Correlation between gene mutation status and molecular subtypes

Overview

Introduction

This pipeline computes the correlation between significantly recurrent gene mutations and molecular subtypes.

Summary

Testing the association between mutation status of 13 genes and 10 molecular subtypes across 284 patients, 17 significant findings detected with P value < 0.05 and Q value < 0.25.

EGFR mutation correlated to 'CN_CNMF', 'RPPA_CNMF', and 'RPPA_CHIERARCHICAL'.
IDH1 mutation correlated to 'MRNA_CNMF', 'MRNA_CHIERARCHICAL', 'MIR_CNMF', 'MIR_CHIERARCHICAL', 'CN_CNMF', 'METHLYATION_CNMF', and 'MRNASEQ_CNMF'.
TP53 mutation correlated to 'MRNA_CNMF', 'MRNA_CHIERARCHICAL', 'MIR_CNMF', 'CN_CNMF', and 'MRNASEQ_CNMF'.
NF1 mutation correlated to 'CN_CNMF' and 'METHLYATION_CNMF'.

Results

Overview of the results

Table 1. Get Full Table Overview of the association between mutation status of 13 genes and 10 molecular subtypes. Shown in the table are P values (Q values). Thresholded by P value < 0.05 and Q value < 0.25, 17 significant findings detected.


		Clinical Features	MRNA CNMF	MRNA CHIERARCHICAL	MIR CNMF	MIR CHIERARCHICAL	CN CNMF	METHLYATION CNMF	RPPA CNMF	RPPA CHIERARCHICAL	MRNASEQ CNMF	MRNASEQ CHIERARCHICAL
	nMutated (%)	nWild-Type	Fisher's exact test	Fisher's exact test	Fisher's exact test	Fisher's exact test	Fisher's exact test	Fisher's exact test	Fisher's exact test	Fisher's exact test	Fisher's exact test	Fisher's exact test
IDH1	14 (5%)	270	0.000142 (0.0164)	2.25e-07 (2.75e-05)	0.000227 (0.0259)	1.24e-05 (0.00148)	1.68e-05 (0.00198)	0.00151 (0.166)	0.00352 (0.363)	0.0203 (1.00)	0.000712 (0.0798)	0.00263 (0.275)
TP53	79 (28%)	205	0.000816 (0.0906)	0.00163 (0.176)	0.000313 (0.0354)	0.0272 (1.00)	0.000166 (0.0191)	0.00837 (0.828)	0.0384 (1.00)	0.00968 (0.948)	0.00184 (0.196)	0.0375 (1.00)
EGFR	74 (26%)	210	0.00653 (0.66)	0.00262 (0.275)	0.242 (1.00)	0.217 (1.00)	7.49e-07 (9.06e-05)	0.00564 (0.576)	6.37e-05 (0.00746)	1.46e-06 (0.000176)	0.0413 (1.00)	0.357 (1.00)
NF1	29 (10%)	255	0.0649 (1.00)	0.0428 (1.00)	0.0897 (1.00)	0.501 (1.00)	0.00154 (0.168)	0.00167 (0.179)	0.23 (1.00)	0.12 (1.00)	0.566 (1.00)	0.915 (1.00)
PIK3R1	32 (11%)	252	0.42 (1.00)	0.691 (1.00)	0.467 (1.00)	0.205 (1.00)	0.115 (1.00)	0.407 (1.00)	0.988 (1.00)	0.273 (1.00)	0.406 (1.00)	0.649 (1.00)
BRAF	6 (2%)	278	0.704 (1.00)	0.465 (1.00)	0.616 (1.00)	0.175 (1.00)	0.586 (1.00)		1 (1.00)	0.0781 (1.00)	0.791 (1.00)	1 (1.00)
PTEN	87 (31%)	197	0.0424 (1.00)	0.736 (1.00)	0.0452 (1.00)	0.594 (1.00)	0.584 (1.00)	0.917 (1.00)	0.378 (1.00)	0.389 (1.00)	0.27 (1.00)	0.196 (1.00)
PIK3CA	30 (11%)	254	0.652 (1.00)	0.201 (1.00)	0.571 (1.00)	0.785 (1.00)	0.501 (1.00)	0.916 (1.00)	0.754 (1.00)	0.281 (1.00)	0.262 (1.00)	0.838 (1.00)
RB1	24 (8%)	260	0.0289 (1.00)	0.347 (1.00)	0.0653 (1.00)	0.357 (1.00)	0.0873 (1.00)	0.0709 (1.00)	0.493 (1.00)	0.691 (1.00)	0.0818 (1.00)	0.0754 (1.00)
PRB2	6 (2%)	278	0.718 (1.00)	0.382 (1.00)	0.441 (1.00)	0.634 (1.00)	0.772 (1.00)
CDC27	6 (2%)	278	0.121 (1.00)	0.382 (1.00)	0.261 (1.00)	0.29 (1.00)	0.449 (1.00)	0.227 (1.00)	0.278 (1.00)	0.325 (1.00)
STAG2	12 (4%)	272	0.801 (1.00)	0.301 (1.00)	0.21 (1.00)	0.132 (1.00)	0.756 (1.00)	0.752 (1.00)	0.00694 (0.694)	0.184 (1.00)	0.479 (1.00)	0.771 (1.00)
TPTE2	8 (3%)	276	0.427 (1.00)	0.665 (1.00)	0.318 (1.00)	0.289 (1.00)	0.271 (1.00)	0.438 (1.00)	0.624 (1.00)	0.409 (1.00)	0.376 (1.00)	0.741 (1.00)

