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 16 genes and 12 molecular subtypes across 178 patients, 10 significant findings detected with P value < 0.05 and Q value < 0.25.

  • CDKN2A mutation correlated to 'MRNA_CNMF'.

  • TP53 mutation correlated to 'CN_CNMF',  'METHLYATION_CNMF', and 'MRNASEQ_CNMF'.

  • NFE2L2 mutation correlated to 'MRNA_CNMF',  'MRNA_CHIERARCHICAL',  'MRNASEQ_CNMF',  'MRNASEQ_CHIERARCHICAL', and 'MIRSEQ_CHIERARCHICAL'.

  • KEAP1 mutation correlated to 'MRNA_CHIERARCHICAL'.

Results
Overview of the results

Table 1.  Get Full Table Overview of the association between mutation status of 16 genes and 12 molecular subtypes. Shown in the table are P values (Q values). Thresholded by P value < 0.05 and Q value < 0.25, 10 significant findings detected.

Clinical
Features 		MRNA
CNMF 		MRNA
CHIERARCHICAL 		CN
CNMF 		METHLYATION
CNMF 		RPPA
CNMF 		RPPA
CHIERARCHICAL 		MRNASEQ
CNMF 		MRNASEQ
CHIERARCHICAL 		MIRSEQ
CNMF 		MIRSEQ
CHIERARCHICAL 		MIRSEQ
MATURE
CNMF 		MIRSEQ
MATURE
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 Fisher's exact test Fisher's exact test Fisher's exact test Fisher's exact test
NFE2L2 27 (15%) 151 0.00024
(0.0415) 		0.00073
(0.126) 		0.0194
(1.00) 		0.0365
(1.00) 		0.253
(1.00) 		0.144
(1.00) 		3.23e-06
(0.000569) 		1.36e-06
(0.000243) 		0.0289
(1.00) 		1.75e-06
(0.000309) 		0.589
(1.00) 		0.14
(1.00)
TP53 141 (79%) 37 0.0449
(1.00) 		0.038
(1.00) 		4.15e-05
(0.00726) 		0.0014
(0.238) 		1
(1.00) 		0.902
(1.00) 		0.000841
(0.144) 		0.0131
(1.00) 		0.136
(1.00) 		0.519
(1.00) 		0.824
(1.00) 		0.726
(1.00)
CDKN2A 26 (15%) 152 0.00141
(0.239) 		0.0482
(1.00) 		0.0119
(1.00) 		0.668
(1.00) 		0.34
(1.00) 		0.204
(1.00) 		0.353
(1.00) 		0.667
(1.00) 		0.783
(1.00) 		1
(1.00) 		1
(1.00) 		0.0993
(1.00)
KEAP1 22 (12%) 156 0.0015
(0.251) 		0.000229
(0.0398) 		0.122
(1.00) 		0.0758
(1.00) 		0.204
(1.00) 		0.0963
(1.00) 		0.159
(1.00) 		0.0438
(1.00) 		0.699
(1.00) 		0.823
(1.00) 		0.00504
(0.842) 		0.61
(1.00)
PIK3CA 27 (15%) 151 0.69
(1.00) 		0.597
(1.00) 		0.258
(1.00) 		0.545
(1.00) 		1
(1.00) 		0.709
(1.00) 		0.365
(1.00) 		0.891
(1.00) 		0.614
(1.00) 		0.739
(1.00) 		0.456
(1.00) 		0.726
(1.00)
PTEN 14 (8%) 164 0.381
(1.00) 		0.448
(1.00) 		0.226
(1.00) 		0.134
(1.00) 		0.721
(1.00) 		0.473
(1.00) 		0.636
(1.00) 		0.146
(1.00) 		0.574
(1.00) 		0.43
(1.00) 		0.357
(1.00) 		1
(1.00)
CSMD3 81 (46%) 97 0.323
(1.00) 		0.931
(1.00) 		0.738
(1.00) 		0.508
(1.00) 		0.265
(1.00) 		0.769
(1.00) 		0.529
(1.00) 		0.816
(1.00) 		0.664
(1.00) 		1
(1.00) 		0.419
(1.00) 		0.164
(1.00)
MLL2 36 (20%) 142 0.301
(1.00) 		0.926
(1.00) 		0.485
(1.00) 		0.314
(1.00) 		0.696
(1.00) 		0.22
(1.00) 		0.442
(1.00) 		0.625
(1.00) 		0.986
(1.00) 		0.6
(1.00) 		0.614
(1.00) 		1
(1.00)
FBXW7 11 (6%) 167 0.493
(1.00) 		0.946
(1.00) 		0.925
(1.00) 		0.621
(1.00) 		0.785
(1.00) 		0.899
(1.00) 		0.718
(1.00) 		1
(1.00) 		0.797
(1.00) 		0.49
(1.00)
RB1 12 (7%) 166 0.314
(1.00) 		0.189
(1.00) 		0.807
(1.00) 		0.108
(1.00) 		0.657
(1.00) 		0.433
(1.00) 		1
(1.00) 		0.354
(1.00) 		0.574
(1.00) 		0.911
(1.00) 		1
(1.00)
HS6ST1 5 (3%) 173 0.276
(1.00) 		0.294
(1.00) 		0.538
(1.00) 		0.572
(1.00) 		0.078
(1.00) 		1
(1.00) 		1
(1.00)
ZNF567 3 (2%) 175 0.358
(1.00) 		0.359
(1.00) 		0.424
(1.00) 		0.45
(1.00) 		0.427
(1.00) 		0.25
(1.00) 		0.188
(1.00) 		1
(1.00)
ELTD1 18 (10%) 160 0.0382
(1.00) 		0.324
(1.00) 		0.0744
(1.00) 		0.6
(1.00) 		0.341
(1.00) 		0.648
(1.00) 		0.578
(1.00) 		0.434
(1.00) 		0.0916
(1.00) 		0.721
(1.00) 		0.305
(1.00) 		0.419
(1.00)
ASCL4 6 (3%) 172 0.0969
(1.00) 		0.534
(1.00) 		1
(1.00) 		0.783
(1.00) 		0.817
(1.00) 		0.835
(1.00) 		0.318
(1.00) 		0.245
(1.00) 		0.909
(1.00) 		0.216
(1.00)
OR2G6 16 (9%) 162 0.381
(1.00) 		0.23
(1.00) 		0.847
(1.00) 		1
(1.00) 		1
(1.00) 		0.717
(1.00) 		0.185
(1.00) 		0.0446
(1.00) 		0.406
(1.00) 		0.244
(1.00) 		0.668
(1.00) 		0.61
(1.00)
NOTCH1 14 (8%) 164 0.817
(1.00) 		0.92
(1.00) 		0.463
(1.00) 		0.0342
(1.00) 		0.591
(1.00) 		0.824
(1.00) 		0.678
(1.00) 		0.407
(1.00) 		0.183
(1.00) 		0.843
(1.00) 		0.483
(1.00) 		0.668
(1.00)
'CDKN2A MUTATION STATUS' versus 'MRNA_CNMF'

