Correlation between gene mutation status and selected clinical features

Overview

Introduction

This pipeline computes the correlation between significantly recurrent gene mutations and selected clinical features.

Summary

Testing the association between mutation status of 37 genes and 8 clinical features across 286 patients, 15 significant findings detected with Q value < 0.25.

IDH1 mutation correlated to 'Time to Death' and 'AGE'.
TP53 mutation correlated to 'AGE' and 'HISTOLOGICAL.TYPE'.
ATRX mutation correlated to 'AGE' and 'HISTOLOGICAL.TYPE'.
CIC mutation correlated to 'HISTOLOGICAL.TYPE'.
NOTCH1 mutation correlated to 'HISTOLOGICAL.TYPE'.
FUBP1 mutation correlated to 'HISTOLOGICAL.TYPE'.
NF1 mutation correlated to 'Time to Death'.
PTEN mutation correlated to 'Time to Death' and 'AGE'.
EGFR mutation correlated to 'Time to Death' and 'AGE'.
PLCG1 mutation correlated to 'Time to Death'.

Results

Overview of the results

Table 1. Get Full Table Overview of the association between mutation status of 37 genes and 8 clinical features. Shown in the table are P values (Q values). Thresholded by Q value < 0.25, 15 significant findings detected.


		Clinical Features	Time to Death	AGE	GENDER	KARNOFSKY PERFORMANCE SCORE	HISTOLOGICAL TYPE	RADIATIONS RADIATION REGIMENINDICATION	RACE	ETHNICITY
	nMutated (%)	nWild-Type	logrank test	Wilcoxon-test	Fisher's exact test	Wilcoxon-test	Fisher's exact test	Fisher's exact test	Fisher's exact test	Fisher's exact test
IDH1	218 (76%)	68	2.35e-10 (6.67e-08)	0.000853 (0.232)	0.209 (1.00)	0.0487 (1.00)	0.0249 (1.00)	0.763 (1.00)	0.176 (1.00)	0.328 (1.00)
TP53	145 (51%)	141	0.227 (1.00)	1.53e-06 (0.000429)	0.153 (1.00)	0.284 (1.00)	1e-05 (0.00279)	0.0276 (1.00)	0.468 (1.00)	1 (1.00)
ATRX	118 (41%)	168	0.0519 (1.00)	1.94e-07 (5.46e-05)	0.334 (1.00)	0.0949 (1.00)	1e-05 (0.00279)	0.0873 (1.00)	0.748 (1.00)	1 (1.00)
PTEN	13 (5%)	273	2.18e-10 (6.22e-08)	0.000651 (0.178)	0.573 (1.00)	0.115 (1.00)	0.00612 (1.00)	0.537 (1.00)	0.143 (1.00)	1 (1.00)
EGFR	16 (6%)	270	0 (0)	1.84e-07 (5.22e-05)	0.797 (1.00)	0.00205 (0.551)	0.334 (1.00)	0.162 (1.00)	0.541 (1.00)	1 (1.00)
CIC	53 (19%)	233	0.0461 (1.00)	0.298 (1.00)	0.358 (1.00)	0.437 (1.00)	1e-05 (0.00279)	0.135 (1.00)	0.756 (1.00)	1 (1.00)
NOTCH1	29 (10%)	257	0.673 (1.00)	0.0464 (1.00)	1 (1.00)	0.705 (1.00)	4e-05 (0.011)	0.293 (1.00)	0.66 (1.00)	1 (1.00)
FUBP1	26 (9%)	260	0.921 (1.00)	0.00344 (0.921)	1 (1.00)	0.601 (1.00)	1e-05 (0.00279)	1 (1.00)	1 (1.00)	0.617 (1.00)
NF1	19 (7%)	267	0.000627 (0.172)	0.178 (1.00)	0.815 (1.00)	0.368 (1.00)	0.0847 (1.00)	0.116 (1.00)	0.247 (1.00)	0.259 (1.00)
PLCG1	4 (1%)	282	1.93e-06 (0.00054)	0.0574 (1.00)	1 (1.00)	0.629 (1.00)	0.686 (1.00)	0.585 (1.00)	0.173 (1.00)	1 (1.00)
IDH2	12 (4%)	274	0.235 (1.00)	0.254 (1.00)	0.771 (1.00)	0.894 (1.00)	0.00895 (1.00)	0.754 (1.00)	0.436 (1.00)	0.106 (1.00)
