Clinical and Prognostic Implications of 1p/19q, IDH, BRAF, MGMT Promoter, and TERT Promoter Alterations, and Expression of Ki-67 and p53 in Human Gliomas

Figures & data

Table 1 Correlations Between Clinicopathological Characteristics and Alterations on IDH1/2, MGMTp, TERTp, BRAF, and 1p/19q in 103 Human Gliomas

	IDH1/2 (%)			p value	MGMTp (%)		p value	TERTp (%)		p value	BRAF (%)		p value	1p/19q (%)				p value
	IDH1-mu	IDH2-mu	Wt		M	UM		Mu	Wt		Mu	Wt		1p-del	19q-del	Codel	Wt
Sex				0.887			0.206			0.472			0.598					0.770
Male, n=45	19 (42.2)	1 (2.2)	25 (55.6)		29 (64.4)	16 (35.6)		28 (62.2)	17 (37.8)		2 (4.4)	43 (95.6)		2 (4.4)	1 (2.2)	14 (31.1)	28 (62.2)
Female, n=58	26 (44.8)	2 (3.4)	30 (51.7)		44 (75.9)	14 (24.1)		32 (55.2)	26 (44.8)		4 (6.9)	54 (93.1)		3 (5.2)	3 (5.2)	21 (36.2)	31 (53.4)
Age (years)				0.044*			0.157			0.131			0.230					0.526
< 60, n=84	41 (48.8)	3 (3.6)	40 (47.6)		57 (67.9)	27 (32.1)		46 (54.8)	38 (45.2)		6 (7.1)	78 (92.9)		5 (5.9)	4 (4.8)	28 (33.3)	47 (56.0)
≥ 60, n=19	4 (21.1)	0 (0.0)	15 (78.9)		16 (84.2)	3 (15.8)		14 (73.7)	5 (26.3)		0 (0.0)	19 (100)		0 (0.0)	0 (0.0)	7 (36.8)	12 (63.2)
Histology				<0.001**			0.029*			<0.001**			0.304					<0.001**
A, n=17	8 (47.1)	0 (0.0)	9 (52.9)		12 (70.6)	5 (29.4)		2 (11.8)	15 (88.2)		3 (17.6)	14 (82.4)		1 (5.9)	0 (0.0)	2 (11.8)	14 (82.4)
AA, n=19	11 (57.9)	0 (0.0)	8 (42.1)		10 (52.6)	9 (47.4)		6 (31.6)	13 (68.4)		1 (5.3)	18 (94.7)		1 (5.3)	1 (5.3)	3 (15.8)	14 (73.7)
O, n=18	13 (72.2)	2 (11.1)	3 (16.7)		17 (94.4)	1 (5.6)		17 (94.4)	1 (5.6)		0 (0.0)	17 (94.4)		0 (0.0)	0 (0.0)	16 (88.9)	2 (11.1)
AO, n=12	8 (66.7)	1 (8.3)	3 (25.0)		11 (91.7)	1 (8.3)		9 (75.0)	3 (25.0)		0 (0.0)	11 (91.7)		0 (0.0)	0 (0.0)	11 (91.7)	1 (8.3)
OA, n=1	1 (100.0)	0 (0.0)	0 (0.0)		1 (100.0)	0 (0.0)		1 (100.0)	0 (0.0)		0 (0.0)	1 (100.0)		0 (0.0)	0 (0.0)	1 (100.0)	0 (0.0)
GBM, n=36	4 (11.1)	0 (0.0)	32 (88.9)		22 (61.1)	14 (38.9)		25 (69.4)	11 (30.6)		2 (5.6)	34 (94.4)		3 (8.3)	3 (8.3)	2 (5.6)	28 (77.8)
Grade				<0.001**			0.110			0.091			0.932					<0.001**
