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 7 clinical features across 145 patients, 11 significant findings detected with Q value < 0.25.

Amp Peak 4(7q32.3) cnvs correlated to 'AGE'.
Amp Peak 6(10p15.3) cnvs correlated to 'AGE'.
Amp Peak 9(12q14.1) cnvs correlated to 'Time to Death'.
Amp Peak 11(19q13.2) cnvs correlated to 'Time to Death'.
Del Peak 1(1p36.31) cnvs correlated to '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(10q26.13) cnvs correlated to 'Time to Death'.
Del Peak 19(19q13.43) 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 7 clinical features. Shown in the table are P values (Q values). Thresholded by Q value < 0.25, 11 significant findings detected.


		Clinical Features	Time to Death	AGE	GENDER	KARNOFSKY PERFORMANCE SCORE	HISTOLOGICAL TYPE	RADIATIONS RADIATION REGIMENINDICATION	NEOADJUVANT THERAPY
	nCNV (%)	nWild-Type	logrank test	t-test	Fisher's exact test	t-test	Fisher's exact test	Fisher's exact test	Fisher's exact test
Del Peak 11(9p21 3)	56 (39%)	89	6.01e-05 (0.0148)	0.000671 (0.162)	0.605 (1.00)	0.668 (1.00)	0.354 (1.00)	5.35e-05 (0.0133)	0.237 (1.00)
Del Peak 1(1p36 31)	53 (37%)	92	0.689 (1.00)	0.00241 (0.579)	0.486 (1.00)	1 (1.00)	1.54e-10 (3.87e-08)	0.000399 (0.097)	0.605 (1.00)
Amp Peak 4(7q32 3)	56 (39%)	89	0.247 (1.00)	5.27e-05 (0.0131)	0.0405 (1.00)	0.967 (1.00)	0.843 (1.00)	0.0239 (1.00)	1 (1.00)
Amp Peak 6(10p15 3)	26 (18%)	119	0.499 (1.00)	0.000208 (0.0506)	0.668 (1.00)	0.913 (1.00)	0.0432 (1.00)	0.83 (1.00)	0.519 (1.00)
Amp Peak 9(12q14 1)	12 (8%)	133	1.74e-05 (0.00437)	0.0813 (1.00)	0.762 (1.00)	0.708 (1.00)	0.198 (1.00)	0.762 (1.00)	0.238 (1.00)
Amp Peak 11(19q13 2)	11 (8%)	134	4.67e-05 (0.0117)	0.00364 (0.862)	0.759 (1.00)	0.441 (1.00)	0.619 (1.00)	0.526 (1.00)	0.209 (1.00)
Del Peak 12(10q26 13)	45 (31%)	100	0.000138 (0.0337)	0.0352 (1.00)	0.205 (1.00)	0.529 (1.00)	0.0512 (1.00)	0.274 (1.00)	1 (1.00)
Del Peak 19(19q13 43)	83 (57%)	62	0.0315 (1.00)	0.492 (1.00)	0.616 (1.00)	0.983 (1.00)	0.000136 (0.0335)	0.173 (1.00)	0.314 (1.00)
Amp Peak 1(1q32 1)	18 (12%)	127	0.0339 (1.00)	0.00293 (0.697)	0.613 (1.00)	0.0768 (1.00)	0.408 (1.00)	0.308 (1.00)	0.32 (1.00)
Amp Peak 2(4q12)	8 (6%)	137	0.866 (1.00)	0.784 (1.00)	0.288 (1.00)	0.276 (1.00)	0.049 (1.00)	1 (1.00)	0.00267 (0.639)
Amp Peak 3(7p11 2)	40 (28%)	105	0.00813 (1.00)	0.00436 (1.00)	0.189 (1.00)	0.516 (1.00)	0.278 (1.00)	0.0586 (1.00)	0.582 (1.00)
Amp Peak 5(8q24 21)	31 (21%)	114	0.696 (1.00)	0.34 (1.00)	0.102 (1.00)	0.355 (1.00)	0.196 (1.00)	0.0656 (1.00)	0.84 (1.00)
Amp Peak 7(11q23 3)	30 (21%)	115	0.56 (1.00)	0.111 (1.00)	0.0993 (1.00)	0.847 (1.00)	0.445 (1.00)	0.68 (1.00)	1 (1.00)
Amp Peak 8(12p13 32)	24 (17%)	121	0.817 (1.00)	0.331 (1.00)	0.177 (1.00)	0.319 (1.00)	0.452 (1.00)	1 (1.00)	0.119 (1.00)
