1
Supplementary Data
Supplementary Table 1. Characteristics of both the entire cohort of patients/tumors included in the EORTC clinical trial 26951 and the cohort of patients/tumors included in
the present translational study.
Gender
Contrast Enhancement
Type of surgery
Brain location
Age
W.H.O. PS
Treatment
Patients/tumors included in the EORTC clinical
trial 26951
n=368
Patients/tumors included in the present
translational study
n=60
Male (%)
58
57
Female (%)
42
43
No (%)
Yes (%)
18
82
15
85
Biopsy (%)
14
3
Resection (%)
86
97
Frontal (%)
45
33
Non frontal (%)
55
67
Median (years)
49.4
48.0
Range (years-years)
(19-69)
(19-68)
0-1 (%)
2 (%)
84
16
77
23
RT alone (%)
50
52
RT + PCV (%)
50
48
86
88
14
12
Oligodendroglioma (%)
73
72
Oligoastrocytoma (%)
27
28
Previous surgical resection for No (%)
a lower grade of malignancy
Yes (%)
Tumor type
p-value
0.03
Abbreviations: RT, radiotherapy; PCV, procarbazine+lomustine+vincristine; W.H.O. PS, World Health Organization Performance Status; statistically significant p-value are
mentioned in the last column.
2
Supplementary Table 2. Characteristics of the cohort of patients/tumors from the clinical trial EORTC 26951 with a centrally reviewed-validated diagnosis of AOTs : (i) on
the left column, patients/tumors without available frozen tissue and (ii) on the right column, patients/tumors with available frozen tissue allowing their inclusion in the present
translational study.
Patients/tumors without available frozen tissue
Patients/tumors with available frozen tissue
p-value
n=212
n=45
Male (%)
59
60
Gender
Female (%)
41
40
No (%)
17
16
Contrast Enhancement
Yes (%)
83
84
Biopsy (%)
16
4
Type of surgery
Resection (%)
84
96
Frontal (%)
48
29
Brain location
p=0.03
Non frontal (%)
52
71
Median (years)
49.5
48.0
Age
Range (years-years)
19-68
19-67
0-1 (%)
86
78
WHO PS
2 (%)
14
22
RT alone (%)
49
51
Treatment
RT + PCV (%)
51
49
84
93
Previous surgical resection for No (%)
a lower grade of malignancy Yes (%)
16
7
Oligodendroglioma (%)
68
73
Tumor type
Oligoastrocytoma (%)
32
27
Abbreviations: RT, radiotherapy; PCV, procarbazine+lomustine+vincristine; W.H.O. PS, World Health Organization Performance Status; statistically significant p-value are
mentioned in the last column.
3
Supplementary Table 3. The most frequently lost genomic regions in the entire population of anaplastic oligodendroglial tumors
BAC name
Chr
Start
End
Gene(s)
Frequency (%)
DBACA1ZE09
9
14.0
14.2
NFIB
58.0
DBACA1ZG03
10
72.9
73.1
CDH23
57.6
ADELA11ZH09
9
21.7
21.9
MTAP
55.0
DBACA11ZB06
10
129.0
129.2
TACC2, BTBD16, PLEKHA1
55.0
