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 3 genes and 9 molecular subtypes across 69 patients, 4 significant findings detected with P value < 0.05 and Q value < 0.25.

  • KRAS mutation correlated to 'MRNA_CHIERARCHICAL' and 'CN_CNMF'.

  • TP53 mutation correlated to 'MRNA_CNMF' and 'MRNA_CHIERARCHICAL'.

Results
Overview of the results

Table 1.  Get Full Table Overview of the association between mutation status of 3 genes and 9 molecular subtypes. Shown in the table are P values (Q values). Thresholded by P value < 0.05 and Q value < 0.25, 4 significant findings detected.

Clinical
Features 		MRNA
CNMF 		MRNA
CHIERARCHICAL 		CN
CNMF 		RPPA
CNMF 		RPPA
CHIERARCHICAL 		MRNASEQ
CNMF 		MRNASEQ
CHIERARCHICAL 		MIRSEQ
CNMF 		MIRSEQ
CHIERARCHICAL
nMutated (%) nWild-Type Fisher's exact test Fisher's exact test Chi-square test Fisher's exact test Chi-square test Fisher's exact test Fisher's exact test Fisher's exact test Fisher's exact test
KRAS 38 (55%) 31 0.262
(1.00) 		0.00629
(0.151) 		0.00169
(0.0439) 		0.78
(1.00) 		0.817
(1.00) 		0.0269
(0.619) 		1
(1.00) 		0.292
(1.00) 		0.0465
(1.00)
TP53 45 (65%) 24 0.000442
(0.0119) 		0.00311
(0.0777) 		0.348
(1.00) 		0.167
(1.00) 		0.603
(1.00) 		0.177
(1.00) 		0.755
(1.00) 		0.812
(1.00) 		0.288
(1.00)
APC 57 (83%) 12 0.568
(1.00) 		0.849
(1.00) 		0.227
(1.00) 		0.362
(1.00) 		0.598
(1.00) 		1
(1.00) 		0.27
(1.00) 		0.337
(1.00) 		1
(1.00)
'APC MUTATION STATUS' versus 'MRNA_CNMF'

P value = 0.568 (Fisher's exact test), Q value = 1

Table S1.  Gene #1: 'APC MUTATION STATUS' versus Molecular Subtype #1: 'MRNA_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 24 21 19
APC MUTATED 19 16 17
APC WILD-TYPE 5 5 2
'APC MUTATION STATUS' versus 'MRNA_CHIERARCHICAL'

P value = 0.849 (Fisher's exact test), Q value = 1

Table S2.  Gene #1: 'APC MUTATION STATUS' versus Molecular Subtype #2: 'MRNA_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 23 26 15
APC MUTATED 18 22 12
APC WILD-TYPE 5 4 3
'APC MUTATION STATUS' versus 'CN_CNMF'

P value = 0.227 (Chi-square test), Q value = 1

Table S3.  Gene #1: 'APC MUTATION STATUS' versus Molecular Subtype #3: 'CN_CNMF'

nPatients CLUS_2 CLUS_3 CLUS_4 CLUS_5 CLUS_6
ALL 17 18 17 11 5
APC MUTATED 11 16 15 9 5
APC WILD-TYPE 6 2 2 2 0
'APC MUTATION STATUS' versus 'RPPA_CNMF'

P value = 0.362 (Fisher's exact test), Q value = 1

Table S4.  Gene #1: 'APC MUTATION STATUS' versus Molecular Subtype #4: 'RPPA_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 16 14 23
APC MUTATED 11 12 20
APC WILD-TYPE 5 2 3
'APC MUTATION STATUS' versus 'RPPA_CHIERARCHICAL'

P value = 0.598 (Chi-square test), Q value = 1

Table S5.  Gene #1: 'APC MUTATION STATUS' versus Molecular Subtype #5: 'RPPA_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3 CLUS_4 CLUS_5
ALL 2 4 12 21 14
APC MUTATED 1 3 11 16 12
APC WILD-TYPE 1 1 1 5 2
'APC MUTATION STATUS' versus 'MRNASEQ_CNMF'

P value = 1 (Fisher's exact test), Q value = 1

Table S6.  Gene #1: 'APC MUTATION STATUS' versus Molecular Subtype #6: 'MRNASEQ_CNMF'

nPatients CLUS_2 CLUS_3
ALL 6 61
APC MUTATED 5 51
APC WILD-TYPE 1 10
'APC MUTATION STATUS' versus 'MRNASEQ_CHIERARCHICAL'

P value = 0.27 (Fisher's exact test), Q value = 1

Table S7.  Gene #1: 'APC MUTATION STATUS' versus Molecular Subtype #7: 'MRNASEQ_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_4
ALL 62 4 1
APC MUTATED 53 2 1
APC WILD-TYPE 9 2 0
'APC MUTATION STATUS' versus 'MIRSEQ_CNMF'