Amp Peak 10(17q24 3)	11 (8%)	134	0.00231 (0.557)	0.215 (1.00)	0.759 (1.00)	0.848 (1.00)	0.925 (1.00)	0.2 (1.00)	0.361 (1.00)
Amp Peak 12(Xp22 33)	12 (8%)	133	0.504 (1.00)	0.715 (1.00)	1 (1.00)	0.772 (1.00)	0.0138 (1.00)	0.762 (1.00)	1 (1.00)
Amp Peak 13(Xp11 22)	14 (10%)	131	0.591 (1.00)	0.741 (1.00)	1 (1.00)	0.312 (1.00)	0.305 (1.00)	0.158 (1.00)	0.0952 (1.00)
Amp Peak 14(Xq11 2)	19 (13%)	126	0.651 (1.00)	0.157 (1.00)	0.457 (1.00)	0.313 (1.00)	0.059 (1.00)	0.215 (1.00)	0.466 (1.00)
Del Peak 2(1q44)	10 (7%)	135	0.683 (1.00)	0.0214 (1.00)	1 (1.00)	0.95 (1.00)	0.121 (1.00)	1 (1.00)	0.527 (1.00)
Del Peak 3(2q37 3)	25 (17%)	120	0.669 (1.00)	0.0447 (1.00)	0.827 (1.00)	0.865 (1.00)	0.452 (1.00)	0.66 (1.00)	0.512 (1.00)
Del Peak 4(3p21 1)	15 (10%)	130	0.321 (1.00)	0.0379 (1.00)	1 (1.00)	0.441 (1.00)	0.305 (1.00)	0.102 (1.00)	0.789 (1.00)
Del Peak 5(3q29)	17 (12%)	128	0.378 (1.00)	0.293 (1.00)	0.118 (1.00)	0.179 (1.00)	0.0994 (1.00)	0.794 (1.00)	0.8 (1.00)
Del Peak 6(4q34 1)	48 (33%)	97	0.665 (1.00)	0.74 (1.00)	0.38 (1.00)	0.769 (1.00)	0.224 (1.00)	1 (1.00)	0.48 (1.00)
Del Peak 7(4q35 1)	50 (34%)	95	0.77 (1.00)	0.766 (1.00)	0.481 (1.00)	0.896 (1.00)	0.282 (1.00)	1 (1.00)	0.228 (1.00)
Del Peak 8(5q35 2)	22 (15%)	123	0.0953 (1.00)	0.443 (1.00)	0.35 (1.00)	0.588 (1.00)	0.13 (1.00)	0.0974 (1.00)	0.647 (1.00)
Del Peak 9(6p24 1)	14 (10%)	131	0.161 (1.00)	0.586 (1.00)	0.395 (1.00)	0.895 (1.00)	0.00544 (1.00)	0.401 (1.00)	0.401 (1.00)
Del Peak 10(6q25 1)	23 (16%)	122	0.0379 (1.00)	0.469 (1.00)	0.363 (1.00)	0.791 (1.00)	0.00712 (1.00)	0.0192 (1.00)	0.499 (1.00)
Del Peak 13(11p15 5)	30 (21%)	115	0.524 (1.00)	0.0453 (1.00)	0.411 (1.00)	0.342 (1.00)	0.0626 (1.00)	0.0965 (1.00)	0.414 (1.00)
Del Peak 14(13q14 13)	44 (30%)	101	0.944 (1.00)	0.485 (1.00)	0.363 (1.00)	0.113 (1.00)	0.0455 (1.00)	0.0976 (1.00)	0.47 (1.00)
Del Peak 15(13q34)	31 (21%)	114	0.43 (1.00)	0.161 (1.00)	0.541 (1.00)	0.548 (1.00)	0.299 (1.00)	0.0237 (1.00)	0.688 (1.00)
Del Peak 16(14q24 3)	38 (26%)	107	0.00884 (1.00)	0.573 (1.00)	0.0359 (1.00)	0.535 (1.00)	0.0696 (1.00)	1 (1.00)	0.576 (1.00)
Del Peak 17(17q25 3)	7 (5%)	138	0.696 (1.00)	0.646 (1.00)	0.699 (1.00)	0.315 (1.00)	0.614 (1.00)	1 (1.00)	1 (1.00)
Del Peak 18(18q23)	24 (17%)	121	0.293 (1.00)	0.481 (1.00)	0.261 (1.00)	0.72 (1.00)	0.848 (1.00)	0.112 (1.00)	0.375 (1.00)
Del Peak 20(22q13 31)	21 (14%)	124	0.304 (1.00)	0.898 (1.00)	0.641 (1.00)	0.517 (1.00)	0.0145 (1.00)	0.815 (1.00)	0.483 (1.00)
Del Peak 21(Xp22 31)	36 (25%)	109	0.888 (1.00)	0.518 (1.00)	0.564 (1.00)	0.845 (1.00)	0.939 (1.00)	0.562 (1.00)	0.443 (1.00)
Del Peak 22(Xq21 1)	21 (14%)	124	0.88 (1.00)	0.397 (1.00)	0.351 (1.00)	0.815 (1.00)	0.177 (1.00)	0.484 (1.00)	0.815 (1.00)

