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 43 peak regions and 8 clinical features across 489 patients, 7 significant findings detected with Q value < 0.25.

  • Del Peak 13(3p11.1) cnvs correlated to 'GENDER'.

  • Del Peak 14(3q11.2) cnvs correlated to 'GENDER'.

  • Del Peak 15(3q13.13) cnvs correlated to 'AGE' and 'GENDER'.

  • Del Peak 25(9p21.3) cnvs correlated to 'Time to Death' and 'PATHOLOGICSPREAD(M)'.

  • Del Peak 31(19p13.3) cnvs correlated to 'Time to Death'.

Results
Overview of the results

Table 1.  Get Full Table Overview of the association between significant copy number variation of 43 regions and 8 clinical features. Shown in the table are P values (Q values). Thresholded by Q value < 0.25, 7 significant findings detected.

Clinical
Features 		Time
to
Death 		AGE GENDER KARNOFSKY
PERFORMANCE
SCORE 		PATHOLOGY
T 		PATHOLOGY
N 		PATHOLOGICSPREAD(M) 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 Fisher's exact test
Del Peak 15(3q13 13) 111 (23%) 378 0.702
(1.00) 		0.000619
(0.202) 		4.93e-06
(0.00164) 		0.788
(1.00) 		0.39
(1.00) 		0.539
(1.00) 		0.454
(1.00) 		1
(1.00)
Del Peak 25(9p21 3) 91 (19%) 398 6.05e-05
(0.02) 		0.0762
(1.00) 		0.0102
(1.00) 		0.0261
(1.00) 		0.00642
(1.00) 		0.335
(1.00) 		8.35e-05
(0.0276) 		0.234
(1.00)
Del Peak 13(3p11 1) 193 (39%) 296 0.562
(1.00) 		0.0123
(1.00) 		0.000217
(0.0714) 		0.689
(1.00) 		0.305
(1.00) 		0.803
(1.00) 		0.16
(1.00) 		0.653
(1.00)
Del Peak 14(3q11 2) 125 (26%) 364 0.818
(1.00) 		0.0029
(0.932) 		4.61e-07
(0.000153) 		0.788
(1.00) 		0.188
(1.00) 		0.377
(1.00) 		0.253
(1.00) 		1
(1.00)
Del Peak 31(19p13 3) 12 (2%) 477 0.000455
(0.149) 		0.681
(1.00) 		0.76
(1.00) 		0.0339
(1.00) 		0.322
(1.00) 		0.407
(1.00) 		1
(1.00)
Amp Peak 1(1q32 1) 46 (9%) 443 0.921
(1.00) 		0.0183
(1.00) 		1
(1.00) 		0.499
(1.00) 		0.28
(1.00) 		0.391
(1.00) 		0.519
(1.00) 		0.391
(1.00)
Amp Peak 2(3q26 32) 46 (9%) 443 0.814
(1.00) 		0.456
(1.00) 		0.519
(1.00) 		0.124
(1.00) 		0.0972
(1.00) 		1
(1.00) 		0.05
(1.00) 		0.0721
(1.00)
Amp Peak 3(4q32 1) 11 (2%) 478 0.0977
(1.00) 		0.213
(1.00) 		0.203
(1.00) 		0.411
(1.00) 		0.107
(1.00) 		0.465
(1.00) 		1
(1.00) 		1
(1.00)
Amp Peak 4(5q15) 163 (33%) 326 0.53
(1.00) 		0.000817
(0.266) 		0.366
(1.00) 		0.568
(1.00) 		0.186
(1.00) 		1
(1.00) 		0.894
(1.00) 		0.339
(1.00)
Amp Peak 5(5q35 3) 275 (56%) 214 0.018
(1.00) 		0.13
(1.00) 		0.294
(1.00) 		0.906
