Correlation between copy number variation genes and selected clinical features

Overview

Introduction

This pipeline computes the correlation between significant copy number variation (cnv) genes and selected clinical features.

Summary

Testing the association between copy number variation of 36 peak regions and 6 clinical features across 178 patients, 13 significant findings detected with Q value < 0.25.

Amp Peak 1(1q32.1) cnvs correlated to 'AGE'.
Amp Peak 4(7q32.3) cnvs correlated to 'AGE'.
Amp Peak 9(12q14.1) cnvs correlated to 'Time to Death'.
Amp Peak 10(19q13.2) cnvs correlated to 'Time to Death'.
Del Peak 1(1p36.31) cnvs correlated to 'AGE', 'HISTOLOGICAL.TYPE', and 'RADIATIONS.RADIATION.REGIMENINDICATION'.
Del Peak 11(9p21.3) cnvs correlated to 'Time to Death', 'AGE', and 'RADIATIONS.RADIATION.REGIMENINDICATION'.
Del Peak 12(10q26.2) cnvs correlated to 'Time to Death'.
Del Peak 17(14q24.3) cnvs correlated to 'Time to Death'.
Del Peak 20(19q13.42) cnvs correlated to 'HISTOLOGICAL.TYPE'.

Results

Overview of the results

Table 1. Get Full Table Overview of the association between significant copy number variation of 36 regions and 6 clinical features. Shown in the table are P values (Q values). Thresholded by Q value < 0.25, 13 significant findings detected.