P value = 0.337 (Fisher's exact test), Q value = 1

Table S8.  Gene #1: 'APC MUTATION STATUS' versus Molecular Subtype #8: 'MIRSEQ_CNMF'

nPatients CLUS_1 CLUS_3 CLUS_4 CLUS_5
ALL 2 3 6 54
APC MUTATED 1 3 6 45
APC WILD-TYPE 1 0 0 9
'APC MUTATION STATUS' versus 'MIRSEQ_CHIERARCHICAL'

P value = 1 (Fisher's exact test), Q value = 1

Table S9.  Gene #1: 'APC MUTATION STATUS' versus Molecular Subtype #9: 'MIRSEQ_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2
ALL 4 61
APC MUTATED 4 51
APC WILD-TYPE 0 10
'KRAS MUTATION STATUS' versus 'MRNA_CNMF'

P value = 0.262 (Fisher's exact test), Q value = 1

Table S10.  Gene #2: 'KRAS MUTATION STATUS' versus Molecular Subtype #1: 'MRNA_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 24 21 19
KRAS MUTATED 16 11 8
KRAS WILD-TYPE 8 10 11
'KRAS MUTATION STATUS' versus 'MRNA_CHIERARCHICAL'

P value = 0.00629 (Fisher's exact test), Q value = 0.15

Table S11.  Gene #2: 'KRAS MUTATION STATUS' versus Molecular Subtype #2: 'MRNA_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 23 26 15
KRAS MUTATED 16 8 11
KRAS WILD-TYPE 7 18 4

Figure S1.  Get High-res Image Gene #2: 'KRAS MUTATION STATUS' versus Molecular Subtype #2: 'MRNA_CHIERARCHICAL'

'KRAS MUTATION STATUS' versus 'CN_CNMF'

P value = 0.00169 (Chi-square test), Q value = 0.044

Table S12.  Gene #2: 'KRAS MUTATION STATUS' versus Molecular Subtype #3: 'CN_CNMF'

nPatients CLUS_2 CLUS_3 CLUS_4 CLUS_5 CLUS_6
ALL 17 18 17 11 5
KRAS MUTATED 3 13 9 8 5
KRAS WILD-TYPE 14 5 8 3 0

Figure S2.  Get High-res Image Gene #2: 'KRAS MUTATION STATUS' versus Molecular Subtype #3: 'CN_CNMF'

'KRAS MUTATION STATUS' versus 'RPPA_CNMF'

P value = 0.78 (Fisher's exact test), Q value = 1

Table S13.  Gene #2: 'KRAS MUTATION STATUS' versus Molecular Subtype #4: 'RPPA_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 16 14 23
KRAS MUTATED 7 8 12
KRAS WILD-TYPE 9 6 11
'KRAS MUTATION STATUS' versus 'RPPA_CHIERARCHICAL'

P value = 0.817 (Chi-square test), Q value = 1

Table S14.  Gene #2: 'KRAS MUTATION STATUS' versus Molecular Subtype #5: 'RPPA_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3 CLUS_4 CLUS_5
ALL 2 4 12 21 14
KRAS MUTATED 1 2 6 9 9
KRAS WILD-TYPE 1 2 6 12 5
'KRAS MUTATION STATUS' versus 'MRNASEQ_CNMF'

P value = 0.0269 (Fisher's exact test), Q value = 0.62

Table S15.  Gene #2: 'KRAS MUTATION STATUS' versus Molecular Subtype #6: 'MRNASEQ_CNMF'

nPatients CLUS_2 CLUS_3
ALL 6 61
KRAS MUTATED 6 30
KRAS WILD-TYPE 0 31

Figure S3.  Get High-res Image Gene #2: 'KRAS MUTATION STATUS' versus Molecular Subtype #6: 'MRNASEQ_CNMF'

'KRAS MUTATION STATUS' versus 'MRNASEQ_CHIERARCHICAL'

P value = 1 (Fisher's exact test), Q value = 1

Table S16.  Gene #2: 'KRAS MUTATION STATUS' versus Molecular Subtype #7: 'MRNASEQ_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_4
ALL 62 4 1
KRAS MUTATED 33 2 1
KRAS WILD-TYPE 29 2 0
'KRAS MUTATION STATUS' versus 'MIRSEQ_CNMF'

P value = 0.292 (Fisher's exact test), Q value = 1

Table S17.  Gene #2: 'KRAS MUTATION STATUS' versus Molecular Subtype #8: 'MIRSEQ_CNMF'

nPatients CLUS_1 CLUS_3 CLUS_4 CLUS_5
ALL 2 3 6 54
KRAS MUTATED 1 2 1 30
KRAS WILD-TYPE 1 1 5 24
'KRAS MUTATION STATUS' versus 'MIRSEQ_CHIERARCHICAL'

P value = 0.0465 (Fisher's exact test), Q value = 1

Table S18.  Gene #2: 'KRAS MUTATION STATUS' versus Molecular Subtype #9: 'MIRSEQ_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2
ALL 4 61
KRAS MUTATED 0 34
KRAS WILD-TYPE 4 27