Grade II–III, n=67	41 (61.2)	3 (4.5)	23 (34.3)		51 (76.1)	16 (23.9)		35 (52.2)	32 (47.8)		4 (6.0)	63 (94.0)		2 (3.0)	1 (1.5)	33 (49.3)	34 (50.7)
Grade IV, n=36	4 (11.1)	0 (0.0)	15 (78.9)		22 (61.1)	14 (38.9)		25 (69.4)	11 (30.6)		2 (5.6)	34 (94.4)		3 (8.3)	3 (8.3)	2 (5.6)	28 (77.8)
Tumor location				0.110			0.064			0.917			0.387					0.002**
Left, n=49	24 (49.0)	1 (2.0)	24 (49.0)		39 (79.6)	10 (20.4)		28 (57.1)	21 (42.9)		2 (4.1)	47 (95.9)		3 (6.1)	1 (2.0)	19 (38.8)	26 (53.1)
Right, n=43	20 (46.5)	2 (4.7)	21 (48.8)		29 (67.4)	14 (32.6)		26 (60.5)	17 (39.5)		4 (9.3)	39 (09.7)		1 (2.3)	0 (0.0)	15 (34.9)	27 (63.8)
Others, n=11	1 (9.1)	0 (0.0)	10 (90.9)		5 (45.5)	6 (54.5)		6 (54.5)	5 (45.5)		0 (0.0)	11 (100.00)		1 (9.1)	3 (27.3)	1 (9.1)	6 (54.5)
IDH1/2				\			0.009**			0.700			0.502					<0.001**
Mu, n=48	\	\	\		40 (83.3)	8 (16.7)		27 (56.3)	21 (43.8)		2 (4.2)	46 (95.8)		0 (0.0)	1 (2.1)	29 (60.4)	18 (37.5)
Wt, n=55	\	\	\		33 (60.0)	22 (40.0)		33 (60.0)	22 (40.0)		4 (7.3)	51 (92.7)		5 (9.1)	3 (5.5)	6 (10.9)	41 (74.5)
MGMTp				0.027*			\			0.016*			0.037*					0.002**
M, n=73	37 (50.7)	3 (4.1)	33 (45.2)		\	\		48 (65.8)	25 (34.2)		2 (2.7)	71 (97.3)		4 (5.5)	2 (2.7)	33 (45.2)	34 (46.6)
UM, n=30	8 (26.7)	0 (0.0)	22 (73.3)		\	\		12 (40.0)	18 (60.0)		4 (13.3)	26 (86.7)		1 (3.3)	2 (6.7)	2 (6.7)	25 (83.3)
TERTp				0.865			0.016*			\			0.202					<0.001**
M, n=73	37 (50.7)	3 (4.1)	33 (45.2)		\	\		48 (65.8)	25 (34.2)		2 (2.7)	71 (97.3)		4 (5.5)	2 (2.7)	33 (45.2)	34 (46.6)
UM, n=30	8 (26.7)	0 (0.0)	22 (73.3)		\	\		12 (40.0)	18 (60.0)		4 (13.3)	26 (86.7)		1 (3.3)	2 (6.7)	2 (6.7)	25 (83.3)
BRAF				0.759			0.037*			0.202			\					0.172
Mu, n=6	2 (33.3)	0 (0.0)	4 (66.7)		2 (33.3)	4 (66.7)		2 (33.3)	4 (66.7)		\	\		1 (16.7)	0 (0.0)	0 (0.0)	5 (83.3)
Wt, n=97	43 (44.3)	3 (3.1)	51 (52.6)		71 (73.2)	26 (26.8)		58 (59.8)	39 (40.2)		\	\		4 (4.1)	4 (4.1)	35 (36.1)	54 (55.7)
1p/19q				<0.001**			<0.001**			<0.001**			0.070					\
Codel, n=35	26 (74.3)	3 (8.6)	6 (17.1)		33 (94.3)	2 (5.7)		30 (85.7)	5 (14.3)		0 (0.0)	35 (100.0)		\	\	\	\
Others, n=68	19 (27.9)	0 (0.0)	49 (72.1)		40 (58.8)	28 (41.2)		30 (44.1)	38 (55.9)		6 (8.8)	62 (91.2)		\	\	\	\