P value = 0.00141 (Fisher's exact test), Q value = 0.24

Table S1.  Gene #1: 'CDKN2A MUTATION STATUS' versus Clinical Feature #1: 'MRNA_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3 CLUS_4
ALL 37 48 17 19
CDKN2A MUTATED 0 13 3 2
CDKN2A WILD-TYPE 37 35 14 17

Figure S1.  Get High-res Image Gene #1: 'CDKN2A MUTATION STATUS' versus Clinical Feature #1: 'MRNA_CNMF'

'TP53 MUTATION STATUS' versus 'CN_CNMF'

P value = 4.15e-05 (Fisher's exact test), Q value = 0.0073

Table S2.  Gene #2: 'TP53 MUTATION STATUS' versus Clinical Feature #3: 'CN_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 64 69 45
TP53 MUTATED 39 63 39
TP53 WILD-TYPE 25 6 6

Figure S2.  Get High-res Image Gene #2: 'TP53 MUTATION STATUS' versus Clinical Feature #3: 'CN_CNMF'

'TP53 MUTATION STATUS' versus 'METHLYATION_CNMF'

P value = 0.0014 (Fisher's exact test), Q value = 0.24

Table S3.  Gene #2: 'TP53 MUTATION STATUS' versus Clinical Feature #4: 'METHLYATION_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 27 29 18
TP53 MUTATED 16 28 15
TP53 WILD-TYPE 11 1 3

Figure S3.  Get High-res Image Gene #2: 'TP53 MUTATION STATUS' versus Clinical Feature #4: 'METHLYATION_CNMF'

'TP53 MUTATION STATUS' versus 'MRNASEQ_CNMF'