(1.00) 		0.153
(1.00) 		0.145
(1.00) 		0.528
(1.00) 		0.392
(1.00)
Amp Peak 6(6p21 1) 7 (1%) 482 0.482
(1.00) 		0.238
(1.00) 		1
(1.00) 		0.293
(1.00) 		1
(1.00) 		1
(1.00) 		1
(1.00)
Amp Peak 7(6q12) 8 (2%) 481 0.0451
(1.00) 		0.592
(1.00) 		0.72
(1.00) 		0.0159
(1.00) 		1
(1.00) 		1
(1.00) 		1
(1.00)
Amp Peak 8(7q36 1) 129 (26%) 360 0.54
(1.00) 		0.446
(1.00) 		0.106
(1.00) 		0.624
(1.00) 		0.16
(1.00) 		1
(1.00) 		0.00638
(1.00) 		0.118
(1.00)
Amp Peak 9(9p24 1) 12 (2%) 477 0.422
(1.00) 		0.483
(1.00) 		0.121
(1.00) 		0.343
(1.00) 		1
(1.00) 		1
(1.00) 		1
(1.00)
Amp Peak 10(13q14 2) 15 (3%) 474 0.727
(1.00) 		0.736
(1.00) 		0.279
(1.00) 		0.0508
(1.00) 		1
(1.00) 		0.264
(1.00) 		0.00834
(1.00)
Amp Peak 11(14q13 2) 8 (2%) 481 0.245
(1.00) 		0.313
(1.00) 		1
(1.00) 		0.135
(1.00) 		1
(1.00) 		1
(1.00) 		1
(1.00)
Amp Peak 12(15q26 1) 16 (3%) 473 0.75
(1.00) 		0.704
(1.00) 		0.595
(1.00) 		0.073
(1.00) 		0.544
(1.00) 		0.286
(1.00) 		1
(1.00)
Del Peak 1(1p36 11) 63 (13%) 426 0.159
(1.00) 		0.0627
(1.00) 		0.118
(1.00) 		0.115
(1.00) 		0.75
(1.00) 		1
(1.00) 		0.355
(1.00) 		0.126
(1.00)
Del Peak 2(1p31 1) 51 (10%) 438 0.393
(1.00) 		0.105
(1.00) 		0.0191
(1.00) 		0.484
(1.00) 		0.903
(1.00) 		0.409
(1.00) 		0.681
(1.00) 		0.0869
(1.00)
Del Peak 3(1q44) 27 (6%) 462 0.388
(1.00) 		0.491
(1.00) 		1
(1.00) 		0.228
(1.00) 		0.608
(1.00) 		1
(1.00) 		1
(1.00)
Del Peak 4(2q37 3) 45 (9%) 444 0.957
(1.00) 		0.871
(1.00) 		0.0714
(1.00) 		0.921
(1.00) 		1
(1.00) 		0.518
(1.00) 		1
(1.00)
Del Peak 5(3p26 2) 387 (79%) 102 0.00359
(1.00) 		0.841
(1.00) 		0.64
(1.00) 		0.666
(1.00) 		0.0112
(1.00) 		0.145
(1.00) 		0.216
(1.00) 		1
(1.00)
Del Peak 6(3p21 1) 395 (81%) 94 0.0166
(1.00) 		0.949
(1.00) 		0.905
(1.00) 		0.569
(1.00) 		0.00333
(1.00) 		0.238
(1.00) 		0.874
(1.00) 		1
(1.00)
Del Peak 7(3p14 2) 346 (71%) 143 0.0631
(1.00) 		0.518
(1.00) 		0.144
(1.00) 		0.801
(1.00) 		0.057
(1.00) 		0.191
(1.00) 		0.41
(1.00) 		0.632
(1.00)
Del Peak 8(3p14 1) 335 (69%) 154 0.267
(1.00) 		0.351
(1.00) 		0.0243
(1.00) 		0.801
(1.00) 		0.0216
(1.00) 		0.299
(1.00) 		0.28
(1.00) 		0.652
(1.00)
Del Peak 9(3p14 1) 305 (62%) 184 0.137
(1.00) 		0.255
(1.00) 		0.0141
(1.00) 		0.962
(1.00) 		0.0175
(1.00) 		0.208
(1.00) 		0.244
(1.00) 		1
(1.00)
Del Peak 10(3p12 3) 281 (57%) 208 0.342
(1.00) 		0.647
(1.00) 		0.00956
(1.00) 		0.906
(1.00) 		0.0671
(1.00) 		0.461
(1.00) 		0.448
(1.00) 		1
