Introduction
Materials and methods
Patient selection
Central pathology review
Molecular analysis
Statistical analysis
Results
Molecular classification based on IDH and TERT defines distinct subgroups of adult gliomas in Cohort 1
Cohort 1 | Cohort 2 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Histology | DA | AA | GBM | OA | AOA | OL | AO | All | GBMa
| |
Total | 63 | 106 | 337 | 67 | 103 | 47 | 35 | 758 | 193 | |
IDH1/2 n(%) | R132H | 36 (57) | 38 (36) | 16 (5) | 56 (84) | 59 (57) | 42 (89) | 27 (77) | 274 (36) | 0 (0) |
Other mutation | 2 (3) | 2 (2) | 0 (0) | 2 (3) | 2 (2) | 3 (6) | 1 (3) | 12 (2) | 0 (0) | |
All mutation | 38 (60) | 40 (38) | 16 (5) | 58 (87) | 61 (59) | 45 (96) | 28 (80) | 286 (38) | 0 (0) | |
TERT n(%) | C228T | 12 (19) | 29 27) | 136 (40) | 27 (40) | 30 (29) | 27 (57) | 17 (49) | 278 (37) | 94 (49) |
C250T | 5 (8) | 6 (6) | 58 (17) | 6 (9) | 15 (15) | 12 (26) | 9 (26) | 111 15) | 21 (11) | |
C228T&C250T | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (0.1) | 0 (0) | |
All mutation | 18 (29) | 35 (33) | 194 (58) | 33 (49) | 45 (44) | 39 (83) | 26 (74) | 390 (51) | 115 (60) | |
1p/19q n(%) | Total 1p/19q loss | 9/63 (14) | 6/106 (6) | 6/336 (2) | 27/67 (40) | 32/103 (31) | 41/47 (87) | 27/35 (77) | 148/757 (20) | N/A |
MGMT n(%) | Methylated | 35/62 (56) | 45/106 (42) | 126/336 (38) | 44/66 (67) | 67/103 (65) | 39/47 (83) | 30/35 (86) | 386/755 (51) | 66/193 (34) |
H3.3/H3.1 n(%) | K27M | 2/34 (6) | 6/71 (9) | 12/316 (4) | 0/20 (0) | 1/47 (2) | 0/12 (0) | 0/10 (0) | 21/510 (4) | 0/193 (0) |
Other mutation | 0/34 (0) | 0/71 (0) | 0/316 (0) | 0/20 (0) | 1/47 (2) | 1/12 (8) | 0/10 (0) | 2/510 (0.4) | 0/193 (0) | |
BRAF (V600) n(%) | V600E | 1/34 (3) | 3/70 (4) | 8/313 (3) | 0/20 (0) | 0/47 (0) | 0/12 (0) | 0/10 (0) | 12/506 (2) | 4/193 (2) |
CDKN2A n(%) | Homozygous Del | 3/48 (6) | 13/74 (18) | 86/229 (37) | 0/42 (0) | 11/64 (17) | 0/28 (0) | 3/20 (15) | 116/505 (23) | N/A |
Heterozygous Del | 2/48 (4) | 15/74 (20) | 40/229 (17) | 1/42 (2) | 9/64 (14) | 2/28 (7) | 3/20 (15) | 72/505 (14) | N/A |
All | Group Aa
| Group Ba
| Group Ca
| Group Da
| p-valueb
| |
---|---|---|---|---|---|---|
Total | 758 | 155 | 131 | 237 | 235 | |
Mean Age at diagnosis(year) | 53.7 | 44.7 | 41.7 | 56.7 | 63.4 | <0.0001 |
Sex M/F | 426/332 | 90/65 | 75/56 | 134/103 | 127/108 | 0.87 |
Surgery n (%) | ||||||
Biopsy only | 121 (16) | 16 (10) | 19 (15) | 49 (21) | 37 (16) | 0.05 |
KPS n (%) | ||||||
100 | 160 (21) | 66 (43) | 51 (40) | 26 (11) | 17 (7) | <0.0001 |
90 | 268 (35) | 63 (41) | 58 (45) | 83 (35) | 64 (27) | |
