |||
Low risk | 16 | 16 | 0 |
Medium risk | 52 | 52 | 0 |
High risk | 70 | 12 | 58 |
None | 46 | 8 | 37 |
Histopathological evaluation and classification
DNA methylation analysis
Analysis of β-catenin by immunohistochemistry and sequencing of CTNNB1
Fluorescence in situ hybridization (FISH)
Multiplex ligation-dependent probe amplification (MLPA)
Statistical analysis
Results
Prospective testing of single markers in a training, test and independent validation cohort
Clinical and biological variables | Available cases | HR | 95 % CI |
p* |
---|---|---|---|---|
M stage | 183 | 0.030 | ||
M1 vs. M0 | 20 vs. 111 | 1.822 | 0.721–4.605 | |
M2/3 vs. M0 | 52 vs. 111 | 2.417 | 1.254–4.660 | |
M1 vs. M2/3 | 20 vs. 52 | 0.754 | 0.298–1.907 | |
Reference confirmed M0 stage | 184 | 0.010 | ||
No vs. yes | 73 vs. 111 | 2.231 | 1.208–4.122 | |
Treatment stratum | 179 | 0.003 | ||
HIT 2000 BIS 4 vs. HIT 2000 AB 4 | 22 vs. 96 | 2.758 | 1.066–7.136 | |
MET-HIT 2000 AB 4 vs. HIT 2000 AB 4 | 48 vs. 96 | 3.082 | 1.428–6.653 | |
MET-HIT 2000 BIS 4 after amendment vs. HIT 2000 AB 4 | 11 vs. 96 | 3.763 | 1.190–11.878 | |
MET-HIT 2000 BIS 4 before amendment vs. HIT 2000 AB 4 | 2 vs. 96 | 18.858 | 3.988–89.163 | |
HIT 2000 BIS 4 vs. MET-HIT 2000 AB 4 | 22 vs. 48 | 0.895 | 0.367–2.180 | |
MET-HIT 2000 BIS 4 after amendment vs. MET-HIT 2000 AB 4 | 11 vs. 48 | 1.220 | 0.407–3.660 | |
MET-HIT 2000 BIS 4 before amendment vs. MET-HIT 2000 AB 4 | 2 vs. 48 | 6.118 | 1.353–27.663 | |
MET-HIT 2000 BIS 4 after amendment vs. HIT 2000 BIS 4 | 11 vs. 22 | 1.364 | 0.397–4.689 | |
MET-HIT 2000 BIS 4 before amendment vs. HIT 2000 BIS 4 | 2 vs. 22 | 6.839 | 1.364–34.278 | |
MET-HIT 2000 BIS 4 b. Amendment vs. MET-HIT 2000 BIS 4 a. Amendment | 2 vs. 11 | 5.015 | 0.894–28.149 | |
Presence of large cell component | 184 | 0.022 | ||
Yes vs. no | 7 vs. 177 | 4.267 | 1.511–12.056 | |
Presence of endothelial proliferation | 184 | 0.035 | ||
No vs. yes | 59 vs. 125 | 0.448 | 0.199–1.009 | |
Pattern of synaptophysin expression | 184 | 0.006 | ||
Speckled yes vs. no | 55 vs. 129 | 2.651 | 1.369–5.136 | |
Categorized TOP2A copy number | 155 | 0.003 | ||
>2.7 vs. < 2.7 | 44 vs. 111 | 0.291 | 0.113–0.746 | |
TOP2A copy-number (continuous) | 155 | 0.673 | 0.452–1.002 | 0.039 |
6q status (array-based) | 172 | 0.031 | ||
Gain vs. bal | 16 vs. 143 | 0.717 | 0.220–2.332 | |
Loss vs. bal | 13 vs. 143 | NE | – | |
6q status (FISH) | 176 | 0.034 | ||
Gain vs. bal | 19 vs. 141 | 0.381 | 0.092–1.584 | |
Loss vs. bal | 16 vs. 141 | 0.183 | 0.025–1.337 | |
Loss vs. gain | 16 vs. 19 | 0.480 | 0.043–5.307 | |
MYC status (FISH) | 181 | 0.036 | ||
Amplif vs. bal | 6 vs. 175 | 3.711 | 1.317–10.453 | |
450k subgrouping | 175 | 0.007 | ||
Group_3 vs. Group_4 | 46 vs. 72 | 2.037 | 1.014–4.089 | |
SHH vs. Group_4 | 42 vs. 72 | 0.895 | 0.382–2.099 | |
SHH vs. Group_3 | 42 vs. 46 | 0.440 | 0.187–1.032 | |
WNT vs. Group_4 | 15 vs. 72 | NE | – |
Molecular subgroups are strongly associated with clinical outcome
Available cases | EFS | OS | |
---|---|---|---|
p* |
p* | ||
Group_3 vs. Group_4 | 46 vs. 72 | 0.048 | 0.076 |
SHH vs. Group_4 | 42 vs. 72 | 0.807 | 0.431 |
WNT vs. Group_4 | 15 vs. 72 | 0.083 | 0.260 |
SHH vs. Group_3 | 42 vs. 46 | 0.052 | 0.039 |
WNT vs. Group_3 | 15 vs. 46 | 0.018 | 0.095 |
WNT vs. SHH | 15 vs. 42 | 0.080 | 0.326 |
Variable | Available cases | HR | 95 % CI |
p* |
---|---|---|---|---|
Age at diagnosis | N/S*** | |||
<4 vs. >4 | 33 vs. 133 | – | – | |
M_Stage | 0.045 | |||
M1–M4 vs. M0 | 66 vs. 100 | 2.064 | 0.998–4.269 | |
Residual tumor | N/S*** | |||
>1.5 cm2 vs. <1.5 cm2
| 21 vs. 145 | – | – | |
WHO classification | N/S*** | |||
Desmoplastic/nodular vs. classic | 33 vs. 119 | – | – | |
MBEN vs. classic | 5 vs. 119 | – | – | |
Anaplastic vs. classic | 8 vs. 119 | – | – | |
Large cell vs. classic | 1 vs. 119 | – | – | |
MYC_status | N/S*** | |||
Amplified vs. balanced | 7 vs. 159 | – | – | |
450k subgrouping | 0.032 | |||
Group_3 vs. Group_4 | 45 vs. 70 | 2.141 | 1.042–4.400 | |
SHH vs. Group_4 | 38 vs. 70 | 1.329 | 0.497–3.556 | |
SHH vs. Group_3 | 38 vs. 45 | 0.621 | 0.234–1.644 | |
WNT vs. Group_4 | 13 vs. 70 | NE | – |