'EGFR MUTATION STATUS' versus 'CN_CNMF'

P value = 7.49e-07 (Fisher's exact test), Q value = 9.1e-05

Table S1. Gene #1: 'EGFR MUTATION STATUS' versus Clinical Feature #5: 'CN_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	87	108	79
EGFR MUTATED	16	47	9
EGFR WILD-TYPE	71	61	70

Figure S1. Get High-res Image Gene #1: 'EGFR MUTATION STATUS' versus Clinical Feature #5: 'CN_CNMF'

'EGFR MUTATION STATUS' versus 'RPPA_CNMF'

P value = 6.37e-05 (Fisher's exact test), Q value = 0.0075

Table S2. Gene #1: 'EGFR MUTATION STATUS' versus Clinical Feature #7: 'RPPA_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	41	38	31	33
EGFR MUTATED	13	5	16	2
EGFR WILD-TYPE	28	33	15	31

Figure S2. Get High-res Image Gene #1: 'EGFR MUTATION STATUS' versus Clinical Feature #7: 'RPPA_CNMF'

'EGFR MUTATION STATUS' versus 'RPPA_CHIERARCHICAL'

P value = 1.46e-06 (Fisher's exact test), Q value = 0.00018

Table S3. Gene #1: 'EGFR MUTATION STATUS' versus Clinical Feature #8: 'RPPA_CHIERARCHICAL'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	47	28	68
EGFR MUTATED	24	6	6
EGFR WILD-TYPE	23	22	62

Figure S3. Get High-res Image Gene #1: 'EGFR MUTATION STATUS' versus Clinical Feature #8: 'RPPA_CHIERARCHICAL'

'IDH1 MUTATION STATUS' versus 'MRNA_CNMF'

P value = 0.000142 (Fisher's exact test), Q value = 0.016

Table S4. Gene #4: 'IDH1 MUTATION STATUS' versus Clinical Feature #1: 'MRNA_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	69	41	74	57
IDH1 MUTATED	1	3	0	9
IDH1 WILD-TYPE	68	38	74	48

Figure S4. Get High-res Image Gene #4: 'IDH1 MUTATION STATUS' versus Clinical Feature #1: 'MRNA_CNMF'

'IDH1 MUTATION STATUS' versus 'MRNA_CHIERARCHICAL'

P value = 2.25e-07 (Fisher's exact test), Q value = 2.8e-05

Table S5. Gene #4: 'IDH1 MUTATION STATUS' versus Clinical Feature #2: 'MRNA_CHIERARCHICAL'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	66	78	97
IDH1 MUTATED	0	13	0
IDH1 WILD-TYPE	66	65	97