P value = 0.000841 (Fisher's exact test), Q value = 0.14

Table S4.  Gene #2: 'TP53 MUTATION STATUS' versus Clinical Feature #7: 'MRNASEQ_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3 CLUS_4
ALL 42 61 49 26
TP53 MUTATED 33 55 40 13
TP53 WILD-TYPE 9 6 9 13

Figure S4.  Get High-res Image Gene #2: 'TP53 MUTATION STATUS' versus Clinical Feature #7: 'MRNASEQ_CNMF'

'NFE2L2 MUTATION STATUS' versus 'MRNA_CNMF'

P value = 0.00024 (Fisher's exact test), Q value = 0.041

Table S5.  Gene #3: 'NFE2L2 MUTATION STATUS' versus Clinical Feature #1: 'MRNA_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3 CLUS_4
ALL 37 48 17 19
NFE2L2 MUTATED 0 14 1 1
NFE2L2 WILD-TYPE 37 34 16 18

Figure S5.  Get High-res Image Gene #3: 'NFE2L2 MUTATION STATUS' versus Clinical Feature #1: 'MRNA_CNMF'

'NFE2L2 MUTATION STATUS' versus 'MRNA_CHIERARCHICAL'

P value = 0.00073 (Fisher's exact test), Q value = 0.13

Table S6.  Gene #3: 'NFE2L2 MUTATION STATUS' versus Clinical Feature #2: 'MRNA_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3 CLUS_4
ALL 7 52 20 42
NFE2L2 MUTATED 1 14 0 1
NFE2L2 WILD-TYPE 6 38 20 41

Figure S6.  Get High-res Image Gene #3: 'NFE2L2 MUTATION STATUS' versus Clinical Feature #2: 'MRNA_CHIERARCHICAL'

'NFE2L2 MUTATION STATUS' versus 'MRNASEQ_CNMF'

P value = 3.23e-06 (Fisher's exact test), Q value = 0.00057

Table S7.  Gene #3: 'NFE2L2 MUTATION STATUS' versus Clinical Feature #7: 'MRNASEQ_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3 CLUS_4
ALL 42 61 49 26
NFE2L2 MUTATED 2 21 1 3
NFE2L2 WILD-TYPE 40 40 48 23

Figure S7.  Get High-res Image Gene #3: 'NFE2L2 MUTATION STATUS' versus Clinical Feature #7: 'MRNASEQ_CNMF'

'NFE2L2 MUTATION STATUS' versus 'MRNASEQ_CHIERARCHICAL'

P value = 1.36e-06 (Fisher's exact test), Q value = 0.00024

Table S8.  Gene #3: 'NFE2L2 MUTATION STATUS' versus Clinical Feature #8: 'MRNASEQ_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 34 60 84
NFE2L2 MUTATED 1 21 5
NFE2L2 WILD-TYPE 33 39 79

Figure S8.  Get High-res Image Gene #3: 'NFE2L2 MUTATION STATUS' versus Clinical Feature #8: 'MRNASEQ_CHIERARCHICAL'

'NFE2L2 MUTATION STATUS' versus 'MIRSEQ_CHIERARCHICAL'

P value = 1.75e-06 (Fisher's exact test), Q value = 0.00031

Table S9.  Gene #3: 'NFE2L2 MUTATION STATUS' versus Clinical Feature #10: 'MIRSEQ_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 30 32 100
NFE2L2 MUTATED 14 0 12
NFE2L2 WILD-TYPE 16 32 88

Figure S9.  Get High-res Image Gene #3: 'NFE2L2 MUTATION STATUS' versus Clinical Feature #10: 'MIRSEQ_CHIERARCHICAL'

'KEAP1 MUTATION STATUS' versus 'MRNA_CHIERARCHICAL'

P value = 0.000229 (Fisher's exact test), Q value = 0.04

Table S10.  Gene #6: 'KEAP1 MUTATION STATUS' versus Clinical Feature #2: 'MRNA_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3 CLUS_4
ALL 7 52 20 42
KEAP1 MUTATED 3 13 0 1
KEAP1 WILD-TYPE 4 39 20 41

Figure S10.  Get High-res Image Gene #6: 'KEAP1 MUTATION STATUS' versus Clinical Feature #2: 'MRNA_CHIERARCHICAL'

Methods & Data
Input

  • Mutation data file = LUSC-TP.mutsig.cluster.txt

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

  • Number of patients = 178

  • Number of significantly mutated genes = 16

  • Number of Molecular subtypes = 12

  • 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)
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