Correlation between copy number variation genes (focal events) and molecular subtypes
Overview
Introduction

This pipeline computes the correlation between significant copy number variation (cnv focal) genes and molecular subtypes.

Summary

Testing the association between copy number variation 23 focal events and 10 molecular subtypes across 36 patients, 8 significant findings detected with P value < 0.05 and Q value < 0.25.

  • del_1p36.21 cnv correlated to 'METHLYATION_CNMF' and 'MRNASEQ_CHIERARCHICAL'.

  • del_6q13 cnv correlated to 'CN_CNMF'.

  • del_6q25.3 cnv correlated to 'CN_CNMF'.

  • del_14q22.1 cnv correlated to 'RPPA_CHIERARCHICAL'.

  • del_14q32.12 cnv correlated to 'CN_CNMF'.

  • del_14q32.11 cnv correlated to 'CN_CNMF'.

  • del_14q32.33 cnv correlated to 'CN_CNMF'.

Results
Overview of the results

Table 1.  Get Full Table Overview of the association between significant copy number variation of 23 focal events and 10 molecular subtypes. Shown in the table are P values (Q values). Thresholded by P value < 0.05 and Q value < 0.25, 8 significant findings detected.

Clinical
Features 		CN
CNMF 		METHLYATION
CNMF 		RPPA
CNMF 		RPPA
CHIERARCHICAL 		MRNASEQ
CNMF 		MRNASEQ
CHIERARCHICAL 		MIRSEQ
CNMF 		MIRSEQ
CHIERARCHICAL 		MIRSEQ
MATURE
CNMF 		MIRSEQ
MATURE
CHIERARCHICAL
nCNV (%) 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
del 1p36 21 30 (83%) 6 0.0203
(0.333) 		0.00201
(0.116) 		0.109
(0.657) 		0.292
(0.723) 		0.019
(0.333) 		0.00838
(0.241) 		0.39
(0.797) 		0.131
(0.683) 		0.677
(0.915) 		0.151
(0.683)
del 6q13 21 (58%) 15 0.00801
(0.241) 		0.235
(0.722) 		0.45
(0.818) 		0.181
(0.683) 		0.272
(0.723) 		0.252
(0.723) 		0.758
(0.93) 		0.343
(0.766) 		0.176
(0.683) 		0.47
(0.818)
del 6q25 3 25 (69%) 11 0.00338
(0.155) 		0.0147
(0.333) 		0.11
(0.657) 		0.0817
(0.537) 		0.0554
(0.494) 		0.0615
(0.505) 		0.137
(0.683) 		0.182
(0.683) 		0.0769
(0.525) 		0.0356
(0.494)
del 14q22 1 14 (39%) 22 0.0388
(0.494) 		0.767
(0.934) 		0.246
(0.723) 		0.00757
(0.241) 		1
(1.00) 		0.12
(0.674) 		0.966
(1.00) 		0.973
(1.00) 		0.732
(0.93) 		0.411
(0.803)
del 14q32 12 20 (56%) 16 0.000242
(0.0185) 		0.0566
(0.494) 		0.268
(0.723) 		0.471
(0.818) 		0.913
(1.00) 		0.058
(0.494) 		0.967
(1.00) 		0.757
(0.93) 		0.175
(0.683) 		0.372
(0.785)
del 14q32 11 20 (56%) 16 0.000242
(0.0185) 		0.0554
(0.494) 		0.266
(0.723) 		0.471
(0.818) 		0.911
(1.00) 		0.0573
(0.494) 		0.967
(1.00) 		0.756
(0.93) 		0.175
(0.683) 		0.367
(0.785)
del 14q32 33 20 (56%) 16 0.000242
(0.0185) 		0.0551
(0.494) 		0.266
(0.723) 		0.472
(0.818) 		0.913
(1.00) 		0.0577
(0.494) 		0.966
(1.00) 		0.755
(0.93) 		0.175
(0.683) 		0.368
(0.785)
amp 1p22 3 15 (42%) 21 0.736
(0.93) 		0.233
(0.722) 		0.34
(0.766) 		0.74
(0.93) 		0.199
(0.683) 		0.0716
(0.515) 		0.167
(0.683) 		0.199
(0.683) 		0.736
(0.93) 		0.426
(0.803)
amp 1q22 24 (67%) 12 0.302
(0.723) 		0.292
(0.723) 		0.701
(0.916) 		0.742
(0.93) 		0.12
(0.674) 		0.351
(0.769) 		0.924