Figure S5. Get High-res Image Gene #4: 'IDH1 MUTATION STATUS' versus Clinical Feature #2: 'MRNA_CHIERARCHICAL'

'IDH1 MUTATION STATUS' versus 'MIR_CNMF'

P value = 0.000227 (Fisher's exact test), Q value = 0.026

Table S6. Gene #4: 'IDH1 MUTATION STATUS' versus Clinical Feature #3: 'MIR_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	57	72	30	44
IDH1 MUTATED	0	10	0	0
IDH1 WILD-TYPE	57	62	30	44

Figure S6. Get High-res Image Gene #4: 'IDH1 MUTATION STATUS' versus Clinical Feature #3: 'MIR_CNMF'

'IDH1 MUTATION STATUS' versus 'MIR_CHIERARCHICAL'

P value = 1.24e-05 (Fisher's exact test), Q value = 0.0015

Table S7. Gene #4: 'IDH1 MUTATION STATUS' versus Clinical Feature #4: 'MIR_CHIERARCHICAL'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	73	81	49
IDH1 MUTATED	0	1	9
IDH1 WILD-TYPE	73	80	40

Figure S7. Get High-res Image Gene #4: 'IDH1 MUTATION STATUS' versus Clinical Feature #4: 'MIR_CHIERARCHICAL'

'IDH1 MUTATION STATUS' versus 'CN_CNMF'

P value = 1.68e-05 (Fisher's exact test), Q value = 0.002

Table S8. Gene #4: 'IDH1 MUTATION STATUS' versus Clinical Feature #5: 'CN_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	87	108	79
IDH1 MUTATED	2	0	11
IDH1 WILD-TYPE	85	108	68

Figure S8. Get High-res Image Gene #4: 'IDH1 MUTATION STATUS' versus Clinical Feature #5: 'CN_CNMF'

'IDH1 MUTATION STATUS' versus 'METHLYATION_CNMF'

P value = 0.00151 (Fisher's exact test), Q value = 0.17

Table S9. Gene #4: 'IDH1 MUTATION STATUS' versus Clinical Feature #6: 'METHLYATION_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	38	28	16	26
IDH1 MUTATED	0	0	0	5
IDH1 WILD-TYPE	38	28	16	21

Figure S9. Get High-res Image Gene #4: 'IDH1 MUTATION STATUS' versus Clinical Feature #6: 'METHLYATION_CNMF'

'IDH1 MUTATION STATUS' versus 'MRNASEQ_CNMF'

P value = 0.000712 (Fisher's exact test), Q value = 0.08

Table S10. Gene #4: 'IDH1 MUTATION STATUS' versus Clinical Feature #9: 'MRNASEQ_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	44	62	35
IDH1 MUTATED	7	0	1
IDH1 WILD-TYPE	37	62	34

Figure S10. Get High-res Image Gene #4: 'IDH1 MUTATION STATUS' versus Clinical Feature #9: 'MRNASEQ_CNMF'

'TP53 MUTATION STATUS' versus 'MRNA_CNMF'

P value = 0.000816 (Fisher's exact test), Q value = 0.091

Table S11. Gene #5: 'TP53 MUTATION STATUS' versus Clinical Feature #1: 'MRNA_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	69	41	74	57
TP53 MUTATED	16	18	11	23
TP53 WILD-TYPE	53	23	63	34

Figure S11. Get High-res Image Gene #5: 'TP53 MUTATION STATUS' versus Clinical Feature #1: 'MRNA_CNMF'

'TP53 MUTATION STATUS' versus 'MRNA_CHIERARCHICAL'

P value = 0.00163 (Fisher's exact test), Q value = 0.18

Table S12. Gene #5: 'TP53 MUTATION STATUS' versus Clinical Feature #2: 'MRNA_CHIERARCHICAL'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	66	78	97
TP53 MUTATED	13	34	21
TP53 WILD-TYPE	53	44	76