(1.00)
Del Peak 11(3p12 2) 252 (52%) 237 0.881
(1.00) 		0.489
(1.00) 		0.0177
(1.00) 		0.777
(1.00) 		0.1
(1.00) 		0.464
(1.00) 		0.26
(1.00) 		0.677
(1.00)
Del Peak 12(3p12 1) 210 (43%) 279 0.675
(1.00) 		0.0394
(1.00) 		0.00408
(1.00) 		0.18
(1.00) 		0.308
(1.00) 		0.625
(1.00) 		0.206
(1.00) 		0.397
(1.00)
Del Peak 16(4q24) 35 (7%) 454 0.00936
(1.00) 		0.993
(1.00) 		0.143
(1.00) 		0.0261
(1.00) 		0.00169
(0.547) 		1
(1.00) 		0.0881
(1.00) 		0.311
(1.00)
Del Peak 17(4q34 3) 37 (8%) 452 0.069
(1.00) 		0.974
(1.00) 		0.858
(1.00) 		0.0261
(1.00) 		0.00188
(0.608) 		1
(1.00) 		0.15
(1.00) 		0.326
(1.00)
Del Peak 18(5p15 33) 6 (1%) 483 0.538
(1.00) 		0.481
(1.00) 		0.423
(1.00) 		1
(1.00) 		1
(1.00) 		1
(1.00) 		1
(1.00)
Del Peak 19(6q16 1) 86 (18%) 403 0.586
(1.00) 		0.661
(1.00) 		0.105
(1.00) 		0.864
(1.00) 		0.996
(1.00) 		0.062
(1.00) 		0.409
(1.00) 		0.214
(1.00)
Del Peak 20(6q26) 105 (21%) 384 0.417
(1.00) 		0.0982
(1.00) 		0.0845
(1.00) 		0.864
(1.00) 		0.848
(1.00) 		0.0925
(1.00) 		1
(1.00) 		0.293
(1.00)
Del Peak 21(7q31 1) 3 (1%) 486 0.946
(1.00) 		0.793
(1.00) 		1
(1.00) 		0.0284
(1.00) 		1
(1.00) 		0.394
(1.00) 		1
(1.00)
Del Peak 22(8p12) 111 (23%) 378 0.297
(1.00) 		0.0331
(1.00) 		0.142
(1.00) 		0.0575
(1.00) 		0.901
(1.00) 		0.377
(1.00) 		0.766
(1.00) 		1
(1.00)
Del Peak 23(8p11 21) 83 (17%) 406 0.96
(1.00) 		0.157
(1.00) 		0.0573
(1.00) 		0.0875
(1.00) 		0.97
(1.00) 		1
(1.00) 		1
(1.00) 		1
(1.00)
Del Peak 24(9p23) 82 (17%) 407 0.00479
(1.00) 		0.0372
(1.00) 		0.0158
(1.00) 		0.0261
(1.00) 		0.122
(1.00) 		1
(1.00) 		0.00372
(1.00) 		0.198
(1.00)
Del Peak 26(10q21 1) 45 (9%) 444 0.469
(1.00) 		0.173
(1.00) 		0.142
(1.00) 		0.171
(1.00) 		0.00442
(1.00) 		1
(1.00) 		1
(1.00) 		1
(1.00)
Del Peak 27(10q23 31) 57 (12%) 432 0.194
(1.00) 		0.0733
(1.00) 		0.103
(1.00) 		0.66
(1.00) 		0.000882
(0.287) 		0.214
(1.00) 		0.847
(1.00) 		1
(1.00)
Del Peak 28(13q13 3) 41 (8%) 448 0.0173
(1.00) 		0.227
(1.00) 		1
(1.00) 		0.00419
(1.00) 		0.01
(1.00) 		0.66
(1.00) 		0.111
(1.00) 		1
(1.00)
Del Peak 29(14q31 1) 163 (33%) 326 0.0791
(1.00) 		0.0611
(1.00) 		0.366
(1.00) 		0.508
(1.00) 		0.0284
(1.00) 		0.0783
(1.00) 		0.186
(1.00) 		0.0444
(1.00)
Del Peak 30(18q12 3) 47 (10%) 442 0.796
(1.00) 		0.135
(1.00) 		0.335
(1.00) 		0.482
(1.00) 		0.737
(1.00) 		1
(1.00) 		0.403
(1.00) 		0.398
(1.00)
'Del Peak 13(3p11.1) mutation analysis' versus 'GENDER'

