Correlation between molecular features and genetic subtypes of Glioblastoma: critical analysis in 109 cases

Galatro, Thais F; Sola, Paula; Moretti, Isabele F; Miura, Flavio K; Oba-Shinjo, Sueli M; Marie, Suely KN; Lerario, Antonio M

doi:10.5935/MedicalExpress.2017.05.05

Brasil

Español English

ORIGINAL RESEARCH • MedicalExpress (São Paulo, online) 4 (5) • Sep-Oct 2017 • https://doi.org/10.5935/MedicalExpress.2017.05.05 copy

Correlation between molecular features and genetic subtypes of Glioblastoma: critical analysis in 109 cases

Correlação entre as características moleculares e os subtipos genéticos dos glioblastomas: análise crítica de 109 casos

Authorship SCIMAGO INSTITUTIONS RANKINGS

OBJECTIVE:

Glioblastoma, the most common and lethal brain tumor, is also one of the most defying forms of malignancies in terms of treatment. Integrated genomic analysis has searched deeper into the molecular architecture of GBM, revealing a new sub-classification and promising precision in the care for patients with specific alterations.

METHOD:

Here, we present the classification of a Brazilian glioblastoma cohort into its main molecular subtypes. Using a high-throughput DNA sequencing procedure, we have classified this cohort into proneural, classical and mesenchymal sub-types. Next, we tested the possible use of the overexpression of the EGFR and CHI3L1 genes, detected through immunohistochemistry, for the identification of the classical and mesenchymal subtypes, respectively.

RESULTS:

Our results demonstrate that genetic identification of the glioblastoma subtypes is not possible using single targeted mutations alone, particularly in the case of the Mesenchymal subtype. We also show that it is not possible to single out the mesenchymal cases through CHI3L1 expression.

CONCLUSION:

Our data indicate that the Mesenchymal subtype, the most malignant of the glioblastomas, needs further and more thorough research to be ensure adequate identification.