(1.00) 		0.407
(0.803) 		1
(1.00) 		0.687
(0.915)
amp 11q13 3 8 (22%) 28 1
(1.00) 		0.536
(0.818) 		0.152
(0.683) 		0.0188
(0.333) 		0.599
(0.894) 		0.0439
(0.494) 		0.297
(0.723) 		0.97
(1.00) 		0.694
(0.915) 		0.854
(0.983)
amp 12q13 2 10 (28%) 26 1
(1.00) 		0.804
(0.96) 		0.0646
(0.512) 		0.191
(0.683) 		0.805
(0.96) 		0.906
(1.00) 		0.263
(0.723) 		0.518
(0.818) 		0.26
(0.723) 		0.63
(0.905)
del 3p25 3 28 (78%) 8 0.0438
(0.494) 		0.538
(0.818) 		1
(1.00) 		0.39
(0.797) 		0.777
(0.941) 		0.0692
(0.513) 		0.419
(0.803) 		0.76
(0.93) 		0.424
(0.803) 		0.854
(0.983)
del 3p13 28 (78%) 8 0.0438
(0.494) 		0.284
(0.723) 		0.621
(0.901) 		0.372
(0.785) 		1
(1.00) 		0.287
(0.723) 		0.541
(0.818) 		0.242
(0.722) 		0.694
(0.915) 		0.992
(1.00)
del 4q34 3 23 (64%) 13 0.502
(0.818) 		0.475
(0.818) 		0.111
(0.657) 		0.167
(0.683) 		0.193
(0.683) 		0.329
(0.754) 		0.192
(0.683) 		0.482
(0.818) 		1
(1.00) 		0.536
(0.818)
del 5q13 3 8 (22%) 28 0.236
(0.722) 		0.168
(0.683) 		0.391
(0.797) 		0.302
(0.723) 		0.0254
(0.39) 		0.159
(0.683) 		0.855
(0.983) 		0.668
(0.915) 		0.694
(0.915) 		0.569
(0.856)
del 8p23 1 13 (36%) 23 0.502
(0.818) 		0.131
(0.683) 		0.527
(0.818) 		0.413
(0.803) 		0.0777
(0.525) 		0.0682
(0.513) 		0.612
(0.901) 		0.315
(0.738) 		0.31
(0.735) 		0.242
(0.722)
del 9p21 3 23 (64%) 13 0.502
(0.818) 		1
(1.00) 		0.81
(0.96) 		0.161
(0.683) 		0.683
(0.915) 		0.162
(0.683) 		0.173
(0.683) 		0.623
(0.901) 		0.159
(0.683) 		0.736
(0.93)
del 9q21 11 19 (53%) 17 0.525
(0.818) 		0.347
(0.768) 		0.259
(0.723) 		0.0113
(0.289) 		0.696
(0.915) 		0.187
(0.683) 		0.318
(0.738) 		0.427
(0.803) 		0.516
(0.818) 		0.517
(0.818)
del 10q26 12 12 (33%) 24 0.732
(0.93) 		0.203
(0.685) 		1
(1.00) 		0.808
(0.96) 		0.44
(0.809) 		0.684
(0.915) 		0.473
(0.818) 		0.215
(0.703) 		0.499
(0.818) 		0.225
(0.719)
del 11q25 13 (36%) 23 0.299
(0.723) 		0.914
(1.00) 		0.301
(0.723) 		0.0916
(0.585) 		0.211
(0.702) 		0.642
(0.915) 		0.815
(0.962) 		0.217
(0.703) 		0.484
(0.818) 		0.169
(0.683)
del 12q24 13 8 (22%) 28 0.434
(0.805) 		1
(1.00) 		1
(1.00) 		1
(1.00) 		0.47
(0.818) 		0.615
(0.901) 		0.54
(0.818) 		0.669
(0.915) 		0.424
(0.803) 		0.854
(0.983)
del 13q21 32 16 (44%) 20 1
(1.00) 		1
(1.00) 		0.527
(0.818) 		0.481
(0.818) 		0.833
(0.977) 		0.875
(1.00) 		0.62
(0.901) 		0.489
(0.818) 		1
(1.00) 		0.286
(0.723)
del 16q23 1 7 (19%) 29 0.684
(0.915) 		0.331
(0.754) 		0.391
(0.797) 		0.43
(0.803) 		0.665
(0.915) 		0.414
(0.803) 		0.658
(0.915) 		0.0192
(0.333) 		1
(1.00) 		0.663
(0.915)
'del_1p36.21' versus 'METHLYATION_CNMF'

P value = 0.00201 (Fisher's exact test), Q value = 0.12

Table S1.  Gene #5: 'del_1p36.21' versus Molecular Subtype #2: 'METHLYATION_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 13 10 13
DEL PEAK 1(1P36.21) MUTATED 7 10 13
DEL PEAK 1(1P36.21) WILD-TYPE 6 0 0

Figure S1.  Get High-res Image Gene #5: 'del_1p36.21' versus Molecular Subtype #2: 'METHLYATION_CNMF'

'del_1p36.21' versus 'MRNASEQ_CHIERARCHICAL'