80 | 126 (17) | 13 (8) | 7 (5) | 43 (18) | 63 (27) | |
70 | 94 (12) | 6 (4) | 8 (6) | 38 (16) | 42 (18) | |
− 60 | 107 (14) | 7 (5) | 4 (3) | 47 (20) | 49 (21) | |
Adjuvant therapy n (%) | ||||||
CRT | 559/748 (75) | 83/150 (55) | 70/131 (53) | 201/235 (86) | 205/232 (88) | <0.0001 |
Chemo only | 58/748 (8) | 32/150 (21) | 5/131 (4) | 7/235 (3) | 14/232 (6) | |
RT only | 43/748 (6) | 4/150 (3) | 16/131 (12) | 13/235 (6) | 10/232 (4) | |
None | 88/748 (12) | 31/150 (21) | 40/131 (31) | 14/235 (6) | 3/232 (1) | |
Location n(%) | ||||||
Cerebrum (with frontal involvement) | 370/756 (49) | 119/154 (77) | 82/131 (63) | 86/237 (36) | 83/234 (35) | <0.0001 |
Cerebrum (other) | 348/756 (47) | 34/154 (23) | 48/131 (37) | 122/237(53) | 144/234 (63) | |
Thalamus | 25/756 (3) | 1/154 (0.7) | 0/131 (0) | 18/237 (8) | 6/234 (3) | |
Infratentorium | 13/756 (2) | 0/154 (0) | 1/131 (0.8) | 11/237 (5) | 1/234 (0.4) | |
Histology n (%) | ||||||
DA | 63 (8) | 12 (8) | 26 (20) | 19 (8) | 6 (3) | <0.0001 |
AA | 106 (14) | 7 (5) | 33 (25) | 38 (16) | 28 (12) | |
GBM | 337 (44) | 9 (6) | 7 (5) | 136 (57) | 185 (79) | |
OA | 67 (9) | 30 (19) | 28 (21) | 6 (3) | 3 (1) | |
AOA | 103 (14) | 32 (21) | 29 (22) | 29 (12) | 13 (6) | |
OL | 47 (6) | 39 (25) | 6 (5) | 2 (1) | 0 (0) | |
AO | 35 (5) | 26 (17) | 2 (2) | 7 (3) | 0 (0) | |
Molecular background n(%) | ||||||
Total 1p/19q loss | 148/757 (20) | 144/155 (93) | 4/131 (3) | 0/237 (0) | 0/234 (0) | <0.0001 |
MGMT methylation | 386/755 (51) | 143/155 (92) | 88/129 (68) | 72/236 (31) | 83/235 (35) | <0.0001 |
H3.3/H3.1 mutation | 23/510 (5) | 1/31 (3) | 0/21 (0) | 21/233 (9) | 1/235 (0.4) | 0.0001 |
BRAF V600E | 12/506 (2) | 0/31 (0) | 0/21 (0) | 9/233 (4) | 3/221 (1) | 0.21 |
CDKN2A
| ||||||
Homozygous Del | 116/505 (23) | 4/89 (4) | 7/86 (8) | 37/163 (23) | 68/167 (41) | <0.0001 |
Heterozygous Del | 72/505 (14) | 5/89 (6) | 6/86 (7) | 22/163 (13) | 39/167 (23) |
Univariate | Multivariate | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
OS | PFS | OS | PFS | ||||||||||
HR | 95 % C.I. | p-value | HR | 95 % C.I. | p-value | HR | 95 % C.I. | p-value | HR | 95 % C.I. | p-value | ||
Histology | Astro grade II | 0.91 | 0.518–1.594 | 0.74 | 1.23 | 0.788–1.906 | 0.37 | 0.58 | 0.323–1.027 | 0.06 | 0.92 | 0.585–1.461 | 0.74 |
Astro grade III | 2.14 | 1.410–3.245 | 0.0003 | 1.85 | 1.291–2.638 | 0.0008 | 1.02 | 0.658–1.566 | 0.95 | 0.99 | 0.682–1.447 | 0.97 | |
GBM | 4.02 | 2.860–5.635 | <0.0001 | 3.73 | 2.801–4.974 | <0.0001 | 1.24 | 0.842–1.813 | 0.28 | 1.43 | 1.024–1.989 | 0.04 | |