KEYWORDS:
glioblastoma; classification; DNA sequence analysis; CHI3L1; EGFR

Diagnosis	Case	Sample ID	2016 WHO grading^ɸ ɸ Classificaion according to the 2016 WHO grading, based on IDH1 mutational status. Wt, wild-type; mut, mutated; ND, non-determined. last update - dec/2014	Gender^† † M, male. F, female,	Age^‡ ‡ Age at diagnosis, years,	Date of birth	Date of surgery	Overall Survival^§ § m, months,	CHI3L1	EGFR
GBM	1	35	GBM IDH wt	M	53	25/11/47	24/11/00	45m
GBM	2	74	GBM IDH wt	M	74	25/10/26	19/3/01	17m	2	4
GBM	3	175	GBM IDH wt	F	56	7/4/45	26/10/01	5m
GBM	4	194	GBM IDH wt	M	71	29/05/30	30/11/01	22m	1	4
GBM	5	204	GBM IDH wt	F	70	1/1/30	21/12/01	7m
GBM	6	208	GBM IDH wt	M	62	9/8/39	4/1/02	6m	3	2
GBM	7	256	GBM IDH wt	M	41	25/11/60	21/03/02	2m
GBM	8	269	GBM IDH wt	F	65	28/02/37	12/4/02	0	3	2
GBM	9	274	GBM IDH wt	F	47	20/12/54	19/04/02	17m
GBM	10	297	GBM IDH wt	F	78	14/06/23	23/05/02	11m	0	4
GBM	11	317	GBM IDH wt	F	71	22/12/30	24/06/02	2m
GBM	12	356	GBM IDH wt	M	74	17/06/28	30/08/02	11m	1	0
GBM	13	370	GBM IDH wt	M	45	12/7/57	27/09/02	13m
GBM	14	384	GBM IDH wt	M	45	27/04/57	25/10/02	14m
GBM	15	391	GBM IDH wt	F	54	16/03/48	7/11/02	12m
GBM	16	397	GBM IDH mut	F	58	8/12/43	20/11/02	5m	2	1
GBM	17	405	GBM IDH wt	M	74	12/7/57	10/12/02
GBM	18	427	GBM IDH wt	F	51	11/11/51	23/01/03	5m
GBM	19	450	GBM IDH wt	F	61	26/08/41	6/3/03	14m
GBM	20	458	GBM IDH wt	M	62	23/04/42	16/03/03	3m	3	1
GBM	21	485	GBM IDH wt	M	67	18/02/36	1/5/03	6m	3	0
GBM	22	496	GBM IDH wt	F	57	30/10/45	22/05/03	8m	3	4
GBM	23	498	GBM IDH wt	F	17	6/2/86	23/05/03	4m	1	3
GBM	24	503	GBM IDH wt	M	63	17/07/39	2/6/03	2m
GBM	25	510	GBM IDH wt	M	56	11/10/46	10/6/03	23m
GBM	26	522	GBM IDH mut	M	48	20/05/55	27/06/03	24m	3	0
GBM	27	524	GBM IDH wt	F	59	5/11/43	30/06/03	8m	2	4
GBM	28	547	GBM IDH mut	M	71	15/08/31	31/07/03	13m	2	1
GBM	29	555	GBM IDH wt	M	57	20/07/46	14/08/03	18m
GBM	30	592	GBM IDH wt	F	40	1/10/62	24/09/03		2	0
GBM	31	629	GBM IDH wt	M	64	25/06/38	11/11/03	14m	3	1
GBM	32	632	GBM IDH mut	F	41	15/08/62	13/11/03	28m	3	0
GBM	33	638	GBM IDH wt	M	55	15/08/62	13/11/03	2m
GBM	34	640	GBM IDH wt	F	58	12/12/44	21/11/03	5m
GBM	35	642	GBM IDH wt	M	42	14/04/62	21/11/03	17m	2	3
GBM	36	663	GBM IDH wt	M	66	11/12/37	5/12/03	7m
GBM	37	684	GBM IDH wt	F	56	15/12/47	12/2/04	1m
GBM	38	687	GBM IDH wt	M	45	7/3/58	16/02/04	9m
GBM	39	698	GBM IDH wt	M	58	25/09/45	27/02/04	7m	2	2
GBM	40	724	GBM IDH wt	F	62	1/2/42	8/4/04		2	3
GBM	41	743	GBM IDH wt	M	52	9/6/52	6/5/04	2m	1	3
GBM	42	750	GBM IDH wt	M	51	23/09/52	13/05/04	6m
GBM	43	792	GBM IDH wt	M	35	21/12/69	16/07/04	5m	2	0
GBM	44	795	GBM IDH wt	M	28	15/06/76	22/08/04	11m	3	4
GBM	45	852	GBM IDH wt	M	60	19/08/44	22/10/04	13m	2	0
GBM	46	854	GBM IDH wt	M	46	17/06/58	27/10/04		1	4
GBM	47	875	GBM IDH wt	M	35	21/12/69	23/11/04		1	0
GBM	48	879	GBM IDH wt	M	61	27/07/43	2/12/04	3m	3	1
GBM	49	881	GBM IDH wt	M	49	25/01/55	7/12/04	4m	1	4
GBM	50	884	GBM IDH wt	F	52	15/01/52	10/12/04	27m	0	4
