Correlation between gene mutation status and molecular subtypes
Overview
Introduction

This pipeline computes the correlation between significantly recurrent gene mutations and molecular subtypes.

Summary

Testing the association between mutation status of 41 genes and 8 molecular subtypes across 323 patients, 20 significant findings detected with P value < 0.05 and Q value < 0.25.

  • BRAF mutation correlated to 'METHLYATION_CNMF',  'RPPA_CNMF',  'RPPA_CHIERARCHICAL',  'MRNASEQ_CNMF',  'MRNASEQ_CHIERARCHICAL',  'MIRSEQ_CNMF', and 'MIRSEQ_CHIERARCHICAL'.

  • HRAS mutation correlated to 'CN_CNMF',  'METHLYATION_CNMF',  'RPPA_CNMF',  'MRNASEQ_CNMF',  'MRNASEQ_CHIERARCHICAL',  'MIRSEQ_CNMF', and 'MIRSEQ_CHIERARCHICAL'.

  • NRAS mutation correlated to 'METHLYATION_CNMF',  'RPPA_CHIERARCHICAL',  'MRNASEQ_CNMF',  'MRNASEQ_CHIERARCHICAL',  'MIRSEQ_CNMF', and 'MIRSEQ_CHIERARCHICAL'.

Results
Overview of the results

Table 1.  Get Full Table Overview of the association between mutation status of 41 genes and 8 molecular subtypes. Shown in the table are P values (Q values). Thresholded by P value < 0.05 and Q value < 0.25, 20 significant findings detected.