		Clinical Features	Time to Death	AGE	GENDER	KARNOFSKY PERFORMANCE SCORE	HISTOLOGICAL TYPE	RADIATIONS RADIATION REGIMENINDICATION
	nCNV (%)	nWild-Type	logrank test	t-test	Fisher's exact test	t-test	Fisher's exact test	Fisher's exact test
Del Peak 1(1p36 31)	69 (39%)	109	0.974 (1.00)	0.000459 (0.0945)	0.644 (1.00)	0.934 (1.00)	3.16e-10 (6.82e-08)	0.000673 (0.138)
Del Peak 11(9p21 3)	66 (37%)	112	5.14e-05 (0.0109)	0.000171 (0.0357)	0.755 (1.00)	0.328 (1.00)	0.405 (1.00)	4.37e-05 (0.00931)
Amp Peak 1(1q32 1)	21 (12%)	157	0.0626 (1.00)	0.000363 (0.0751)	0.357 (1.00)	0.079 (1.00)	0.508 (1.00)	0.249 (1.00)
Amp Peak 4(7q32 3)	65 (37%)	113	0.349 (1.00)	0.000236 (0.049)	0.0277 (1.00)	0.898 (1.00)	0.612 (1.00)	0.0188 (1.00)
Amp Peak 9(12q14 1)	13 (7%)	165	2.7e-05 (0.00578)	0.0514 (1.00)	0.562 (1.00)	0.492 (1.00)	0.127 (1.00)	0.774 (1.00)
Amp Peak 10(19q13 2)	12 (7%)	166	7.69e-05 (0.0162)	0.00175 (0.355)	1 (1.00)	0.497 (1.00)	0.696 (1.00)	0.147 (1.00)
Del Peak 12(10q26 2)	56 (31%)	122	0.000139 (0.0292)	0.00873 (1.00)	0.105 (1.00)	0.366 (1.00)	0.104 (1.00)	0.419 (1.00)
Del Peak 17(14q24 3)	45 (25%)	133	0.000758 (0.155)	0.121 (1.00)	0.0233 (1.00)	0.961 (1.00)	0.195 (1.00)	0.606 (1.00)
Del Peak 20(19q13 42)	100 (56%)	78	0.0155 (1.00)	0.515 (1.00)	0.879 (1.00)	0.622 (1.00)	1.86e-06 (4e-04)	0.65 (1.00)
Amp Peak 2(4q12)	8 (4%)	170	0.876 (1.00)	0.836 (1.00)	0.289 (1.00)	0.319 (1.00)	0.0202 (1.00)	0.727 (1.00)
Amp Peak 3(7p11 2)	47 (26%)	131	0.00607 (1.00)	0.00554 (1.00)	0.121 (1.00)	0.563 (1.00)	0.266 (1.00)	0.127 (1.00)
Amp Peak 5(8q24 21)	36 (20%)	142	0.92 (1.00)	0.633 (1.00)	0.258 (1.00)	0.31 (1.00)	0.0877 (1.00)	0.0952 (1.00)
Amp Peak 6(10p15 1)	29 (16%)	149	0.674 (1.00)	0.00907 (1.00)	0.413 (1.00)	0.664 (1.00)	0.0228 (1.00)	0.417 (1.00)
Amp Peak 7(11q23 3)	34 (19%)	144	0.695 (1.00)	0.0856 (1.00)	0.185 (1.00)	0.6 (1.00)	0.39 (1.00)	0.343 (1.00)
Amp Peak 8(12p13 32)	30 (17%)	148	0.954 (1.00)	0.116 (1.00)	0.157 (1.00)	0.452 (1.00)	0.546 (1.00)	1 (1.00)
Amp Peak 11(Xp22 33)	13 (7%)	165	0.614 (1.00)	0.964 (1.00)	1 (1.00)	0.631 (1.00)	0.0111 (1.00)	0.387 (1.00)
Amp Peak 12(Xp11 22)	17 (10%)	161	0.5 (1.00)	0.474 (1.00)	1 (1.00)	0.836 (1.00)	0.304 (1.00)	0.0718 (1.00)
Amp Peak 13(Xq11 2)	23 (13%)	155	0.564 (1.00)	0.672 (1.00)	0.37 (1.00)	0.715 (1.00)	0.0673 (1.00)	0.121 (1.00)
Del Peak 2(1q44)	12 (7%)	166	0.916 (1.00)	0.08 (1.00)	1 (1.00)	0.913 (1.00)	0.045 (1.00)	0.775 (1.00)
Del Peak 3(2q37 3)	29 (16%)	149	0.628 (1.00)	0.112 (1.00)	1 (1.00)	0.565 (1.00)	0.225 (1.00)	0.417 (1.00)
Del Peak 4(3p21 1)	18 (10%)	160	0.354 (1.00)	0.0231 (1.00)	0.806 (1.00)	0.652 (1.00)	0.519 (1.00)	0.135 (1.00)
Del Peak 5(3q29)	19 (11%)	159	0.469 (1.00)	0.777 (1.00)	0.147 (1.00)	0.0488 (1.00)	0.133 (1.00)	0.47 (1.00)
Del Peak 6(4q33)	58 (33%)	120	0.528 (1.00)	0.862 (1.00)	0.259 (1.00)	0.568 (1.00)	0.161 (1.00)	0.632 (1.00)
Del Peak 7(4q35 2)	59 (33%)	119	0.474 (1.00)	0.805 (1.00)	0.2 (1.00)	0.704 (1.00)	0.111 (1.00)	0.751 (1.00)
Del Peak 8(5q35 2)	24 (13%)	154	0.107 (1.00)	0.445 (1.00)	0.379 (1.00)	0.339 (1.00)	0.224 (1.00)	0.0289 (1.00)
Del Peak 9(6p24 1)	16 (9%)	162	0.058 (1.00)	0.48 (1.00)	0.431 (1.00)	0.735 (1.00)	0.00403 (0.813)	0.294 (1.00)
Del Peak 10(6q24 3)	28 (16%)	150	0.0253 (1.00)	0.312 (1.00)	0.412 (1.00)	0.536 (1.00)	0.0226 (1.00)	0.00648 (1.00)
Del Peak 13(11p15 5)	38 (21%)	140	0.451 (1.00)	0.145 (1.00)	0.0963 (1.00)	0.635 (1.00)	0.0315 (1.00)	0.271 (1.00)
Del Peak 14(12p13 1)	14 (8%)	164	0.178 (1.00)	0.967 (1.00)	0.4 (1.00)	0.727 (1.00)	0.329 (1.00)	0.264 (1.00)
Del Peak 15(13q14 2)	58 (33%)	120	0.472 (1.00)	0.905 (1.00)	0.629 (1.00)	0.0641 (1.00)	0.127 (1.00)	0.15 (1.00)
Del Peak 16(13q34)	43 (24%)	135	0.327 (1.00)	0.544 (1.00)	0.38 (1.00)	0.404 (1.00)	0.63 (1.00)	0.114 (1.00)
Del Peak 18(17q25 3)	10 (6%)	168	0.565 (1.00)	0.586 (1.00)	1 (1.00)	0.721 (1.00)	0.773 (1.00)	0.755 (1.00)
Del Peak 19(18q23)	30 (17%)	148	0.64 (1.00)	0.2 (1.00)	0.688 (1.00)	0.882 (1.00)	0.935 (1.00)	0.16 (1.00)
Del Peak 21(22q13 31)	28 (16%)	150	0.152 (1.00)	0.406 (1.00)	0.412 (1.00)	0.711 (1.00)	0.00606 (1.00)	1 (1.00)
Del Peak 22(Xp22 31)	44 (25%)	134	0.675 (1.00)	0.849 (1.00)	0.484 (1.00)	0.643 (1.00)	0.879 (1.00)	0.488 (1.00)
Del Peak 23(Xq21 1)	29 (16%)	149	0.678 (1.00)	0.235 (1.00)	0.543 (1.00)	0.978 (1.00)	0.176 (1.00)	0.546 (1.00)