Notes: Significance analysis was two-tailed, and p<0.05 was considered statistically significant. * at p<0.05 level, ** at p<0.01 level. \: no data, for no correlation analysis here.

Abbreviations: IDH1/2, isocitrate dehydrogenase 1 and 2; TERTp, telomerase reverse transcriptase promoter; MGMTp, O6-methylguanine-DNA methyltransferase promoter; 1p/19q, chromosome arms 1p and 19q; BRAF, v-raf murine sarcoma oncogene homologue B1; Mu, mutation; Wt, wild-type; M, methylation; UM, unmethylation; 1p-del, 1p-deletion; 19q-del, 19q-deletion; Codel, codeletion; A, astrocytoma; AA, anaplastic astrocytoma; AO, anaplastic oligodendroglioma; AOA, anaplastic oligoastrocytoma; O, oligodendroglioma; OA, oligoastrocytoma; GM, glioblastoma.

Table 2 Ki-67 and p53 Immunoreactivity in 103 Human Gliomas

	p53 Cases, n (%)					Ki-67 Cases, n (%)
	Score 0	Score 1	Score 2	Score 3	p value	Score 0	Score 1	Score 2	Score 3	p value
Grade					0.101					<0.001**
II–III, n=67	20 (29.9)	33 (49.3)	9 (13.4)	5 (7.5)		19 (28.4)	46 (68.7)	2 (3.0)	0 (0.0)
IV, n=36	5 (13.9)	16 (44.4)	9 (25.0)	6 (16.7)		0 (0.0)	14 (38.9)	20 (55.6)	2 (5.6)
IDH					0.516					0.003**
Mu, n=48	13 (27.1)	21 (43.8)	7 (14.6)	7 (14.6)		13 (27.1)	31 (64.6)	4 (8.3)	0 (0.0)
Wt, n=55	12 (21.8)	28 (50.9)	11 (20.0)	4 (7.3)		6 (10.9)	29 (42.7)	18 (32.7)	2 (3.6)
MGMTp					0.200					0.572
M, n=73	19 (26.0)	37 (50.7)	9 (12.3)	8 (11.0)		15 (20.5)	42 (57.5)	14 (19.2)	2 (2.7)
UM, n=30	6 (20.0)	12 (40.0)	9 (30.0)	3 (10.0)		4 (13.3)	18 (60.0)	8 (26.7)	0 (0.0)
TERTp					0.003**					0.211
Mu, n=60	16 (26.7)	35 (58.3)	7 (11.7)	2 (3.3)		9 (15.0)	33 (55.0)	17 (28.3)	1 (1.7)
Wt, n=43	9 (20.9)	14 (32.6)	11 (25.6)	9 (20.9)		10 (23.3)	27 (62.8)	5 (11.6)	1 (2.3)
BRAF					0.671					0.230
Mu, n=6	2 (33.3)	3 (50.0)	0 (0.0)	1 (16.7)		3 (50.0)	2 (33.3)	1 (16.7)	0 (0.0)
Wt, n=97	23 (23.7)	46 (47.4)	18 (18.6)	10 (10.3)		16 (16.5)	58 (59.8)	21 (21.6)	2 (2.1)
1p/19q					0.001**					0.011*
Codel, n=35	12 (34.3)	22 (62.9)	0 (0.0)	1 (2.9)		9 (25.7)	24 (68.6)	1 (2.9)	1 (2.9)
Others, n=68	13 (19.1)	27 (39.7)	18 (26.5)	10 (14.7)		10 (14.7)	36 (52.9)	21 (30.9)	1 (1.5)

Notes: Significance analysis was two-tailed, and p<0.05 was considered statistically significant. * at p<0.05 level, ** at p<0.01 level.

Abbreviations: IDH, isocitrate dehydrogenase; TERTp, telomerase reverse transcriptase promoter; MGMTp, O6-methylguanine-DNA methyltransferase promoter; 1p/19q, chromosome arms 1p and 19q; BRAF, v-raf murine sarcoma oncogene homologue B1; Mu, mutation; Wt, wild-type; M, methylation; UM, unmethylation; Codel, codeletion.

Figure 1 Prognostic values of patient age, histological grade, MGMT promoter methylation, IDH mutation, TERT promoter mutation, 1p/19q codeletion, and Ki-67 and p53 expressions by Kaplan–Meier Estimates of Overall Survival in 103 gliomas.

Notes: Older age (>60 years) (A), higher histological grade (B), and overexpression Ki-67 (G) and p53 (H) predicted worse survival rates in glioma patients, while MGMT promoter methylation (MGMTp-M) (C), IDH mutation (IDH-mu) (D), TERT promoter mutation (TERTp-mu) (E), and 1p/19q codeletion (1p/19q-codel) (F) predicted better survival rates. Significance analysis was two-tailed, and p<0.05 was considered statistically significant.Abbreviations: IDH, isocitrate dehydrogenase;TERTp, telomerase reverse transcriptase promoter; MGMTp, O6-methylguanine-DNA methyltransferase promoter; 1p/19q-codel, chromosome arms 1p and 19q codeletion; BRAF, v-raf murine sarcoma oncogene homologue B1; Mu, mutation; Wt, wild-type; M, methylation; UM, unmethylation.