Clinical
Features
CN
CNMF
METHLYATION
CNMF
RPPA
CNMF
RPPA
CHIERARCHICAL
MRNASEQ
CNMF
MRNASEQ
CHIERARCHICAL
MIRSEQ
CNMF
MIRSEQ
CHIERARCHICAL
nMutated (%) 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
BRAF 183 (57%) 140 0.0194
(1.00)
3.62e-38
(9.99e-36)
9.4e-07
(0.000252)
2.51e-11
(6.84e-09)
4.03e-46
(1.13e-43)
1.56e-39
(4.31e-37)
9.88e-42
(2.75e-39)
1.03e-43
(2.86e-41)
HRAS 12 (4%) 311 0.000222
(0.0582)
1.48e-06
(0.000393)
9.23e-05
(0.0243)
0.00529
(1.00)
1.37e-05
(0.00362)
6.79e-06
(0.0018)
1.31e-06
(0.00035)
3.85e-07
(0.000104)
NRAS 26 (8%) 297 0.00692
(1.00)
6.06e-14
(1.67e-11)
1
(1.00)
0.000583
(0.152)
4.7e-11
(1.27e-08)
4.03e-11
(1.09e-08)
9.19e-13
(2.51e-10)
2.47e-13
(6.78e-11)
EMG1 6 (2%) 317 0.548
(1.00)
1
(1.00)
0.327
(1.00)
0.0846
(1.00)
1
(1.00)
1
(1.00)
1
(1.00)
0.778
(1.00)
PTTG1IP 4 (1%) 319 1
(1.00)
1
(1.00)
0.242
(1.00)
0.252
(1.00)
0.469
(1.00)
0.393
(1.00)
RPTN 8 (2%) 315 0.805
(1.00)
0.442
(1.00)
0.265
(1.00)
0.801
(1.00)
0.0249
(1.00)
0.415
(1.00)
0.82
(1.00)
0.666
(1.00)
EIF1AX 5 (2%) 318 0.731
(1.00)
0.0278
(1.00)
0.444
(1.00)
0.132
(1.00)
0.0621
(1.00)
0.0109
(1.00)
0.0581
(1.00)
0.236
(1.00)
CCDC15 5 (2%) 318 0.731
(1.00)
0.115
(1.00)
1
(1.00)
0.381
(1.00)
0.132
(1.00)
0.136
(1.00)
0.63
(1.00)
0.53
(1.00)
ZNF845 6 (2%) 317 0.42
(1.00)
0.637
(1.00)
0.639
(1.00)
0.125
(1.00)
0.943
(1.00)
0.166
(1.00)
0.777
(1.00)
0.328
(1.00)
ZNF878 4 (1%) 319 1
(1.00)
0.487
(1.00)
0.0454
(1.00)
0.833
(1.00)
0.691
(1.00)
1
(1.00)
TG 16 (5%) 307 1
(1.00)
0.0205
(1.00)
0.34
(1.00)
0.492
(1.00)
0.406
(1.00)
0.293
(1.00)
0.0452
(1.00)
0.0253
(1.00)
PRB2 6 (2%) 317 1
(1.00)
0.637
(1.00)
0.0801
(1.00)
0.851
(1.00)
0.474
(1.00)
0.723
(1.00)
0.522
(1.00)
0.598
(1.00)
R3HDM2 4 (1%) 319 0.0124
(1.00)
0.063
(1.00)
0.0699
(1.00)
0.0388
(1.00)
0.0191
(1.00)
0.00822
(1.00)
IL32 3 (1%) 320 1
(1.00)
0.742
(1.00)
1
(1.00)
0.78
(1.00)
0.202
(1.00)
0.645
(1.00)
TMCO2 3 (1%) 320 1
(1.00)
0.416
(1.00)
0.778
(1.00)
0.2
(1.00)
0.492
(1.00)
0.303
(1.00)
0.401
(1.00)
0.778
(1.00)
PPTC7 3 (1%) 320 0.0791
(1.00)
0.0627
(1.00)
0.172
(1.00)
0.0916
(1.00)
0.299
(1.00)
0.403
(1.00)
MUC7 5 (2%) 318 0.731
(1.00)
0.372
(1.00)
0.683
(1.00)
0.26
(1.00)
0.805
(1.00)
0.848
(1.00)
0.866
(1.00)
0.629
(1.00)
LYPD3 3 (1%) 320 0.547
(1.00)
0.416
(1.00)
0.492
(1.00)
0.303
(1.00)
0.644
(1.00)
0.778
(1.00)
TMEM90B 3 (1%) 320 0.135
(1.00)
1
(1.00)
1
(1.00)
0.78
(1.00)
1
(1.00)
1
(1.00)
ZNF799 5 (2%) 318 0.465
(1.00)
1
(1.00)
0.505
(1.00)
1
(1.00)
0.592
(1.00)
0.848
(1.00)
0.451
(1.00)
1
(1.00)
PPM1D 5 (2%) 318 1
(1.00)
1
(1.00)
0.778
(1.00)
0.125
(1.00)
0.693
(1.00)
0.848
(1.00)
0.866
(1.00)
0.329
(1.00)
MAP3K3 4 (1%) 319 0.061
(1.00)
0.224
(1.00)
0.459
(1.00)
0.0846
(1.00)
0.274
(1.00)
0.184
(1.00)
0.469
(1.00)
0.555
(1.00)
TROAP 3 (1%) 320 1
(1.00)
0.742
(1.00)
0.778
(1.00)
0.535
(1.00)
0.746
(1.00)
1
(1.00)
0.519
(1.00)
0.403
(1.00)
SYNPO2L 3 (1%) 320 0.547
(1.00)
1
(1.00)
1
(1.00)
0.78
(1.00)
1
(1.00)
1
(1.00)
ATAD2 4 (1%) 319 1
(1.00)
0.823
(1.00)
0.808
(1.00)
1
(1.00)
0.691
(1.00)
1
(1.00)
KRAS 3 (1%) 320 1
(1.00)
0.0627
(1.00)
0.172
(1.00)
0.0916
(1.00)
0.0616
(1.00)
0.0276
(1.00)
SLC5A11 3 (1%) 320 0.547
(1.00)
0.742
(1.00)
0.299
(1.00)
0.403
(1.00)
PRG4 4 (1%) 319 0.23
(1.00)
0.104
(1.00)
0.0128
(1.00)
0.142
(1.00)
0.469
(1.00)
0.555
(1.00)
SCUBE2 3 (1%) 320 1
(1.00)
0.281
(1.00)
0.314
(1.00)
0.303
(1.00)
0.644
(1.00)
0.522
(1.00)
ZNF479 3 (1%) 320 1
(1.00)
0.742
(1.00)
1
(1.00)
0.78
(1.00)
0.519
(1.00)
1
(1.00)
SREBF2 3 (1%) 320 1
(1.00)
0.742
(1.00)
0.568
(1.00)
1
(1.00)
0.401
(1.00)
0.778
(1.00)
SLC26A11 3 (1%) 320 0.0791
(1.00)
1
(1.00)
0.368
(1.00)
0.78
(1.00)
0.778
(1.00)
0.301
(1.00)
TSC22D1 3 (1%) 320 1
(1.00)
1
(1.00)
0.746
(1.00)
1
(1.00)
0.778
(1.00)
0.645
(1.00)
ANKRD30A 5 (2%) 318 0.731
(1.00)
0.462
(1.00)
0.749
(1.00)
0.507
(1.00)
0.74
(1.00)
0.865
(1.00)
FAM155A 4 (1%) 319 0.144
(1.00)
0.156
(1.00)
0.778
(1.00)
0.535
(1.00)
0.0372
(1.00)
0.555
(1.00)
SLA 3 (1%) 320 0.547
(1.00)
0.0627
(1.00)
0.286
(1.00)
0.285
(1.00)
0.172
(1.00)
0.0916
(1.00)
0.0616
(1.00)
0.0276
(1.00)
ZFHX3 10 (3%) 313 0.171
(1.00)
0.616
(1.00)
0.48
(1.00)
0.632
(1.00)
0.794
(1.00)
0.437
(1.00)
0.613
(1.00)
0.723
(1.00)
ARMCX3 3 (1%) 320 0.547
(1.00)
0.742
(1.00)
0.646
(1.00)
0.213
(1.00)
0.519
(1.00)
0.202
(1.00)
SLC25A45 3 (1%) 320 0.135
(1.00)
1
(1.00)
0.202
(1.00)
0.403
(1.00)
COL5A3 6 (2%) 317 0.752
(1.00)
0.317
(1.00)
0.778
(1.00)
0.758
(1.00)
0.044
(1.00)
0.753
(1.00)
0.877
(1.00)
0.523
(1.00)
CDC27 3 (1%) 320 1
(1.00)
1
(1.00)
0.368
(1.00)
0.0446
(1.00)
0.778
(1.00)
0.301
(1.00)
'BRAF MUTATION STATUS' versus 'METHLYATION_CNMF'