'Amp Peak 1(1q32.1) mutation analysis' versus 'AGE'

P value = 0.000363 (t-test), Q value = 0.075

Table S1. Gene #1: 'Amp Peak 1(1q32.1) mutation analysis' versus Clinical Feature #2: 'AGE'

	nPatients	Mean (Std.Dev)
ALL	178	43.1 (13.4)
AMP PEAK 1(1Q32.1) MUTATED	21	53.2 (11.9)
AMP PEAK 1(1Q32.1) WILD-TYPE	157	41.8 (13.0)

Figure S1. Get High-res Image Gene #1: 'Amp Peak 1(1q32.1) mutation analysis' versus Clinical Feature #2: 'AGE'

'Amp Peak 4(7q32.3) mutation analysis' versus 'AGE'

P value = 0.000236 (t-test), Q value = 0.049

Table S2. Gene #4: 'Amp Peak 4(7q32.3) mutation analysis' versus Clinical Feature #2: 'AGE'

	nPatients	Mean (Std.Dev)
ALL	178	43.1 (13.4)
AMP PEAK 4(7Q32.3) MUTATED	65	48.0 (13.1)
AMP PEAK 4(7Q32.3) WILD-TYPE	113	40.4 (12.8)

Figure S2. Get High-res Image Gene #4: 'Amp Peak 4(7q32.3) mutation analysis' versus Clinical Feature #2: 'AGE'

'Amp Peak 9(12q14.1) mutation analysis' versus 'Time to Death'

P value = 2.7e-05 (logrank test), Q value = 0.0058

Table S3. Gene #9: 'Amp Peak 9(12q14.1) mutation analysis' versus Clinical Feature #1: 'Time to Death'

	nPatients	nDeath	Duration Range (Median), Month
ALL	177	50	0.0 - 211.2 (14.7)
AMP PEAK 9(12Q14.1) MUTATED	13	9	1.2 - 80.0 (12.4)
AMP PEAK 9(12Q14.1) WILD-TYPE	164	41	0.0 - 211.2 (14.9)

Figure S3. Get High-res Image Gene #9: 'Amp Peak 9(12q14.1) mutation analysis' versus Clinical Feature #1: 'Time to Death'

'Amp Peak 10(19q13.2) mutation analysis' versus 'Time to Death'

P value = 7.69e-05 (logrank test), Q value = 0.016

Table S4. Gene #10: 'Amp Peak 10(19q13.2) mutation analysis' versus Clinical Feature #1: 'Time to Death'

	nPatients	nDeath	Duration Range (Median), Month
ALL	177	50	0.0 - 211.2 (14.7)
AMP PEAK 10(19Q13.2) MUTATED	12	6	0.0 - 43.9 (12.8)
AMP PEAK 10(19Q13.2) WILD-TYPE	165	44	0.1 - 211.2 (14.7)