PIK3R1	13 (5%)	273	0.532 (1.00)	0.121 (1.00)	0.155 (1.00)	0.526 (1.00)	0.248 (1.00)	0.216 (1.00)	0.437 (1.00)	1 (1.00)
STK19	8 (3%)	278	0.222 (1.00)	0.534 (1.00)	0.473 (1.00)	0.0434 (1.00)	0.0645 (1.00)	0.11 (1.00)	1 (1.00)	0.0589 (1.00)
PIK3CA	25 (9%)	261	0.0858 (1.00)	0.104 (1.00)	0.679 (1.00)	0.435 (1.00)	0.0429 (1.00)	0.649 (1.00)	1 (1.00)	1 (1.00)
ARID1A	12 (4%)	274	0.121 (1.00)	0.844 (1.00)	0.0142 (1.00)	0.0458 (1.00)	0.317 (1.00)	1 (1.00)	1 (1.00)	0.481 (1.00)
GAGE2B	4 (1%)	282	0.729 (1.00)	0.765 (1.00)	0.632 (1.00)		1 (1.00)	1 (1.00)	1 (1.00)	0.193 (1.00)
CREBZF	5 (2%)	281	0.768 (1.00)	0.231 (1.00)	0.175 (1.00)	0.189 (1.00)	0.223 (1.00)	1 (1.00)	0.212 (1.00)	1 (1.00)
TCF12	8 (3%)	278	0.332 (1.00)	0.0839 (1.00)	1 (1.00)	0.467 (1.00)	0.16 (1.00)	0.443 (1.00)	1 (1.00)	1 (1.00)
SMARCA4	13 (5%)	273	0.105 (1.00)	0.13 (1.00)	0.779 (1.00)	0.0349 (1.00)	0.482 (1.00)	0.0643 (1.00)	1 (1.00)	0.481 (1.00)
VAV3	8 (3%)	278	0.449 (1.00)	0.924 (1.00)	0.473 (1.00)	0.00142 (0.386)	0.742 (1.00)	0.698 (1.00)	1 (1.00)	0.352 (1.00)
TMEM216	3 (1%)	283	0.747 (1.00)	0.782 (1.00)	0.0864 (1.00)		0.489 (1.00)	0.557 (1.00)	1 (1.00)	1 (1.00)
ROBO3	4 (1%)	282	0.664 (1.00)	0.874 (1.00)	0.326 (1.00)	0.208 (1.00)	0.566 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)
IRS4	5 (2%)	281	0.698 (1.00)	0.998 (1.00)	1 (1.00)	0.208 (1.00)	0.379 (1.00)	1 (1.00)	1 (1.00)	0.236 (1.00)
HTRA2	4 (1%)	282	0.84 (1.00)	0.0763 (1.00)	0.632 (1.00)		0.566 (1.00)	0.322 (1.00)	1 (1.00)	0.193 (1.00)
EIF1AX	4 (1%)	282	0.377 (1.00)	0.971 (1.00)	0.132 (1.00)	0.894 (1.00)	0.187 (1.00)	0.585 (1.00)	1 (1.00)	1 (1.00)
FAM47C	7 (2%)	279	0.167 (1.00)	0.923 (1.00)	1 (1.00)	0.568 (1.00)	0.0717 (1.00)	1 (1.00)	1 (1.00)	0.315 (1.00)
DDX5	4 (1%)	282	0.567 (1.00)	0.872 (1.00)	0.632 (1.00)	0.309 (1.00)	0.681 (1.00)	1 (1.00)	1 (1.00)	0.149 (1.00)
ZNF709	3 (1%)	283	0.556 (1.00)	0.56 (1.00)	0.257 (1.00)		0.491 (1.00)	0.212 (1.00)	0.134 (1.00)	1 (1.00)
TRERF1	3 (1%)	283	0.731 (1.00)	0.702 (1.00)	0.0864 (1.00)		0.363 (1.00)	0.557 (1.00)	1 (1.00)	1 (1.00)
BCOR	9 (3%)	277	0.992 (1.00)	0.158 (1.00)	0.0828 (1.00)	0.28 (1.00)	0.477 (1.00)	0.728 (1.00)	0.351 (1.00)	1 (1.00)
SRPX	3 (1%)	283	0.485 (1.00)	0.105 (1.00)	0.0864 (1.00)		0.783 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)
DOCK5	5 (2%)	281	0.00788 (1.00)	0.0213 (1.00)	1 (1.00)	0.696 (1.00)	1 (1.00)	0.636 (1.00)	1 (1.00)	1 (1.00)
GIGYF2	4 (1%)	282	0.00162 (0.438)	0.715 (1.00)	1 (1.00)		0.827 (1.00)	0.0801 (1.00)	1 (1.00)	1 (1.00)
NIPBL	5 (2%)	281	0.0909 (1.00)	0.029 (1.00)	0.386 (1.00)		0.183 (1.00)	1 (1.00)	1 (1.00)	0.236 (1.00)
ZBTB20	13 (5%)	273	0.371 (1.00)	0.614 (1.00)	0.398 (1.00)	0.99 (1.00)	0.369 (1.00)	0.117 (1.00)	0.14 (1.00)	0.481 (1.00)
TRIP12	5 (2%)	281	0.217 (1.00)	0.66 (1.00)	1 (1.00)		0.153 (1.00)	0.158 (1.00)	1 (1.00)	1 (1.00)
KIAA0664	5 (2%)	281	0.981 (1.00)	0.943 (1.00)	1 (1.00)		0.223 (1.00)	0.158 (1.00)	1 (1.00)	1 (1.00)