Figure S4.  Get High-res Image Gene #2: 'KRAS MUTATION STATUS' versus Molecular Subtype #9: 'MIRSEQ_CHIERARCHICAL'

'TP53 MUTATION STATUS' versus 'MRNA_CNMF'

P value = 0.000442 (Fisher's exact test), Q value = 0.012

Table S19.  Gene #3: 'TP53 MUTATION STATUS' versus Molecular Subtype #1: 'MRNA_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 24 21 19
TP53 MUTATED 8 15 17
TP53 WILD-TYPE 16 6 2

Figure S5.  Get High-res Image Gene #3: 'TP53 MUTATION STATUS' versus Molecular Subtype #1: 'MRNA_CNMF'

'TP53 MUTATION STATUS' versus 'MRNA_CHIERARCHICAL'

P value = 0.00311 (Fisher's exact test), Q value = 0.078

Table S20.  Gene #3: 'TP53 MUTATION STATUS' versus Molecular Subtype #2: 'MRNA_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 23 26 15
TP53 MUTATED 8 20 12
TP53 WILD-TYPE 15 6 3

Figure S6.  Get High-res Image Gene #3: 'TP53 MUTATION STATUS' versus Molecular Subtype #2: 'MRNA_CHIERARCHICAL'

'TP53 MUTATION STATUS' versus 'CN_CNMF'

P value = 0.348 (Chi-square test), Q value = 1

Table S21.  Gene #3: 'TP53 MUTATION STATUS' versus Molecular Subtype #3: 'CN_CNMF'

nPatients CLUS_2 CLUS_3 CLUS_4 CLUS_5 CLUS_6
ALL 17 18 17 11 5
TP53 MUTATED 13 9 10 9 3
TP53 WILD-TYPE 4 9 7 2 2
'TP53 MUTATION STATUS' versus 'RPPA_CNMF'

P value = 0.167 (Fisher's exact test), Q value = 1

Table S22.  Gene #3: 'TP53 MUTATION STATUS' versus Molecular Subtype #4: 'RPPA_CNMF'

nPatients CLUS_1 CLUS_2 CLUS_3
ALL 16 14 23
TP53 MUTATED 10 12 13
TP53 WILD-TYPE 6 2 10
'TP53 MUTATION STATUS' versus 'RPPA_CHIERARCHICAL'

P value = 0.603 (Chi-square test), Q value = 1

Table S23.  Gene #3: 'TP53 MUTATION STATUS' versus Molecular Subtype #5: 'RPPA_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_3 CLUS_4 CLUS_5
ALL 2 4 12 21 14
TP53 MUTATED 1 3 10 12 9
TP53 WILD-TYPE 1 1 2 9 5
'TP53 MUTATION STATUS' versus 'MRNASEQ_CNMF'

P value = 0.177 (Fisher's exact test), Q value = 1

Table S24.  Gene #3: 'TP53 MUTATION STATUS' versus Molecular Subtype #6: 'MRNASEQ_CNMF'

nPatients CLUS_2 CLUS_3
ALL 6 61
TP53 MUTATED 2 41
TP53 WILD-TYPE 4 20
'TP53 MUTATION STATUS' versus 'MRNASEQ_CHIERARCHICAL'

P value = 0.755 (Fisher's exact test), Q value = 1

Table S25.  Gene #3: 'TP53 MUTATION STATUS' versus Molecular Subtype #7: 'MRNASEQ_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2 CLUS_4
ALL 62 4 1
TP53 MUTATED 40 2 1
TP53 WILD-TYPE 22 2 0
'TP53 MUTATION STATUS' versus 'MIRSEQ_CNMF'

P value = 0.812 (Fisher's exact test), Q value = 1

Table S26.  Gene #3: 'TP53 MUTATION STATUS' versus Molecular Subtype #8: 'MIRSEQ_CNMF'

nPatients CLUS_1 CLUS_3 CLUS_4 CLUS_5
ALL 2 3 6 54
TP53 MUTATED 1 2 5 34
TP53 WILD-TYPE 1 1 1 20
'TP53 MUTATION STATUS' versus 'MIRSEQ_CHIERARCHICAL'

P value = 0.288 (Fisher's exact test), Q value = 1

Table S27.  Gene #3: 'TP53 MUTATION STATUS' versus Molecular Subtype #9: 'MIRSEQ_CHIERARCHICAL'

nPatients CLUS_1 CLUS_2
ALL 4 61
TP53 MUTATED 4 38
TP53 WILD-TYPE 0 23
Methods & Data
Input

  • Mutation data file = transformed.cor.cli.txt

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

  • Number of patients = 69

  • Number of significantly mutated genes = 3

  • Number of Molecular subtypes = 9

  • 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

Chi-square test

For multi-class clinical features (nominal or ordinal), Chi-square tests (Greenwood and Nikulin 1996) were used to estimate the P values using the 'chisq.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] Greenwood and Nikulin, A guide to chi-squared testing, Wiley, New York. ISBN 047155779X (1996)
[3] 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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