GBM	51	885	GBM IDH wt	F	86	24/04/18	10/12/04	2m
GBM	52	891	GBM IDH wt	M	57	25/10/47	21/12/04	7m
GBM	53	901	GBM IDH mut	M	16	7/11/88	5/1/05	2m	0	1
GBM	54	903	GBM IDH wt	M	55	8/2/45	11/1/05	22m	3	1
GBM	55	925	GBM IDH wt	M	40	8/9/64	25/02/05	12m
GBM	56	930	GBM IDH mut	M	26	1/10/78	3/3/05	31m
GBM	57	1002	GBM IDH wt	M	40	29/01/65	15/07/05	2m	3	2
GBM	58	1003	GBM IDH wt	F	68	25/03/37	17/07/05	4m	2	3
GBM	59	1007	GBM IDH mut	F	28	18/06/77	22/07/05	3m	1	1
GBM	60	1009	GBM IDH wt	F	38	25/10/66	25/07/05	21m	1	1
GBM	61	1070	GBM IDH wt	M	72	9/3/33	29/11/05	8m
GBM	62	1074	GBM IDH wt	M	32	25/07/73	3/12/05		3	0
GBM	63	1084	GBM IDH wt	M	54	18/04/51	13/01/06	5m	2	1
GBM	64	1091	GBM IDH wt	M	55	5/9/49	3/2/06	21m
GBM	65	1103	GBM IDH wt	M	54	18/04/1951	3/3/06		3	2
GBM	66	1118	GBM IDH wt	F	61	10/7/59	18/04/06	2m
GBM	67	1122	GBM IDH wt	M	68	26/07/37	1/5/06	5m
GBM	68	1123	GBM IDH wt	M	53	29/10/53	2/5/06	11m
GBM	69	1124	GBM IDH wt	M	63	19/03/43	5/5/06	4m	1	4
GBM	70	1133	GBM IDH wt	M	52	28/12/53	26/05/06	9m
GBM	71	1144	GBM IDH wt	M	76	15/08/29	25/06/06	2m
GBM	72	1161	GBM IDH wt	M	39	13/01/67	26/07/06	13m
GBM	73	1162	GBM IDH wt	F	68	20/05/38	31/07/06	15m
GBM	74	1169	GBM IDH wt	F	56	13/03/50	9/8/06	2m
GBM	75	1190	GBM IDH wt	F	58	16/09/48	24/10/06	9m
GBM	76	1194	GBM IDH mut	M	26	1/10/78	3/11/06
GBM	77	1199	GBM IDH mut	M	30	6/11/75	24/11/06	11m
GBM	78	1205	GBM IDH wt	M	69	13/12/36	5/12/06		3	3
GBM	79	1212	GBM IDH mut	M	31	6/11/75	5/1/07
GBM	80	1232	GBM IDH wt	M	58	7/4/48	16/02/07	12m
GBM	81	1237	GBM IDH wt	M	59	18/05/47	27/02/07	7m
GBM	82	1243	GBM IDH wt	M	47	22/09/59	13/03/07	10m
GBM	83	1250	GBM IDH wt	M	63	11/1/44	30/03/07	7m
GBM	84	1252	ND	M	45	12/2/61	4/9/07	11m
GBM	85	1272	GBM IDH wt	M	70	5/5/37	18/05/07	6m
GBM	86	1274	GBM IDH wt	M	58	29/05/1948	25/05/07	13m
GBM	87	1282	GBM IDH wt	M	56	29/01/1951	6/7/07	9m
GBM	88	1295	GBM IDH wt	F	60		3/8/07	7m
GBM	89	1299	GBM IDH wt	M	77	29/10/1930	17/08/07	4m
GBM	90	1303	GBM IDH wt	M	49	31/08/1957	7/9/07	5m
GBM	91	1310	GBM IDH wt	M	48	14/11/1958	5/10/07	16m
GBM	92	1315	GBM IDH wt	M	68	31/07/1939	19/10/07	11m
GBM	93	1318	GBM IDH wt	M	58	12/11/49	26/10/07	21m
GBM	94	1319	GBM IDH wt	F	76	25/03/1931	27/10/07	3m
GBM	95	1331	GBM IDH wt	M	66	29/08/1941	21/05/08	0
GBM	96	1332	ND	M	46	1/14/62	5/28/08	7m
GBM	97	1335	GBM IDH mut	F	53	6/2/55	6/20/08	23m
GBM	98	1368	GBM IDH mut	F	29	1/21/86	3/14/09
GBM	99	1380	GBM IDH wt	M	58	18/12/1950	29/04/09	29m
GBM	100	1386	GBM IDH wt	F	66	20/01/1943	20/05/09	2m
GBM	101	1398	GBM IDH wt	M	78	6/7/30	17/06/09	7m
GBM	102	1416	GBM IDH wt	M	32	8/11/77	6/8/09	7m
GBM	103	1417	GBM IDH wt	M	36	29/10/71	7/8/09	4m
GBM	104	1503	GBM IDH wt	F	49	16/12/66	18/02/14
GBM	105	1507	GBM IDH wt	M	45	2/11/70	23/04/14
GBM	106	1509	GBM IDH wt	M	71	28/10/42	9/6/14
GBM	107	1518	GBM IDH wt	M	55	30/01/1959	22/10/14
GBM	108	1520	GBM IDH wt	F	79	29/10/1935	2/12/14
GBM	109	1522	GBM IDH wt	F	53	3/5/61	5/12/14