ADELA8ZD01
10
129.4
129.6
DOCK1
55.0
APADA2ZE02
10
131.1
131.3
MGMT
55.0
DBACA11ZF04
10
128.8
129.0
DOCK1, FLJ45557
54.2
ADELA7ZE09
1
0.8
1.0
SAMD11, NOC2L, KLHL17, PLEKHN1, HES4, ISG15, AGRN, C1orf159
53.8
ADELA4ZE12
10
12.3
12.4
NUDT5, CDC123
53.3
ADELA9ZB01
9
21.9
22.0
MTAP, CDKN2A, CDKN2B
53.1
DBACA20ZC12
10
127.9
128.0
ADAM12
52.5
DBACA11ZD07
10
129.0
129.2
DOCK1
52.1
DBACA5ZG12
10
117.6
117.8
ATRNL1
51.7
DBACA11ZE03
10
124.8
125.0
ACADSB, HMX3, HMX2, BUB3
51.7
DBACA1ZC04
9
31.7
31.8
-
51.4
DBACA25ZC06
10
123.2
123.3
FGFR2
50.9
APADA1ZB10
10
39.0
39.2
-
50.9
DBACA3ZH07
10
91.4
91.6
MPHOSPH1
50.9
DBACA1ZG08
10
80.5
80.7
ZMIZ1
50.8
DBACA25ZD06
10
123.2
123.3
FGFR2
50.8
DBACA25ZB08
10
123.2
123.3
FGFR2
50.8
ADELA13ZD10
10
135.1
135.3
CYP2E1, SYCE1
50.8
ADELA7ZF09
1
8.5
8.7
RERE
50.0
DBACA14ZC01
1
26.8
27.0
ARID1A, PIGV, ZDHHC18
50.0
APADA3ZG01
10
87.5
87.7
GRID1
50.0
ADELA15ZC07
10
89.6
89.8
PTEN
50.0
DBACA11ZE04
10
105.3
105.5
SH3PXD2A
50.0
4
BPADA6ZD04
10
108.1
108.2
-
50.0
DBACA11ZG06
10
111.6
111.8
XPNEP1, ADD3
50.0
BPADA6ZE02
10
119.7
120.0
RAB11FIP2
50.0
ADELA15ZE07
10
123.1
123.2
FGFR2
50.0
APADA2ZC03
10
132.5
132.6
-
50.0
Abbreviations: Chr, chromosome; Start, BAC start in megabase; End, BAC end in megabase; -, no known gene.
5
Supplementary Table 4. The most frequently gained genomic regions in the entire population of anaplastic oligodendroglial tumors
BAC name
Chr
Start
End
Genes
Frequency (%)
ADELA11ZC11
7
116.1
116.2
MET
55.0
DBACA26ZF11
7
86.1
86.2
GRM3
54.2
DBACA2ZB04
7
107.8
108.0
NRCAM, PNPLA8, THAP5, DNAJB9
54.2
DBACA23ZB04
7
115.8
116.0
CAV2
54.2
DBACA20ZD02
7
125.9
126.0
GRM8
54.2
DBACA1ZD05
7
157.1
157.3
PTPRN2
53.4
DBACA20ZG01
7
101.3
101.4
CUX1
53.3
DBACA5ZC07
7
102.3
102.5
FBXL13, LRRC17, ARMC10
53.3
DBACA20ZE01
7
105.0
105.2
-
53.3
APADA1ZE12
7
108.7
108.8
-
53.3
APADA1ZB11
7
110.7
110.9
IMMP2L
53.3
BPADA4ZG12
7
118.4
118.6
-
53.3
DBACA20ZE02
7
127.0
127.2
PAX4, SND1
53.3
APADA2ZE04
7
130.4
130.6
-
53.3
DBACA20ZH02
7
132.0
132.1
PLXNA4, CHCHD3
53.3
BPADA4ZE09
7
133.3
133.5
EXOC4, LRGUK
53.3
ADELA9ZA05
7
136.5
136.7
PTN
53.3
ADELA13ZF09
7
158.4
158.5
WDR60
53.3
DBACA26ZD11
7
86.1
86.2
GRM3
52.6
DBACA23ZB06
7
116.8
117.0
ASZ1, CFTR
52.6
DBACA5ZD08
7
103.3
103.5
RELN
52.5
BPADA4ZB08
7
106.3
106.5
PRKAR2B
52.5
BPADA5ZD06
7
135.0
135.1
NUP205, LOC402694, SLC13A4, UNQ1940
52.5
DBACA6ZH10
7
141.9
142.1
PRSS1
52.5
APADA2ZD04
7
112.1
112.3
TMEM168, FLJ31818
51.9
DBACA23ZD06
7
116.9
117.0
CFTR
51.7
ADELA13ZG01
7
131.5
131.6
PLXNA4
51.7
6
ADELA15ZF03
7
86.5
86.7
DMTF1, C7orf23
51.7
ADELA13ZD03
7
98.2
98.3
TMEM130
51.7
APADA2ZG05