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

P value = 5.27e-05 (t-test), Q value = 0.013

Table S1. Gene #4: 'Amp Peak 4(7q32.3) mutation analysis' versus Clinical Feature #2: 'AGE'

	nPatients	Mean (Std.Dev)
ALL	145	42.8 (13.0)
AMP PEAK 4(7Q32.3) MUTATED	56	48.4 (13.2)
AMP PEAK 4(7Q32.3) WILD-TYPE	89	39.3 (11.7)

Figure S1. Get High-res Image Gene #4: 'Amp Peak 4(7q32.3) mutation analysis' versus Clinical Feature #2: 'AGE'

'Amp Peak 6(10p15.3) mutation analysis' versus 'AGE'

P value = 0.000208 (t-test), Q value = 0.051

Table S2. Gene #6: 'Amp Peak 6(10p15.3) mutation analysis' versus Clinical Feature #2: 'AGE'

	nPatients	Mean (Std.Dev)
ALL	145	42.8 (13.0)
AMP PEAK 6(10P15.3) MUTATED	26	35.2 (10.1)
AMP PEAK 6(10P15.3) WILD-TYPE	119	44.5 (13.1)

Figure S2. Get High-res Image Gene #6: 'Amp Peak 6(10p15.3) mutation analysis' versus Clinical Feature #2: 'AGE'

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

P value = 1.74e-05 (logrank test), Q value = 0.0044

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	145	48	0.0 - 211.2 (18.0)
AMP PEAK 9(12Q14.1) MUTATED	12	9	1.2 - 80.0 (13.7)
AMP PEAK 9(12Q14.1) WILD-TYPE	133	39	0.0 - 211.2 (19.9)

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

'Amp Peak 11(19q13.2) mutation analysis' versus 'Time to Death'

P value = 4.67e-05 (logrank test), Q value = 0.012

Table S4. Gene #11: 'Amp Peak 11(19q13.2) mutation analysis' versus Clinical Feature #1: 'Time to Death'

	nPatients	nDeath	Duration Range (Median), Month
ALL	145	48	0.0 - 211.2 (18.0)
AMP PEAK 11(19Q13.2) MUTATED	11	6	0.0 - 43.9 (15.0)
AMP PEAK 11(19Q13.2) WILD-TYPE	134	42	0.1 - 211.2 (19.0)

Figure S4. Get High-res Image Gene #11: 'Amp Peak 11(19q13.2) mutation analysis' versus Clinical Feature #1: 'Time to Death'

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

P value = 1.54e-10 (Fisher's exact test), Q value = 3.9e-08

Table S5. Gene #15: 'Del Peak 1(1p36.31) mutation analysis' versus Clinical Feature #5: 'HISTOLOGICAL.TYPE'

nPatients	ASTROCYTOMA	OLIGOASTROCYTOMA	OLIGODENDROGLIOMA
ALL	50	36	58
DEL PEAK 1(1P36.31) MUTATED	6	7	40
DEL PEAK 1(1P36.31) WILD-TYPE	44	29	18