Figure S4. Get High-res Image Gene #10: 'Amp Peak 10(19q13.2) mutation analysis' versus Clinical Feature #1: 'Time to Death'

'Del Peak 1(1p36.31) mutation analysis' versus 'AGE'

P value = 0.000459 (t-test), Q value = 0.094

Table S5. Gene #14: 'Del Peak 1(1p36.31) mutation analysis' versus Clinical Feature #2: 'AGE'

	nPatients	Mean (Std.Dev)
ALL	178	43.1 (13.4)
DEL PEAK 1(1P36.31) MUTATED	69	47.5 (12.6)
DEL PEAK 1(1P36.31) WILD-TYPE	109	40.4 (13.2)

Figure S5. Get High-res Image Gene #14: 'Del Peak 1(1p36.31) mutation analysis' versus Clinical Feature #2: 'AGE'

'Del Peak 1(1p36.31) mutation analysis' versus 'HISTOLOGICAL.TYPE'

P value = 3.16e-10 (Fisher's exact test), Q value = 6.8e-08

Table S6. Gene #14: 'Del Peak 1(1p36.31) mutation analysis' versus Clinical Feature #5: 'HISTOLOGICAL.TYPE'

nPatients	ASTROCYTOMA	OLIGOASTROCYTOMA	OLIGODENDROGLIOMA
ALL	55	47	75
DEL PEAK 1(1P36.31) MUTATED	8	11	50
DEL PEAK 1(1P36.31) WILD-TYPE	47	36	25

Figure S6. Get High-res Image Gene #14: 'Del Peak 1(1p36.31) mutation analysis' versus Clinical Feature #5: 'HISTOLOGICAL.TYPE'

'Del Peak 1(1p36.31) mutation analysis' versus 'RADIATIONS.RADIATION.REGIMENINDICATION'

P value = 0.000673 (Fisher's exact test), Q value = 0.14

Table S7. Gene #14: 'Del Peak 1(1p36.31) mutation analysis' versus Clinical Feature #6: 'RADIATIONS.RADIATION.REGIMENINDICATION'

nPatients	NO	YES
ALL	82	96
DEL PEAK 1(1P36.31) MUTATED	43	26
DEL PEAK 1(1P36.31) WILD-TYPE	39	70

Figure S7. Get High-res Image Gene #14: 'Del Peak 1(1p36.31) mutation analysis' versus Clinical Feature #6: 'RADIATIONS.RADIATION.REGIMENINDICATION'

'Del Peak 11(9p21.3) mutation analysis' versus 'Time to Death'

P value = 5.14e-05 (logrank test), Q value = 0.011

Table S8. Gene #24: 'Del Peak 11(9p21.3) mutation analysis' versus Clinical Feature #1: 'Time to Death'

	nPatients	nDeath	Duration Range (Median), Month
ALL	177	50	0.0 - 211.2 (14.7)
DEL PEAK 11(9P21.3) MUTATED	65	26	0.1 - 117.4 (16.8)
DEL PEAK 11(9P21.3) WILD-TYPE	112	24	0.0 - 211.2 (14.5)

Figure S8. Get High-res Image Gene #24: 'Del Peak 11(9p21.3) mutation analysis' versus Clinical Feature #1: 'Time to Death'

'Del Peak 11(9p21.3) mutation analysis' versus 'AGE'

P value = 0.000171 (t-test), Q value = 0.036

Table S9. Gene #24: 'Del Peak 11(9p21.3) mutation analysis' versus Clinical Feature #2: 'AGE'

	nPatients	Mean (Std.Dev)
ALL	178	43.1 (13.4)
DEL PEAK 11(9P21.3) MUTATED	66	48.0 (13.0)
DEL PEAK 11(9P21.3) WILD-TYPE	112	40.3 (12.8)

Figure S9. Get High-res Image Gene #24: 'Del Peak 11(9p21.3) mutation analysis' versus Clinical Feature #2: 'AGE'

'Del Peak 11(9p21.3) mutation analysis' versus 'RADIATIONS.RADIATION.REGIMENINDICATION'