P value = 3.62e-38 (Fisher's exact test), Q value = 1e-35

Table S1.  Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #2: 'METHLYATION_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 105 52 166
BRAF MUTATED 10 30 143
BRAF WILD-TYPE 95 22 23

Figure S1.  Get High-res Image Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #2: 'METHLYATION_CNMF'

'BRAF MUTATION STATUS' versus 'RPPA_CNMF'

P value = 9.4e-07 (Fisher's exact test), Q value = 0.00025

Table S2.  Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #3: 'RPPA_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 62 76 79
BRAF MUTATED 19 57 42
BRAF WILD-TYPE 43 19 37

Figure S2.  Get High-res Image Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #3: 'RPPA_CNMF'

'BRAF MUTATION STATUS' versus 'RPPA_CHIERARCHICAL'

P value = 2.51e-11 (Fisher's exact test), Q value = 6.8e-09

Table S3.  Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #4: 'RPPA_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 96 32 89
BRAF MUTATED 30 16 72
BRAF WILD-TYPE 66 16 17

Figure S3.  Get High-res Image Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #4: 'RPPA_CHIERARCHICAL'

'BRAF MUTATION STATUS' versus 'MRNASEQ_CNMF'

P value = 4.03e-46 (Fisher's exact test), Q value = 1.1e-43

Table S4.  Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #5: 'MRNASEQ_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3 CLUS_4
ALL 102 36 70 95
BRAF MUTATED 6 20 57 90
BRAF WILD-TYPE 96 16 13 5

Figure S4.  Get High-res Image Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #5: 'MRNASEQ_CNMF'

'BRAF MUTATION STATUS' versus 'MRNASEQ_CHIERARCHICAL'

P value = 1.56e-39 (Fisher's exact test), Q value = 4.3e-37

Table S5.  Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #6: 'MRNASEQ_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 110 136 57
BRAF MUTATED 11 120 42
BRAF WILD-TYPE 99 16 15

Figure S5.  Get High-res Image Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #6: 'MRNASEQ_CHIERARCHICAL'

'BRAF MUTATION STATUS' versus 'MIRSEQ_CNMF'