P value = 0.00838 (Fisher's exact test), Q value = 0.24

Table S2.  Gene #5: 'del_1p36.21' versus Molecular Subtype #6: 'MRNASEQ_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3 CLUS_4 CLUS_5 CLUS_6 CLUS_7
ALL 4 5 5 9 6 5 2
DEL PEAK 1(1P36.21) MUTATED 1 4 4 9 6 5 1
DEL PEAK 1(1P36.21) WILD-TYPE 3 1 1 0 0 0 1

Figure S2.  Get High-res Image Gene #5: 'del_1p36.21' versus Molecular Subtype #6: 'MRNASEQ_CHIERARCHICAL'

'del_6q13' versus 'CN_CNMF'

P value = 0.00801 (Fisher's exact test), Q value = 0.24

Table S3.  Gene #10: 'del_6q13' versus Molecular Subtype #1: 'CN_CNMF'

nPatients CLUS_1 CLUS_2
ALL 19 17
DEL PEAK 6(6Q13) MUTATED 7 14
DEL PEAK 6(6Q13) WILD-TYPE 12 3

Figure S3.  Get High-res Image Gene #10: 'del_6q13' versus Molecular Subtype #1: 'CN_CNMF'

'del_6q25.3' versus 'CN_CNMF'

P value = 0.00338 (Fisher's exact test), Q value = 0.16

Table S4.  Gene #11: 'del_6q25.3' versus Molecular Subtype #1: 'CN_CNMF'

nPatients CLUS_1 CLUS_2
ALL 19 17
DEL PEAK 7(6Q25.3) MUTATED 9 16
DEL PEAK 7(6Q25.3) WILD-TYPE 10 1

Figure S4.  Get High-res Image Gene #11: 'del_6q25.3' versus Molecular Subtype #1: 'CN_CNMF'

'del_14q22.1' versus 'RPPA_CHIERARCHICAL'

P value = 0.00757 (Fisher's exact test), Q value = 0.24

Table S5.  Gene #19: 'del_14q22.1' versus Molecular Subtype #4: 'RPPA_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3 CLUS_4
ALL 6 7 8 9
DEL PEAK 15(14Q22.1) MUTATED 0 2 6 1
DEL PEAK 15(14Q22.1) WILD-TYPE 6 5 2 8

Figure S5.  Get High-res Image Gene #19: 'del_14q22.1' versus Molecular Subtype #4: 'RPPA_CHIERARCHICAL'

'del_14q32.12' versus 'CN_CNMF'

P value = 0.000242 (Fisher's exact test), Q value = 0.019

Table S6.  Gene #20: 'del_14q32.12' versus Molecular Subtype #1: 'CN_CNMF'

nPatients CLUS_1 CLUS_2
ALL 19 17
DEL PEAK 16(14Q32.12) MUTATED 5 15
DEL PEAK 16(14Q32.12) WILD-TYPE 14 2

Figure S6.  Get High-res Image Gene #20: 'del_14q32.12' versus Molecular Subtype #1: 'CN_CNMF'

'del_14q32.11' versus 'CN_CNMF'

P value = 0.000242 (Fisher's exact test), Q value = 0.019

Table S7.  Gene #21: 'del_14q32.11' versus Molecular Subtype #1: 'CN_CNMF'

nPatients CLUS_1 CLUS_2
ALL 19 17
DEL PEAK 17(14Q32.11) MUTATED 5 15
DEL PEAK 17(14Q32.11) WILD-TYPE 14 2

Figure S7.  Get High-res Image Gene #21: 'del_14q32.11' versus Molecular Subtype #1: 'CN_CNMF'

'del_14q32.33' versus 'CN_CNMF'

P value = 0.000242 (Fisher's exact test), Q value = 0.019

Table S8.  Gene #22: 'del_14q32.33' versus Molecular Subtype #1: 'CN_CNMF'

nPatients CLUS_1 CLUS_2
ALL 19 17
DEL PEAK 18(14Q32.33) MUTATED 5 15
DEL PEAK 18(14Q32.33) WILD-TYPE 14 2

Figure S8.  Get High-res Image Gene #22: 'del_14q32.33' versus Molecular Subtype #1: 'CN_CNMF'

Methods & Data
Input

  • Copy number data file = all_lesions.txt from GISTIC pipeline

  • Processed Copy number data file = /xchip/cga/gdac-prod/tcga-gdac/jobResults/GDAC_Correlate_Genomic_Events_Preprocess/CHOL-TP/19780559/transformed.cor.cli.txt

  • Molecular subtype file = /xchip/cga/gdac-prod/tcga-gdac/jobResults/GDAC_mergedClustering/CHOL-TP/20125181/CHOL-TP.transferedmergedcluster.txt

  • Number of patients = 36

  • Number of significantly focal cnvs = 23

  • Number of molecular subtypes = 10

  • Exclude genes that fewer than K tumors have alterations, 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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