Oligo grade II | 0.25 | 0.127–0.504 | <0.0001 | 0.48 | 0.313–0.749 | 0.001 | 0.42 | 0.207–0.846 | 0.02 | 0.6 | 0.381–0.928 | 0.02 | |
Oligo grade III | Ref | Ref | Ref | Ref | |||||||||
Molecular group* | Group A | 0.04 | 0.023–0.073 | <0.0001 | 0.1 | 0.070–0.142 | <0.0001 | 0.09 | 0.048–0.180 | <0.0001 | 0.19 | 0.124–0.296 | <0.0001 |
Group B | 0.12 | 0.079–0.184 | <0.0001 | 0.18 | 0.126–0.242 | <0.0001 | 0.29 | 0.172–0.480 | <0.0001 | 0.33 | 0.218–0.492 | <0.0001 | |
Group C | 0.58 | 0.454–0.735 | <0.0001 | 0.62 | 0.499–0.773 | <0.0001 | 0.71 | 0.545–0.919 | 0.01 | 0.7 | 0.553–0.888 | 0.003 | |
Group D | Ref | Ref | Ref | Ref | |||||||||
Location | Cerebrum | 0.79 | 0.482–1.305 | 0.36 | 0.65 | 0.430–0.985 | 0.04 | excluded by the factor selection with step-wise method | 0.67 | 0.427–1.045 | 0.08 | ||
Cerebrum with frontal Involvement | 0.40 | 0.242–0.670 | 0.0005 | 0.31 | 0.203–0.475 | <0.0001 | 0.5 | 0.316–0.779 | 0.002 | ||||
Other | Ref | Ref | Ref | ||||||||||
Age | 1.048a
| 1.040–1.057 | <0.0001 | 1.033a
| 1.027–1.040 | <0.0001 | 1.02a
| 1.011–1.029 | <0.0001 | 1.01a
| 1.003–1.018 | 0.007 | |
Sex | M | Ref | Ref | Ref | Ref | ||||||||
F | 0.91 | 0.724–1.134 | 0.39 | 0.95 | 0.781–1.150 | 0.58 | 0.72 | 0.572–0.905 | 0.005 | 0.81 | 0.663–0.982 | 0.03 | |
KPS | 0.971b
| 0.965–0.976 | <0.0001 | 0.98b
| 0.974–0.985 | <0.0001 | 0.99b
| 0.983–0.997 | 0.008 | excluded by factor selection with step-wise method | |||
Surgery | Biopsy | 1.85 | 1.416–2.427 | <0.0001 | 1.41 | 1.092–1.817 | 0.008 | 2.05 | 1.522–2.755 | <0.0001 | 1.6 | 1.204–2.121 | 0.001 |
Removal | Ref | Ref | Ref | Ref | |||||||||
Adjuvant Therapy | CRT | 2.02 | 1.132–3.601 | 0.02 | 1.78 | 1.110–2.868 | 0.02 | excluded by factor selection with step-wise method | excluded by factor selection with step-wise method | ||||
Chemo | 0.84 | 0.392–1.792 | 0.65 | 0.87 | 0.472–1.587 | 0.64 | |||||||
RT | Ref | Ref | |||||||||||
None | 0.45 | 0.197–1.010 | 0.05 | 0.74 | 0.411–1.333 | 0.32 |
Multivariate Cox regression models revealed differences in prognostic impact of WHO grade among molecular groups
Interaction between TERT and MGMT in IDH-wild-type GBM
Cohort | Alla
| Cohort 1 | Cohort 2 |
P-valueb
|
---|---|---|---|---|
Total | 453 | 260 | 193 | |
Mean Age at diagnosis | 61.0 | 59.3 | 63.3 | 0.0007 |
Sex M/F | 249/204 | 152/108 | 97/96 | 0.0827 |
Locationc
| ||||
Cereberal with frontal involvement | 152 (34) | 87 (33) | 65 (34) | 0.985 |
Cerebral (other) | 277 (61) | 160 (62) | 117 (61) | |
Other | 22 (5) | 13 (5) | 9 (5) | |
KPS | ||||