'IDH1 MUTATION STATUS' versus 'Time to Death'

P value = 2.35e-10 (logrank test), Q value = 6.7e-08

Table S1. Gene #1: 'IDH1 MUTATION STATUS' versus Clinical Feature #1: 'Time to Death'

	nPatients	nDeath	Duration Range (Median), Month
ALL	284	59	0.0 - 182.3 (15.6)
IDH1 MUTATED	216	32	0.0 - 182.3 (17.1)
IDH1 WILD-TYPE	68	27	0.1 - 133.7 (11.6)

Figure S1. Get High-res Image Gene #1: 'IDH1 MUTATION STATUS' versus Clinical Feature #1: 'Time to Death'

'IDH1 MUTATION STATUS' versus 'AGE'

P value = 0.000853 (Wilcoxon-test), Q value = 0.23

Table S2. Gene #1: 'IDH1 MUTATION STATUS' versus Clinical Feature #2: 'AGE'

	nPatients	Mean (Std.Dev)
ALL	286	42.6 (13.5)
IDH1 MUTATED	218	40.9 (12.6)
IDH1 WILD-TYPE	68	47.8 (14.9)

Figure S2. Get High-res Image Gene #1: 'IDH1 MUTATION STATUS' versus Clinical Feature #2: 'AGE'

'TP53 MUTATION STATUS' versus 'AGE'

P value = 1.53e-06 (Wilcoxon-test), Q value = 0.00043

Table S3. Gene #2: 'TP53 MUTATION STATUS' versus Clinical Feature #2: 'AGE'

	nPatients	Mean (Std.Dev)
ALL	286	42.6 (13.5)
TP53 MUTATED	145	38.7 (11.7)
TP53 WILD-TYPE	141	46.6 (14.0)

Figure S3. Get High-res Image Gene #2: 'TP53 MUTATION STATUS' versus Clinical Feature #2: 'AGE'

'TP53 MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 1e-05 (Fisher's exact test), Q value = 0.0028