Table 3 Clinicopathological and Biological Factors Affecting Overall Survival Rates

	Univariate		p value	Multivariate		p value
	OR	95% CI		OR	95% CI
Sex (male vs female)	0.640	0.265–1.546	0.321	0.571	0.192–1.698	0.313
Age (≤ 60y vs > 60y)	3.300	1.166–9.341	0.025*	3.0182	0.817–11.112	0.098
Histological grade (II–III vs IV)	4.073	1.620–10.240	0.003**	1.034	0.298–3.585	0.958
IDH (wt vs mu)	0.174	0.060–0.509	0.001**	0.394	0.100–1.544	0.181
MGMTp (UM vs M)	0.607	0.239–1.544	0.295	0.834	0.260–2.674	0.760
TERTp (wt vs mu)	1.619	0.646–4.059	0.304	1.431	0.442–4.634	0.550
BRAF (wild-type vs mutated)	0.546	0.061–4.897	0.589	0.727	0.058–9.165	0.805
1p/19q-codel (others vs codel)	0.252	0.079–0.802	0.020*	0.399	0.083–1.905	0.249
p53 (negative vs positive)	3.259	0.890–11.942	0.075	3.074	0.725–13.034	0.128
Ki-67 (negative vs positive)	8.069	1.022–63.698	0.048*	3.400	0.360–32.120	0.286
p53/Ki-67 (others vs both positive)	6.476	1.796–23.353	0.004**	5.173	1.271–21.058	0.022*

Notes: Significance analysis was two-tailed, and p<0.05 was considered statistically significant. * at p<0.05 level, ** at p<0.01 level.

Abbreviations: IDH, isocitrate dehydrogenase; TERTp, telomerase reverse transcriptase promoter; MGMTp, O6-methylguanine-DNA methyltransferase promoter; 1p/19q, chromosome arms 1p and 19q; BRAF, v-raf murine sarcoma oncogene homologue B1; Mu, mutation; Wt, wild-type; M, methylation; UM, unmethylation; Codel, codeletion; OR odds ratio; CI confidence interval.

Figure 2 Kaplan–Meier estimates of overall survival in the glioma molecular groups.

Notes: Survival of the molecular subgroups stratified according to MGMT promoter methylation (MGMTp-M), IDH mutation (IDH-mu), TERT promoter mutation (TERTp-mu), and 1p/19q codeletion (1p/19q-codel) in atotal of 103 gliomas (A), comprising 67 grade II–III gliomas (D) and 36 grade IV gliomas (G). 1, quadruple positive (MGMTp-M/IDH-mu/TERTp-mu/1p/19q-codel); 2, IDH-mu only; 3, MGMTp-M/IDH-mu; 4, MGMTp-M only; 5, others; 6, quadruple negative (MGMTp-UM/IDH-wt/TERTp-wt/1p/19q-wt); 7, MGMTp-M/TERTp-mu; 8, TERTp-mu only. Survival of the subgroups stratified according to Ki-67 and p53 overexpression in a total of 103 gliomas (B), comprising 67 grade II–III gliomas (E) and 36 grade IV gliomas (H). Survival of the subgroups stratified according to MGMTp-M, IDH-mu, TERTp-mu, and 1p/19q-codel in a total of 66 Ki-67+/p53+ gliomas (C), comprising 35 Ki-67+/p53+ grade II–III gliomas (F) and 31 Ki-67+/p53+ grade IV gliomas (I). Significance analysis was two-tailed, and p<0.05 was considered statistically significant.

Abbreviations: IDH, isocitrate dehydrogenase; TERTp, telomerase reverse transcriptase promoter; MGMTp, O6-methylguanine-DNA methyltransferase promoter; 1p/19q-codel, chromosome arms 1p and 19q codeletion; BRAF, v-raf murine sarcoma oncogene homologue B1; Mu, mutation; Wt, wild-type; M, methylation; UM, unmethylation.