7
109.8
110.0
-
51.7
APADA1ZH09
7
113.2
113.3
PPP1R3A
51.7
DBACA23ZC06
7
116.9
117.0
CFTR
51.7
DBACA20ZB03
7
150.4
150.5
ABCB8, ACCN3, CDK5, SLC4A2, FASTK, TMUB1, CENTG3, GBX1
51.7
BPADA5ZC05
7
154.3
154.5
DPP6, PAXIP1
51.7
DBACA20ZD01
7
93.1
93.3
-
50.9
DBACA7ZC06
7
123.3
123.5
SPAM1
50.9
ADELA13ZE03
7
150.3
150.4
KCNH2, NOS3, ATG9B, ABCB8, ACCN3, CDK5, SLC4A2, FASTK, TMUB1, CENTG3
50.9
DBACA20ZC01
7
94.1
94.3
SGCE, PEG10
50.8
APADA1ZE03
7
115.0
115.2
-
50.8
DBACA26ZE11
7
86.1
86.2
GRM3
50.0
APADA1ZD09
7
90.6
90.8
PFTK1, FZD1
50.0
DBACA24ZA05
7
91.9
92.0
ANKIB1, GATAD1, PEX1, DFKZP564O0523
50.0
DBACA1ZB07
7
120.2
120.4
TSPAN12, ING3
50.0
ADELA8ZF06
7
125.2
125.4
-
50.0
APADA2ZG02
7
129.2
129.3
NRF1, UBE2H
50.0
BPADA5ZF10
7
137.8
138.0
TRIM24, SVOPL
50.0
BPADA7ZD04
7
146.2
146.4
CNTNAP2
50.0
ADELA7ZB12
7
150.1
150.3
TMEM176B, ABP1, KCNH2, NOS3
50.0
BPADA7ZE06
7
155.8
156.0
-
50.0
Abbreviations: Chr, chromosome; Start, BAC start in megabase; End, BAC end in megabase; -, no known gene
7
Supplementary Table 5. Agreement between array aCGH and FISH investigations
1p/19 codeleted tumors by aCGH (n=13)
EGFR amplified tumors by aCGH (n=15)
1p/19q codeleted by FISH
8
EGFR amplified by FISH
8
1p deleted/19q intact by FISH
2
Not EGFR amplified by FISH
1
1p intact/19q intact by FISH
1
EGFR locus not tested by FISH
6
1p/19q statuses not tested by FISH
2
Abbreviations: aCGH, BAC-array based comparative genomic hybridization; FISH, fluorescent in situ hybridization
8
Supplementary Table 6. Prognostic BACs used to build the genetic-prognostic tree
Tree branch
BAC name 1
BAC name 2
Chr Start
End
X
Y
Z
Genes
LFDR
X1
ADELA15ZB03
7
55.0
55.2
EGFR
0.01
X2
DBACA23ZF10
7
55.0
55.1
EGFR
0.01
X3
BPADA5ZF07
7
55.3
55.5
LANCL2
0.01
X4
DBACA23ZE10
7
55.0
55.1
EGFR
0.01
Y1
ADELA12ZE06
1
46.5
46.6
C1orf190, RAD54L, LRRC41, UQCRH, NSUN4
0.01
Y2
DBACA2ZH06
1
106.7
106.8
-
0.02
Y3
DBACA3ZA01
1
86.7
86.8
CLCA2
0.03
Y4
DBACA23ZA07
1
47.3
47.4
CYP4Z1, CYP4A22
0.05
Y5
DBACA14ZE02
1
54.0
54.2
TMEM48, YIPF1, DIO1, C1orf41, LRRC42
0.05
Y6
DBACA13ZB11
1
42.1
42.3
HIVEP3
0.05
Y7
BPADA6ZF09
1
52.0
52.1
OSBPL9, NRD1
0.06
Y8
ADELA9ZA03
1
51.6
51.7
EPS15
0.10
Y9
DBACA14ZF02
1
101.3
101.4
DPH5
0.12
Y10
ADELA12ZE02
1
101.3
101.4
-
0.13
Y11
DBACA25ZC08
1
91.8
91.9
-
0.13
Y12
ADELA7ZD03
1
101.2
101.4
SLC30A7, DPH5
0.14
Y13
ADELA13ZC01
1
119.3
119.4
TBX15, WARS2
0.14
Y14
BPADA6ZD01
1
47.0
47.2
CYP4B1, CYP4A11
0.14
Y15
ADELA7ZG05
1
50.3
50.5
ELAVL4
0.14
Y16
ADELA13ZB01
1
101.0
101.1
EXTL2, SLC30A7
0.15
Z1
DBACA16ZG10
21
41.1
41.3
DSCAM
0.08
Z2
APADA2ZB06
21
32.3
32.4
HUNK
0.08
Z3