Figure S5. Get High-res Image Gene #15: '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 = 0.000399 (Fisher's exact test), Q value = 0.097

Table S6. Gene #15: 'Del Peak 1(1p36.31) mutation analysis' versus Clinical Feature #6: 'RADIATIONS.RADIATION.REGIMENINDICATION'

nPatients	NO	YES
ALL	59	86
DEL PEAK 1(1P36.31) MUTATED	32	21
DEL PEAK 1(1P36.31) WILD-TYPE	27	65

Figure S6. Get High-res Image Gene #15: '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 = 6.01e-05 (logrank test), Q value = 0.015

Table S7. Gene #25: 'Del Peak 11(9p21.3) mutation analysis' versus Clinical Feature #1: 'Time to Death'

	nPatients	nDeath	Duration Range (Median), Month
ALL	145	48	0.0 - 211.2 (18.0)
DEL PEAK 11(9P21.3) MUTATED	56	25	4.1 - 117.4 (17.8)
DEL PEAK 11(9P21.3) WILD-TYPE	89	23	0.0 - 211.2 (18.9)

Figure S7. Get High-res Image Gene #25: '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 = 0.000671 (t-test), Q value = 0.16

Table S8. Gene #25: 'Del Peak 11(9p21.3) mutation analysis' versus Clinical Feature #2: 'AGE'

	nPatients	Mean (Std.Dev)
ALL	145	42.8 (13.0)
DEL PEAK 11(9P21.3) MUTATED	56	47.5 (12.9)
DEL PEAK 11(9P21.3) WILD-TYPE	89	39.9 (12.3)

Figure S8. Get High-res Image Gene #25: '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 = 5.35e-05 (Fisher's exact test), Q value = 0.013

Table S9. Gene #25: 'Del Peak 11(9p21.3) mutation analysis' versus Clinical Feature #6: 'RADIATIONS.RADIATION.REGIMENINDICATION'

nPatients	NO	YES
ALL	59	86
DEL PEAK 11(9P21.3) MUTATED	11	45
DEL PEAK 11(9P21.3) WILD-TYPE	48	41

Figure S9. Get High-res Image Gene #25: 'Del Peak 11(9p21.3) mutation analysis' versus Clinical Feature #6: 'RADIATIONS.RADIATION.REGIMENINDICATION'

'Del Peak 12(10q26.13) mutation analysis' versus 'Time to Death'

P value = 0.000138 (logrank test), Q value = 0.034

Table S10. Gene #26: 'Del Peak 12(10q26.13) mutation analysis' versus Clinical Feature #1: 'Time to Death'

	nPatients	nDeath	Duration Range (Median), Month
ALL	145	48	0.0 - 211.2 (18.0)
DEL PEAK 12(10Q26.13) MUTATED	45	28	0.9 - 156.2 (17.5)
DEL PEAK 12(10Q26.13) WILD-TYPE	100	20	0.0 - 211.2 (21.0)

Figure S10. Get High-res Image Gene #26: 'Del Peak 12(10q26.13) mutation analysis' versus Clinical Feature #1: 'Time to Death'

'Del Peak 19(19q13.43) mutation analysis' versus 'HISTOLOGICAL.TYPE'

P value = 0.000136 (Fisher's exact test), Q value = 0.033

Table S11. Gene #33: 'Del Peak 19(19q13.43) mutation analysis' versus Clinical Feature #5: 'HISTOLOGICAL.TYPE'

nPatients	ASTROCYTOMA	OLIGOASTROCYTOMA	OLIGODENDROGLIOMA
ALL	50	36	58
DEL PEAK 19(19Q13.43) MUTATED	20	17	45
DEL PEAK 19(19Q13.43) WILD-TYPE	30	19	13

Figure S11. Get High-res Image Gene #33: 'Del Peak 19(19q13.43) 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.clin.merged.picked.txt
Number of patients = 145
Number of copy number variation regions = 36
Number of selected clinical features = 7
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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