Table S4. Gene #2: 'TP53 MUTATION STATUS' versus Clinical Feature #5: 'HISTOLOGICAL.TYPE'

nPatients	ASTROCYTOMA	OLIGOASTROCYTOMA	OLIGODENDROGLIOMA
ALL	97	76	113
TP53 MUTATED	65	50	30
TP53 WILD-TYPE	32	26	83

Figure S4. Get High-res Image Gene #2: 'TP53 MUTATION STATUS' versus Clinical Feature #5: 'HISTOLOGICAL.TYPE'

'ATRX MUTATION STATUS' versus 'AGE'

P value = 1.94e-07 (Wilcoxon-test), Q value = 5.5e-05

Table S5. Gene #3: 'ATRX MUTATION STATUS' versus Clinical Feature #2: 'AGE'

	nPatients	Mean (Std.Dev)
ALL	286	42.6 (13.5)
ATRX MUTATED	118	37.6 (11.4)
ATRX WILD-TYPE	168	46.1 (13.7)

Figure S5. Get High-res Image Gene #3: 'ATRX MUTATION STATUS' versus Clinical Feature #2: 'AGE'

'ATRX MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 1e-05 (Fisher's exact test), Q value = 0.0028

Table S6. Gene #3: 'ATRX MUTATION STATUS' versus Clinical Feature #5: 'HISTOLOGICAL.TYPE'

nPatients	ASTROCYTOMA	OLIGOASTROCYTOMA	OLIGODENDROGLIOMA
ALL	97	76	113
ATRX MUTATED	49	43	26
ATRX WILD-TYPE	48	33	87

Figure S6. Get High-res Image Gene #3: 'ATRX MUTATION STATUS' versus Clinical Feature #5: 'HISTOLOGICAL.TYPE'

'CIC MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 1e-05 (Fisher's exact test), Q value = 0.0028

Table S7. Gene #4: 'CIC MUTATION STATUS' versus Clinical Feature #5: 'HISTOLOGICAL.TYPE'

nPatients	ASTROCYTOMA	OLIGOASTROCYTOMA	OLIGODENDROGLIOMA
ALL	97	76	113
CIC MUTATED	1	9	43
CIC WILD-TYPE	96	67	70

Figure S7. Get High-res Image Gene #4: 'CIC MUTATION STATUS' versus Clinical Feature #5: 'HISTOLOGICAL.TYPE'

'NOTCH1 MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 4e-05 (Fisher's exact test), Q value = 0.011

Table S8. Gene #5: 'NOTCH1 MUTATION STATUS' versus Clinical Feature #5: 'HISTOLOGICAL.TYPE'

nPatients	ASTROCYTOMA	OLIGOASTROCYTOMA	OLIGODENDROGLIOMA
ALL	97	76	113
NOTCH1 MUTATED	3	3	23
NOTCH1 WILD-TYPE	94	73	90

Figure S8. Get High-res Image Gene #5: 'NOTCH1 MUTATION STATUS' versus Clinical Feature #5: 'HISTOLOGICAL.TYPE'

'FUBP1 MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 1e-05 (Fisher's exact test), Q value = 0.0028

Table S9. Gene #7: 'FUBP1 MUTATION STATUS' versus Clinical Feature #5: 'HISTOLOGICAL.TYPE'

nPatients	ASTROCYTOMA	OLIGOASTROCYTOMA	OLIGODENDROGLIOMA
ALL	97	76	113
FUBP1 MUTATED	1	3	22
FUBP1 WILD-TYPE	96	73	91

Figure S9. Get High-res Image Gene #7: 'FUBP1 MUTATION STATUS' versus Clinical Feature #5: 'HISTOLOGICAL.TYPE'

'NF1 MUTATION STATUS' versus 'Time to Death'

P value = 0.000627 (logrank test), Q value = 0.17

Table S10. Gene #8: 'NF1 MUTATION STATUS' versus Clinical Feature #1: 'Time to Death'

	nPatients	nDeath	Duration Range (Median), Month
ALL	284	59	0.0 - 182.3 (15.6)
NF1 MUTATED	19	8	0.2 - 73.0 (18.0)
NF1 WILD-TYPE	265	51	0.0 - 182.3 (15.5)