Diagnosis	Case#	GBM subtype	EGFR amplification	EGFR mutation	EGFRvIII	NF1 mutation	RB1 mutation or loss	PDGFRA mutation	IDH1 mutation	TP53 mutation	PTEN mutation
GBM	35	MESENCHYMAL					loss
GBM	74	CLASSICAL	+
GBM	175	MESENCHYMAL				c.1630.T
GBM	194	CLASSICAL	+		+
GBM	204	OTHERS
GBM	208	OTHERS
GBM	256	CLASSICAL	+		+
GBM	269	CLASSICAL	+		+					c.375G>T
GBM	274	CLASSICAL	+								c.260_322dup
GBM	297	CLASSICAL	+		+						c.388C>T
GBM	317	OTHERS
GBM	356	CLASSICAL	+
GBM	370	OTHERS
GBM	384	OTHERS
GBM	391	MESENCHYMAL				c.1882delT
GBM	397	PRONEURAL							c.395G>A
GBM	405	OTHERS
GBM	427	CLASSICAL			+
GBM	450	CLASSICAL			+
GBM	458	CLASSICAL			+
GBM	485	CLASSICAL		c.1874C>T
GBM	496	CLASSICAL			+
GBM	498	CLASSICAL			+
GBM	503	PRONEURAL								c.764_766delTCA	c.51_53delAGA
GBM	510	OTHERS
GBM	522	PRONEURAL							c.395G>A	c.298C>T/ c.742C>T
GBM	524	CLASSICAL	+								c.287C>T
GBM	547	PRONEURAL			+				c.395G>A
GBM	555	OTHERS
GBM	592	PRONEURAL						c.863A>G
GBM	629	CLASSICAL			+
GBM	632	PRONEURAL							c.395G>A
GBM	638	CLASSICAL			+
GBM	640	OTHERS
GBM*	642	CLASSICAL									c.210 +1G>A
GBM	663	OTHERS
GBM*	684	CLASSICAL
GBM	687	CLASSICAL			+
GBM	698	MESENCHYMAL				IVS45- -1G>C (splice site)					c.271G>T
GBM	724	CLASSICAL	+
GBM	743	CLASSICAL	+								c.335T>C
GBM	750	CLASSICAL	+		+						c.407G>A
GBM	792	MESENCHYMAL				c.6514_6515delGA				c.742C>T/ c.473G>A
GBM	795	CLASSICAL	+
GBM	852	PRONEURAL						c.1087A>T
GBM	854	CLASSICAL	+		+
GBM	875	MESENCHYMAL				c.1882delT				c.210_211insA
GBM	879	MESENCHYMAL					loss
GBM	881	CLASSICAL	+		+						c.388C>T
GBM	884	CLASSICAL	+
GBM	885	OTHERS
GBM	891	OTHERS								c.524G>A
GBM	901	PRONEURAL			+				c.395G>A
GBM	903	MESENCHYMAL					c.12_13del/c.45_53del
GBM	925	CLASSICAL			+
GBM	930	PRONEURAL			+				c.395G>A
GBM	1002	OTHERS
GBM	1003	CLASSICAL	+		+
GBM	1007	PRONEURAL							c.395G>A	c.206delG
GBM	1009	PRONEURAL								c.733G>A
GBM	1070	MESENCHYMAL					loss
GBM	1074	MESENCHYMAL				c.60+1G>T	c.2211+1G>T			c.184G>T	c.407G>A
GBM	1084	MESENCHYMAL				c.6852_6855del				c.210_211insA
GBM	1091	CLASSICAL									c.158_160delTAG
GBM	1103	MESENCHYMAL			+	c.6852_6855del					c.465T>G
GBM	1118	CLASSICAL									c.355G>T
GBM	1122	MESENCHYMAL				c.499_502del
GBM	1123	CLASSICAL	+		+
GBM	1124	CLASSICAL
GBM	1133	CLASSICAL	+		+
GBM	1144	CLASSICAL			+
GBM	1161	CLASSICAL	+		+
GBM	1162	CLASSICAL			+
GBM	1169	MESENCHYMAL					loss				c.355_356insGG
GBM	1190	MESENCHYMAL				c.7190-11_7190-8del (splice)
GBM	1194	PRONEURAL							c.395G>A
GBM	1199	PRONEURAL							c.395G>A	c.658T>C
GBM	1205	OTHERS
GBM	1212	PRONEURAL	+						c.395G>A	c.658T>C
GBM	1232	OTHERS
GBM	1237	OTHERS
GBM	1243	CLASSICAL			+					c.1043T>C
GBM	1250	CLASSICAL	+
GBM	1252	OTHERS
GBM	1272	CLASSICAL	+
GBM	1274	CLASSICAL	+
GBM	1282	MESENCHYMAL	+			c.3739_3742del
GBM	1295	MESENCHYMAL		c.323G>A			loss			c.210_211insA
GBM	1299	CLASSICAL	+
GBM	1303	OTHERS
GBM	1310	CLASSICAL	+	c.1859G>A							c.464A>G
GBM	1315	PRONEURAL						c.368- -3C>T (splice)		c.97-6C>T (splice)
GBM	1318	CLASSICAL		c.2240_ 2254del
GBM	1319	OTHERS
GBM	1331	CLASSICAL	+	c.685A>T							c.641dupA
GBM	1332	OTHERS
GBM	1335	PRONEURAL							c.395G>A
GBM	1368	PRONEURAL							c.395G>A
GBM	1380	MESENCHYMAL					c.1475delA				c.822G>A
GBM	1386	CLASSICAL		c.760T>A							c.517C>T
GBM	1398	CLASSICAL	+
GBM	1416	CLASSICAL	+
GBM	1417	MESENCHYMAL				c.4742_4749del
GBM	1503	PRONEURAL								loss
GBM	1507	MESENCHYMAL	+			c.1546C>T				c.451C>T
GBM	1509	CLASSICAL									c.115G>A
GBM	1518	CLASSICAL	+
GBM	1520	CLASSICAL		c.1280G>T
GBM	1522	MESENCHYMAL				c.1924C>T					c.765dupA

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