P value = 0.000217 (Fisher's exact test), Q value = 0.071

Table S1.  Gene #25: 'Del Peak 13(3p11.1) mutation analysis' versus Clinical Feature #3: 'GENDER'

nPatients FEMALE MALE
ALL 319 170
DEL PEAK 13(3P11.1) MUTATED 145 48
DEL PEAK 13(3P11.1) WILD-TYPE 174 122

Figure S1.  Get High-res Image Gene #25: 'Del Peak 13(3p11.1) mutation analysis' versus Clinical Feature #3: 'GENDER'

'Del Peak 14(3q11.2) mutation analysis' versus 'GENDER'

P value = 4.61e-07 (Fisher's exact test), Q value = 0.00015

Table S2.  Gene #26: 'Del Peak 14(3q11.2) mutation analysis' versus Clinical Feature #3: 'GENDER'

nPatients FEMALE MALE
ALL 319 170
DEL PEAK 14(3Q11.2) MUTATED 104 21
DEL PEAK 14(3Q11.2) WILD-TYPE 215 149

Figure S2.  Get High-res Image Gene #26: 'Del Peak 14(3q11.2) mutation analysis' versus Clinical Feature #3: 'GENDER'

'Del Peak 15(3q13.13) mutation analysis' versus 'AGE'

P value = 0.000619 (t-test), Q value = 0.2

Table S3.  Gene #27: 'Del Peak 15(3q13.13) mutation analysis' versus Clinical Feature #2: 'AGE'

nPatients Mean (Std.Dev)
ALL 488 60.6 (12.2)
DEL PEAK 15(3Q13.13) MUTATED 111 64.3 (12.8)
DEL PEAK 15(3Q13.13) WILD-TYPE 377 59.5 (11.8)

Figure S3.  Get High-res Image Gene #27: 'Del Peak 15(3q13.13) mutation analysis' versus Clinical Feature #2: 'AGE'

'Del Peak 15(3q13.13) mutation analysis' versus 'GENDER'

P value = 4.93e-06 (Fisher's exact test), Q value = 0.0016

Table S4.  Gene #27: 'Del Peak 15(3q13.13) mutation analysis' versus Clinical Feature #3: 'GENDER'

nPatients FEMALE MALE
ALL 319 170
DEL PEAK 15(3Q13.13) MUTATED 92 19
DEL PEAK 15(3Q13.13) WILD-TYPE 227 151

Figure S4.  Get High-res Image Gene #27: 'Del Peak 15(3q13.13) mutation analysis' versus Clinical Feature #3: 'GENDER'

'Del Peak 25(9p21.3) mutation analysis' versus 'Time to Death'

P value = 6.05e-05 (logrank test), Q value = 0.02

Table S5.  Gene #37: 'Del Peak 25(9p21.3) mutation analysis' versus Clinical Feature #1: 'Time to Death'

nPatients nDeath Duration Range (Median), Month
ALL 486 156 0.1 - 111.0 (34.9)
DEL PEAK 25(9P21.3) MUTATED 91 45 0.2 - 109.9 (30.5)
DEL PEAK 25(9P21.3) WILD-TYPE 395 111 0.1 - 111.0 (36.1)

Figure S5.  Get High-res Image Gene #37: 'Del Peak 25(9p21.3) mutation analysis' versus Clinical Feature #1: 'Time to Death'

'Del Peak 25(9p21.3) mutation analysis' versus 'PATHOLOGICSPREAD(M)'

P value = 8.35e-05 (Fisher's exact test), Q value = 0.028

Table S6.  Gene #37: 'Del Peak 25(9p21.3) mutation analysis' versus Clinical Feature #7: 'PATHOLOGICSPREAD(M)'

nPatients M0 M1
ALL 414 75
DEL PEAK 25(9P21.3) MUTATED 64 27
DEL PEAK 25(9P21.3) WILD-TYPE 350 48

Figure S6.  Get High-res Image Gene #37: 'Del Peak 25(9p21.3) mutation analysis' versus Clinical Feature #7: 'PATHOLOGICSPREAD(M)'

'Del Peak 31(19p13.3) mutation analysis' versus 'Time to Death'

P value = 0.000455 (logrank test), Q value = 0.15

Table S7.  Gene #43: 'Del Peak 31(19p13.3) mutation analysis' versus Clinical Feature #1: 'Time to Death'

nPatients nDeath Duration Range (Median), Month
ALL 486 156 0.1 - 111.0 (34.9)
DEL PEAK 31(19P13.3) MUTATED 12 10 1.9 - 109.9 (24.1)
DEL PEAK 31(19P13.3) WILD-TYPE 474 146 0.1 - 111.0 (35.5)

Figure S7.  Get High-res Image Gene #43: 'Del Peak 31(19p13.3) mutation analysis' versus Clinical Feature #1: 'Time to Death'

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 = KIRC.clin.merged.picked.txt

  • Number of patients = 489

  • Number of copy number variation regions = 43

  • Number of selected clinical features = 8

  • 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)
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