P value = 4.37e-05 (Fisher's exact test), Q value = 0.0093

Table S10. Gene #24: 'Del Peak 11(9p21.3) mutation analysis' versus Clinical Feature #6: 'RADIATIONS.RADIATION.REGIMENINDICATION'

nPatients	NO	YES
ALL	82	96
DEL PEAK 11(9P21.3) MUTATED	17	49
DEL PEAK 11(9P21.3) WILD-TYPE	65	47

Figure S10. Get High-res Image Gene #24: 'Del Peak 11(9p21.3) mutation analysis' versus Clinical Feature #6: 'RADIATIONS.RADIATION.REGIMENINDICATION'

'Del Peak 12(10q26.2) mutation analysis' versus 'Time to Death'

P value = 0.000139 (logrank test), Q value = 0.029

Table S11. Gene #25: 'Del Peak 12(10q26.2) mutation analysis' versus Clinical Feature #1: 'Time to Death'

	nPatients	nDeath	Duration Range (Median), Month
ALL	177	50	0.0 - 211.2 (14.7)
DEL PEAK 12(10Q26.2) MUTATED	56	29	0.1 - 156.2 (15.8)
DEL PEAK 12(10Q26.2) WILD-TYPE	121	21	0.0 - 211.2 (14.5)

Figure S11. Get High-res Image Gene #25: 'Del Peak 12(10q26.2) mutation analysis' versus Clinical Feature #1: 'Time to Death'

'Del Peak 17(14q24.3) mutation analysis' versus 'Time to Death'

P value = 0.000758 (logrank test), Q value = 0.15

Table S12. Gene #30: 'Del Peak 17(14q24.3) mutation analysis' versus Clinical Feature #1: 'Time to Death'

	nPatients	nDeath	Duration Range (Median), Month
ALL	177	50	0.0 - 211.2 (14.7)
DEL PEAK 17(14Q24.3) MUTATED	45	22	0.2 - 130.8 (17.3)
DEL PEAK 17(14Q24.3) WILD-TYPE	132	28	0.0 - 211.2 (14.5)

Figure S12. Get High-res Image Gene #30: 'Del Peak 17(14q24.3) mutation analysis' versus Clinical Feature #1: 'Time to Death'

'Del Peak 20(19q13.42) mutation analysis' versus 'HISTOLOGICAL.TYPE'

P value = 1.86e-06 (Fisher's exact test), Q value = 4e-04

Table S13. Gene #33: 'Del Peak 20(19q13.42) mutation analysis' versus Clinical Feature #5: 'HISTOLOGICAL.TYPE'

nPatients	ASTROCYTOMA	OLIGOASTROCYTOMA	OLIGODENDROGLIOMA
ALL	55	47	75
DEL PEAK 20(19Q13.42) MUTATED	19	22	58
DEL PEAK 20(19Q13.42) WILD-TYPE	36	25	17

Figure S13. Get High-res Image Gene #33: 'Del Peak 20(19q13.42) mutation analysis' versus Clinical Feature #5: 'HISTOLOGICAL.TYPE'

Methods & Data

Input

Copy number data file = All Lesions File (all_lesions.conf_##.txt, where ## is the confidence level). The all lesions file is from GISTIC pipeline and summarizes the results from the GISTIC run. It contains data about the significant regions of amplification and deletion as well as which samples are amplified or deleted in each of these regions. The identified regions are listed down the first column, and the samples are listed across the first row, starting in column 10.
Clinical data file = LGG-TP.clin.merged.picked.txt
Number of patients = 178
Number of copy number variation regions = 36
Number of selected clinical features = 6
Exclude regions that fewer than K tumors have alterations, K = 3

Survival analysis

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

Student's t-test analysis

For continuous numerical clinical features, two-tailed Student's t test with unequal variance (Lehmann and Romano 2005) was applied to compare the clinical values between tumors with and without gene cnvs using 't.test' 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] Lehmann and Romano, Testing Statistical Hypotheses (3E ed.), New York: Springer. ISBN 0387988645 (2005)

[3] 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)

[4] 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)

[5] GISTIC_version2

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