Figure S10. Get High-res Image Gene #8: 'NF1 MUTATION STATUS' versus Clinical Feature #1: 'Time to Death'

'PTEN MUTATION STATUS' versus 'Time to Death'

P value = 2.18e-10 (logrank test), Q value = 6.2e-08

Table S11. Gene #11: 'PTEN MUTATION STATUS' versus Clinical Feature #1: 'Time to Death'

	nPatients	nDeath	Duration Range (Median), Month
ALL	284	59	0.0 - 182.3 (15.6)
PTEN MUTATED	13	7	0.5 - 21.0 (10.4)
PTEN WILD-TYPE	271	52	0.0 - 182.3 (16.1)

Figure S11. Get High-res Image Gene #11: 'PTEN MUTATION STATUS' versus Clinical Feature #1: 'Time to Death'

'PTEN MUTATION STATUS' versus 'AGE'

P value = 0.000651 (Wilcoxon-test), Q value = 0.18

Table S12. Gene #11: 'PTEN MUTATION STATUS' versus Clinical Feature #2: 'AGE'

	nPatients	Mean (Std.Dev)
ALL	286	42.6 (13.5)
PTEN MUTATED	13	55.3 (10.5)
PTEN WILD-TYPE	273	42.0 (13.3)

Figure S12. Get High-res Image Gene #11: 'PTEN MUTATION STATUS' versus Clinical Feature #2: 'AGE'

'EGFR MUTATION STATUS' versus 'Time to Death'

P value = 0 (logrank test), Q value = 0

Table S13. Gene #14: 'EGFR MUTATION STATUS' versus Clinical Feature #1: 'Time to Death'

	nPatients	nDeath	Duration Range (Median), Month
ALL	284	59	0.0 - 182.3 (15.6)
EGFR MUTATED	16	9	0.5 - 13.6 (6.6)
EGFR WILD-TYPE	268	50	0.0 - 182.3 (16.7)

Figure S13. Get High-res Image Gene #14: 'EGFR MUTATION STATUS' versus Clinical Feature #1: 'Time to Death'

'EGFR MUTATION STATUS' versus 'AGE'

P value = 1.84e-07 (Wilcoxon-test), Q value = 5.2e-05

Table S14. Gene #14: 'EGFR MUTATION STATUS' versus Clinical Feature #2: 'AGE'

	nPatients	Mean (Std.Dev)
ALL	286	42.6 (13.5)
EGFR MUTATED	16	61.1 (7.3)
EGFR WILD-TYPE	270	41.5 (12.9)

Figure S14. Get High-res Image Gene #14: 'EGFR MUTATION STATUS' versus Clinical Feature #2: 'AGE'

'PLCG1 MUTATION STATUS' versus 'Time to Death'

P value = 1.93e-06 (logrank test), Q value = 0.00054

Table S15. Gene #26: 'PLCG1 MUTATION STATUS' versus Clinical Feature #1: 'Time to Death'

	nPatients	nDeath	Duration Range (Median), Month
ALL	284	59	0.0 - 182.3 (15.6)
PLCG1 MUTATED	4	3	6.7 - 21.0 (7.2)
PLCG1 WILD-TYPE	280	56	0.0 - 182.3 (15.9)

Figure S15. Get High-res Image Gene #26: 'PLCG1 MUTATION STATUS' versus Clinical Feature #1: 'Time to Death'

Methods & Data

Input

Mutation data file = transformed.cor.cli.txt
Clinical data file = LGG-TP.merged_data.txt
Number of patients = 286
Number of significantly mutated genes = 37
Number of selected clinical features = 8
Exclude genes that fewer than K tumors have mutations, K = 3

Survival analysis

For survival clinical features, the Kaplan-Meier survival curves of tumors with and without gene mutations were plotted and the statistical significance P values were estimated by logrank test (Bland and Altman 2004) using the 'survdiff' function in R

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] Bland and Altman, Statistics notes: The logrank test, BMJ 328(7447):1073 (2004)

[2] 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)

[3] 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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