100 | 56 (12) | 12 (5) | 44 (23) | <0.0001 |
90 | 132 (29) | 81 (31) | 51 (26) | |
80 | 111 (25) | 73 (28) | 38 (20) | |
70 | 85 (19) | 53 (20) | 32 (17) | |
− 60 | 69 (15) | 41 (16) | 28 (15) | |
TERT/MGMT
| ||||
Mut/Met | 88 (19) | 48 (18) | 40 (21) | 0.921 |
Mut/Un-met | 175 (39) | 100 (38) | 75 (39) | |
Wt/Met | 64 (14) | 38 (15) | 26 (13) | |
Wt/Un-met | 126 (28) | 74 (28) | 52 (27) | |
Surgery | ||||
Removal | 421 (93) | 238 (92) | 183 (95) | |
Biopsy only | 32 (7) | 22 (8) | 10 (5) | 0.178 |
Univariate | Multivariate | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
OS | PFS | OS | PFS | ||||||||||
HR | 95 % C.I. | p-value | HR | 95 % C.I. | p-value | HR | 95 % C.I. | p-value | HR | 95 % C.I. | p-value | ||
Cohort | Cohort 1 | 0.81 | 0.643–1.030 | 0.09 | 1.11 | 0.884–1.398 | 0.37 | excluded by factor selection with step-wise method | excluded by factor selection with step-wise method | ||||
Cohort 2 | Ref | Ref | |||||||||||
Location | Cerebrum | 0.91 | 0.504–1.624 | 0.74 | 0.81 | 0.489–1.357 | 0.43 | excluded by factor selection with step-wise method | excluded by factor selection with step-wise method | ||||
Cerebrum with Frontal Involvement | 0.93 | 0.511–1.705 | 0.82 | 0.78 | 0.458–1.317 | 0.35 | |||||||
Other | Ref | Ref | |||||||||||
Age | 1.015a
| 1.004–1.025 | 0.006 | 1.004a
| 0.995–1.013 | 0.38 | 1.01a
| 1.004–1.025 | 0.008 | excluded by factor selection with step-wise method | |||
Sex | M | Ref | Ref | excluded by factor selection with step-wise method | excluded by factor selection with step-wise method | ||||||||
F | 0.72 | 0.570–0.918 | 0.008 | 0.78 | 0.621–0.975 | 0.03 | |||||||
KPS | 0.992b
| 0.985–0.999 | 0.03 | 0.999b
| 0.992–1.006 | 0.74 | 0.99b
| 0.982–0.997 | 0.009 | excluded by factor selection with step-wise method | |||
Surgery | Biopsy | 2.59 | 1.725–3.899 | <0.0001 | 2.06 | 1.349–3.130 | 0.0008 | 3.15 | 2.082–4.769 | <0.0001 | 2.22 | 1.454–3.380 | 0.0002 |
Removal | Ref | Ref | Ref | Ref | |||||||||
TERT
| wild-type | 0.73 | 0.568–0.925 | 0.01 | 0.73 | 0.581–0.922 | 0.008 | Interacts with MGMT | <0.0001 | 0.65 | 0.513–0.821 | 0.0003 | |
mutated | Ref | Ref | Ref | ||||||||||
MGMT
| Methylated | 0.43 | 0.325–0.561 | <0.0001 | 0.51 | 0.396–0.656 | <0.0001 | Interacts with TERT | <0.0001 | 0.48 | 0.368–0.613 | <0.0001 | |
Unmethylated | Ref | Ref | Ref | ||||||||||
TERT-MGMT
| TERT-MGMT interaction | 0.006 | excluded by factor selection with step-wise method | ||||||||||
Wt/Met | 0.32 | ||||||||||||
Mut/Met | 0.27 | ||||||||||||
Wt/Un-met | 0.54 | ||||||||||||
Mut/Un-met | Ref |