P value = 9.88e-42 (Fisher's exact test), Q value = 2.7e-39

Table S6.  Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #7: 'MIRSEQ_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 105 119 98
BRAF MUTATED 6 103 73
BRAF WILD-TYPE 99 16 25

Figure S6.  Get High-res Image Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #7: 'MIRSEQ_CNMF'

'BRAF MUTATION STATUS' versus 'MIRSEQ_CHIERARCHICAL'

P value = 1.03e-43 (Fisher's exact test), Q value = 2.9e-41

Table S7.  Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #8: 'MIRSEQ_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 118 106 98
BRAF MUTATED 94 86 2
BRAF WILD-TYPE 24 20 96

Figure S7.  Get High-res Image Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #8: 'MIRSEQ_CHIERARCHICAL'

'HRAS MUTATION STATUS' versus 'CN_CNMF'

P value = 0.000222 (Fisher's exact test), Q value = 0.058

Table S8.  Gene #3: 'HRAS MUTATION STATUS' versus Clinical Feature #1: 'CN_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 25 246 49
HRAS MUTATED 0 4 8
HRAS WILD-TYPE 25 242 41

Figure S8.  Get High-res Image Gene #3: 'HRAS MUTATION STATUS' versus Clinical Feature #1: 'CN_CNMF'

'HRAS MUTATION STATUS' versus 'METHLYATION_CNMF'

P value = 1.48e-06 (Fisher's exact test), Q value = 0.00039

Table S9.  Gene #3: 'HRAS MUTATION STATUS' versus Clinical Feature #2: 'METHLYATION_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 105 52 166
HRAS MUTATED 12 0 0
HRAS WILD-TYPE 93 52 166

Figure S9.  Get High-res Image Gene #3: 'HRAS MUTATION STATUS' versus Clinical Feature #2: 'METHLYATION_CNMF'

'HRAS MUTATION STATUS' versus 'RPPA_CNMF'

P value = 9.23e-05 (Fisher's exact test), Q value = 0.024

Table S10.  Gene #3: 'HRAS MUTATION STATUS' versus Clinical Feature #3: 'RPPA_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 62 76 79
HRAS MUTATED 9 2 0
HRAS WILD-TYPE 53 74 79

Figure S10.  Get High-res Image Gene #3: 'HRAS MUTATION STATUS' versus Clinical Feature #3: 'RPPA_CNMF'

'HRAS MUTATION STATUS' versus 'MRNASEQ_CNMF'

P value = 1.37e-05 (Fisher's exact test), Q value = 0.0036

Table S11.  Gene #3: 'HRAS MUTATION STATUS' versus Clinical Feature #5: 'MRNASEQ_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3 CLUS_4
ALL 102 36 70 95
HRAS MUTATED 12 0 0 0
HRAS WILD-TYPE 90 36 70 95

Figure S11.  Get High-res Image Gene #3: 'HRAS MUTATION STATUS' versus Clinical Feature #5: 'MRNASEQ_CNMF'

'HRAS MUTATION STATUS' versus 'MRNASEQ_CHIERARCHICAL'

P value = 6.79e-06 (Fisher's exact test), Q value = 0.0018

Table S12.  Gene #3: 'HRAS MUTATION STATUS' versus Clinical Feature #6: 'MRNASEQ_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 110 136 57
HRAS MUTATED 12 0 0
HRAS WILD-TYPE 98 136 57

Figure S12.  Get High-res Image Gene #3: 'HRAS MUTATION STATUS' versus Clinical Feature #6: 'MRNASEQ_CHIERARCHICAL'

'HRAS MUTATION STATUS' versus 'MIRSEQ_CNMF'

P value = 1.31e-06 (Fisher's exact test), Q value = 0.00035

Table S13.  Gene #3: 'HRAS MUTATION STATUS' versus Clinical Feature #7: 'MIRSEQ_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 105 119 98
HRAS MUTATED 12 0 0
HRAS WILD-TYPE 93 119 98

Figure S13.  Get High-res Image Gene #3: 'HRAS MUTATION STATUS' versus Clinical Feature #7: 'MIRSEQ_CNMF'

'HRAS MUTATION STATUS' versus 'MIRSEQ_CHIERARCHICAL'