DBACA25ZB06
21
35.0
35.2
CLIC6, RUNX1
0.09
Z4
DBACA6ZA07
21
32.9
33.0
TCP10L, C21orf59, SYNJ1, C21orf66
0.10
Z5
DBACA26ZC07
21
33.2
33.3
OLIG2
0.10
Z6
DBACA24ZE05
21
39.0
39.1
ETS2
0.10
9
Z7
DBACA17ZA09
21
39.4
39.5
PSMG1, BRWD1
0.10
Z8
DBACA24ZD05
21
39.0
39.1
ETS2
0.11
Z9
DBACA6ZB08
21
36.3
36.5
SETD4, CBR1, CBR3, DOPEY2
0.12
Z10
DBACA6ZF07
21
31.9
32.1
TIAM, SOD1, SFRS15
0.12
Z11
DBACA6ZB07
21
45.6
45.8
COL18A1, C21orf123, COL18A1, SLC19A1
0.12
Z12
DBACA16ZD11
21
35.2
35.4
RUNX1
0.13
Z13
DBACA24ZH07
21
33.4
33.6
IFNAR2, IL10RB
0.15
Abbreviations: Chr, chromosome; Start, BAC start in megabase; End, BAC end in megabase; -, no known gene; LFDR, local false discovery rate
Supplementary Table 7. Clinical, radiological and pathological characteristics of the entire population of anaplastic oligodendroglial tumors and the genetic-prognostic
subgroups identified.
N
Number
Sex
Ratio (male/female)
Age
Median (year)
Range (year-year)
Entire population
Type I
Type II
Type III
Type IV
60
15
13
7
25
1.3 (34/26)
0.9 (7/8)
3.3 (10/3)
1.3 (4/3)
1.1 (13/12)
48.0
55.5
43.6
38.1
43.5
19.2-67.6
36.7-66.8
31.0-65.6
20.7-59
19.2-67.6
72/28
67/33
92/8
57.0/43.0
68/32
Oligodendroglioma/Oligoastrocytoma
%/%
High cellularity
%
92
87
100.0
86
92
Presence of cytonuclear atypia
%
92
87
100.0
86
92
Mitosis
%
90
93
92
86
88
Endothelial abnormalities
%
87
100
77
71
88
Necrosis
%
63
93
46
71
52
Frontal location
%
33
13
77
29
24
Contrast enhancement
%
85
87
77
86
88
10
Supplementary Table 8. Univariate analysis and multivariate analysis in the entire population of anaplastic oligodendroglial tumors
Univariate analysis
Contrast
enhancement
Type of surgery
Brain location
Genomic type
Age
WHO performance status
Treatment
Necrosis
Previous surgical resection for
a lower grade glioma
Endothelial abnormalities
Tumor type
n
Median OS (years)
no
9
1.2
yes
51
2.4
biopsy
2
1.2
resection
58
2.4
frontal
20
NR
non frontal
40
1.6
II and IV
38
6.7
I and III
22
1.2
<48.0
29
6.7
>48.0
31
1.4
0-1
46
3.2
2
14
1.5
RT alone
31
1.5
RT + PCV
29
6.7
No
22
4.2
Yes
38
1.6
No
53
1.6
Yes
7
NR
No
8
NR
Yes
52
1.6
oligodendroglioma
43
2.5
p-value
0.002
<0.0001
<0.0001
0.006
0.002
0.04
0.02
HR (95%CI)
Multivariate analysis
p-value
RR (95% CI)
<0.0001
5.7 (2.8-11.9)
0.0002
3.8 (1.9-7.7)
0.30
(0.19-0.70)
0.22
(0.05-0.25)
0.28
(0.13-0.48)
2.47
(1.43-8.44)
0.37
(0.19-0.68)
0.49
(0.27-0.96)
7.57
(1.21-6.66)
oligoastrocytoma
17
1.5
Abbreviations: WHO, world health organization; RT, radiotherapy; PCV, chemotherapy by procarbazine+lomustine+vincristione; NR, not reached; RR, relative risk; HR,
hazard ration