Figure S12. Get High-res Image Gene #5: 'TP53 MUTATION STATUS' versus Clinical Feature #2: 'MRNA_CHIERARCHICAL'

'TP53 MUTATION STATUS' versus 'MIR_CNMF'

P value = 0.000313 (Fisher's exact test), Q value = 0.035

Table S13. Gene #5: 'TP53 MUTATION STATUS' versus Clinical Feature #3: 'MIR_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	57	72	30	44
TP53 MUTATED	7	33	7	15
TP53 WILD-TYPE	50	39	23	29

Figure S13. Get High-res Image Gene #5: 'TP53 MUTATION STATUS' versus Clinical Feature #3: 'MIR_CNMF'

'TP53 MUTATION STATUS' versus 'CN_CNMF'

P value = 0.000166 (Fisher's exact test), Q value = 0.019

Table S14. Gene #5: 'TP53 MUTATION STATUS' versus Clinical Feature #5: 'CN_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	87	108	79
TP53 MUTATED	34	16	28
TP53 WILD-TYPE	53	92	51

Figure S14. Get High-res Image Gene #5: 'TP53 MUTATION STATUS' versus Clinical Feature #5: 'CN_CNMF'

'TP53 MUTATION STATUS' versus 'MRNASEQ_CNMF'

P value = 0.00184 (Fisher's exact test), Q value = 0.2

Table S15. Gene #5: 'TP53 MUTATION STATUS' versus Clinical Feature #9: 'MRNASEQ_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	44	62	35
TP53 MUTATED	23	13	8
TP53 WILD-TYPE	21	49	27

Figure S15. Get High-res Image Gene #5: 'TP53 MUTATION STATUS' versus Clinical Feature #9: 'MRNASEQ_CNMF'

'NF1 MUTATION STATUS' versus 'CN_CNMF'

P value = 0.00154 (Fisher's exact test), Q value = 0.17

Table S16. Gene #10: 'NF1 MUTATION STATUS' versus Clinical Feature #5: 'CN_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	87	108	79
NF1 MUTATED	4	8	17
NF1 WILD-TYPE	83	100	62

Figure S16. Get High-res Image Gene #10: 'NF1 MUTATION STATUS' versus Clinical Feature #5: 'CN_CNMF'

'NF1 MUTATION STATUS' versus 'METHLYATION_CNMF'

P value = 0.00167 (Fisher's exact test), Q value = 0.18

Table S17. Gene #10: 'NF1 MUTATION STATUS' versus Clinical Feature #6: 'METHLYATION_CNMF'

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	38	28	16	26
NF1 MUTATED	11	1	0	1
NF1 WILD-TYPE	27	27	16	25

Figure S17. Get High-res Image Gene #10: 'NF1 MUTATION STATUS' versus Clinical Feature #6: 'METHLYATION_CNMF'

Methods & Data

Input

Mutation data file = GBM-TP.mutsig.cluster.txt
Molecular subtypes file = GBM-TP.transferedmergedcluster.txt
Number of patients = 284
Number of significantly mutated genes = 13
Number of Molecular subtypes = 10
Exclude genes that fewer than K tumors have mutations, K = 3

Fisher's exact test

For binary or multi-class clinical features (nominal or ordinal), two-tailed Fisher's exact tests (Fisher 1922) were used to estimate the P values using the 'fisher.test' function in R

Q value calculation

For multiple hypothesis correction, Q value is the False Discovery Rate (FDR) analogue of the P value (Benjamini and Hochberg 1995), defined as the minimum FDR at which the test may be called significant. We used the 'Benjamini and Hochberg' method of 'p.adjust' function in R to convert P values into Q values.

References

[1] Fisher, R.A., On the interpretation of chi-square from contingency tables, and the calculation of P, Journal of the Royal Statistical Society 85(1):87-94 (1922)

[2] Benjamini and Hochberg, Controlling the false discovery rate: a practical and powerful approach to multiple testing, Journal of the Royal Statistical Society Series B 59:289-300 (1995)

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