P value = 3.85e-07 (Fisher's exact test), Q value = 1e-04

Table S14.  Gene #3: 'HRAS MUTATION STATUS' versus Clinical Feature #8: 'MIRSEQ_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 118 106 98
HRAS MUTATED 0 0 12
HRAS WILD-TYPE 118 106 86

Figure S14.  Get High-res Image Gene #3: 'HRAS MUTATION STATUS' versus Clinical Feature #8: 'MIRSEQ_CHIERARCHICAL'

'NRAS MUTATION STATUS' versus 'METHLYATION_CNMF'

P value = 6.06e-14 (Fisher's exact test), Q value = 1.7e-11

Table S15.  Gene #4: 'NRAS MUTATION STATUS' versus Clinical Feature #2: 'METHLYATION_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 105 52 166
NRAS MUTATED 26 0 0
NRAS WILD-TYPE 79 52 166

Figure S15.  Get High-res Image Gene #4: 'NRAS MUTATION STATUS' versus Clinical Feature #2: 'METHLYATION_CNMF'

'NRAS MUTATION STATUS' versus 'RPPA_CHIERARCHICAL'

P value = 0.000583 (Fisher's exact test), Q value = 0.15

Table S16.  Gene #4: 'NRAS MUTATION STATUS' versus Clinical Feature #4: 'RPPA_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 96 32 89
NRAS MUTATED 9 5 0
NRAS WILD-TYPE 87 27 89

Figure S16.  Get High-res Image Gene #4: 'NRAS MUTATION STATUS' versus Clinical Feature #4: 'RPPA_CHIERARCHICAL'

'NRAS MUTATION STATUS' versus 'MRNASEQ_CNMF'

P value = 4.7e-11 (Fisher's exact test), Q value = 1.3e-08

Table S17.  Gene #4: 'NRAS MUTATION STATUS' versus Clinical Feature #5: 'MRNASEQ_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3 CLUS_4
ALL 102 36 70 95
NRAS MUTATED 23 0 0 0
NRAS WILD-TYPE 79 36 70 95

Figure S17.  Get High-res Image Gene #4: 'NRAS MUTATION STATUS' versus Clinical Feature #5: 'MRNASEQ_CNMF'

'NRAS MUTATION STATUS' versus 'MRNASEQ_CHIERARCHICAL'

P value = 4.03e-11 (Fisher's exact test), Q value = 1.1e-08

Table S18.  Gene #4: 'NRAS MUTATION STATUS' versus Clinical Feature #6: 'MRNASEQ_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 110 136 57
NRAS MUTATED 23 0 0
NRAS WILD-TYPE 87 136 57

Figure S18.  Get High-res Image Gene #4: 'NRAS MUTATION STATUS' versus Clinical Feature #6: 'MRNASEQ_CHIERARCHICAL'

'NRAS MUTATION STATUS' versus 'MIRSEQ_CNMF'

P value = 9.19e-13 (Fisher's exact test), Q value = 2.5e-10

Table S19.  Gene #4: 'NRAS MUTATION STATUS' versus Clinical Feature #7: 'MIRSEQ_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 105 119 98
NRAS MUTATED 25 0 1
NRAS WILD-TYPE 80 119 97

Figure S19.  Get High-res Image Gene #4: 'NRAS MUTATION STATUS' versus Clinical Feature #7: 'MIRSEQ_CNMF'

'NRAS MUTATION STATUS' versus 'MIRSEQ_CHIERARCHICAL'

P value = 2.47e-13 (Fisher's exact test), Q value = 6.8e-11

Table S20.  Gene #4: 'NRAS MUTATION STATUS' versus Clinical Feature #8: 'MIRSEQ_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 118 106 98
NRAS MUTATED 1 0 25
NRAS WILD-TYPE 117 106 73

Figure S20.  Get High-res Image Gene #4: 'NRAS MUTATION STATUS' versus Clinical Feature #8: 'MIRSEQ_CHIERARCHICAL'

Methods & Data
Input
  • Mutation data file = THCA-TP.mutsig.cluster.txt

  • Molecular subtypes file = THCA-TP.transferedmergedcluster.txt

  • Number of patients = 323

  • Number of significantly mutated genes = 41

  • Number of Molecular subtypes = 8

  • Exclude genes that fewer than K tumors have mutations, 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)