Correlation between gene mutation status and molecular subtypes

Thyroid Adenocarcinoma (Primary solid tumor)

21 April 2013 | analyses__2013_04_21

Maintainer Information

Citation Information

Maintained by TCGA GDAC Team (Broad Institute/MD Anderson Cancer Center/Harvard Medical School)

Cite as Broad Institute TCGA Genome Data Analysis Center (2013): Thyroid Adenocarcinoma (Primary solid tumor cohort) - 21 April 2013: Correlation between gene mutation status and molecular subtypes. Broad Institute of MIT and Harvard. doi:10.7908/C1V122S2

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 (1.01e-35)	9.4e-07 (0.000255)	2.51e-11 (6.84e-09)	3.88e-49 (1.09e-46)	7.76e-49 (2.18e-46)	2.35e-40 (6.57e-38)	3.32e-43 (9.29e-41)
HRAS	12 (4%)	311	0.000222 (0.0586)	1.48e-06 (0.000399)	9.23e-05 (0.0245)	0.00529 (1.00)	1.71e-05 (0.00454)	5.23e-06 (0.0014)	1.69e-06 (0.000453)	9.25e-06 (0.00247)
NRAS	26 (8%)	297	0.00692 (1.00)	6.06e-14 (1.68e-11)	1 (1.00)	0.000583 (0.153)	1.63e-12 (4.47e-10)	1.11e-13 (3.08e-11)	1.87e-12 (5.13e-10)	3.3e-12 (9.02e-10)
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)	1 (1.00)
PTTG1IP	4 (1%)	319	1 (1.00)	1 (1.00)			0.223 (1.00)	0.451 (1.00)	0.471 (1.00)	0.396 (1.00)
RPTN	8 (2%)	315	0.805 (1.00)	0.442 (1.00)	0.265 (1.00)	0.801 (1.00)	0.0267 (1.00)	0.663 (1.00)	0.74 (1.00)	0.672 (1.00)
EIF1AX	5 (2%)	318	0.731 (1.00)	0.0278 (1.00)	0.444 (1.00)	0.132 (1.00)	0.0654 (1.00)	0.0257 (1.00)	0.0634 (1.00)	0.199 (1.00)
CCDC15	5 (2%)	318	0.731 (1.00)	0.115 (1.00)	1 (1.00)	0.381 (1.00)	0.211 (1.00)	0.327 (1.00)	0.627 (1.00)	0.108 (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)	0.552 (1.00)	0.875 (1.00)	0.334 (1.00)
ZNF878	4 (1%)	319	1 (1.00)	0.487 (1.00)			0.0475 (1.00)	0.561 (1.00)	0.694 (1.00)	1 (1.00)
TG	16 (5%)	307	1 (1.00)	0.0205 (1.00)	0.34 (1.00)	0.492 (1.00)	0.145 (1.00)	0.0643 (1.00)	0.0453 (1.00)	0.021 (1.00)
PRB2	6 (2%)	317	1 (1.00)	0.637 (1.00)	0.0801 (1.00)	0.851 (1.00)	0.415 (1.00)	0.623 (1.00)	0.529 (1.00)	0.518 (1.00)
R3HDM2	4 (1%)	319	0.0124 (1.00)	0.063 (1.00)			0.0598 (1.00)	0.0654 (1.00)	0.021 (1.00)	0.00694 (1.00)
IL32	3 (1%)	320	1 (1.00)	0.742 (1.00)			1 (1.00)	1 (1.00)	0.209 (1.00)	1 (1.00)
TMCO2	3 (1%)	320	1 (1.00)	0.416 (1.00)	0.778 (1.00)	0.2 (1.00)	0.5 (1.00)	0.214 (1.00)	0.418 (1.00)	0.778 (1.00)
PPTC7	3 (1%)	320	0.0791 (1.00)	0.0627 (1.00)			0.174 (1.00)	0.0688 (1.00)	0.312 (1.00)	0.292 (1.00)
MUC7	5 (2%)	318	0.731 (1.00)	0.372 (1.00)	0.683 (1.00)	0.26 (1.00)	0.806 (1.00)	0.908 (1.00)	0.869 (1.00)	0.631 (1.00)
LYPD3	3 (1%)	320	0.547 (1.00)	0.416 (1.00)			0.5 (1.00)	0.427 (1.00)	0.653 (1.00)	0.778 (1.00)
TMEM90B	3 (1%)	320	0.135 (1.00)	1 (1.00)			1 (1.00)	1 (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)	0.598 (1.00)	0.908 (1.00)	0.453 (1.00)	1 (1.00)
PPM1D	5 (2%)	318	1 (1.00)	1 (1.00)	0.778 (1.00)	0.125 (1.00)	0.695 (1.00)	0.212 (1.00)	0.869 (1.00)	0.328 (1.00)
MAP3K3	4 (1%)	319	0.061 (1.00)	0.224 (1.00)	0.459 (1.00)	0.0846 (1.00)	0.117 (1.00)	0.313 (1.00)	0.471 (1.00)	0.557 (1.00)
TROAP	3 (1%)	320	1 (1.00)	0.742 (1.00)	0.778 (1.00)	0.535 (1.00)	0.751 (1.00)	0.85 (1.00)	0.533 (1.00)	1 (1.00)
SYNPO2L	3 (1%)	320	0.547 (1.00)	1 (1.00)			1 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)
ATAD2	4 (1%)	319	1 (1.00)	0.823 (1.00)			0.813 (1.00)	0.561 (1.00)	0.694 (1.00)	1 (1.00)
KRAS	3 (1%)	320	1 (1.00)	0.0627 (1.00)			0.174 (1.00)	0.0974 (1.00)	0.0661 (1.00)	0.0243 (1.00)
SLC5A11	3 (1%)	320	0.547 (1.00)	0.742 (1.00)			0.657 (1.00)	0.365 (1.00)	0.312 (1.00)	0.292 (1.00)
PRG4	4 (1%)	319	0.23 (1.00)	0.104 (1.00)			0.0143 (1.00)	0.028 (1.00)	0.471 (1.00)	0.557 (1.00)
SCUBE2	3 (1%)	320	1 (1.00)	0.281 (1.00)			0.32 (1.00)	0.259 (1.00)	0.653 (1.00)	0.643 (1.00)
ZNF479	3 (1%)	320	1 (1.00)	0.742 (1.00)			1 (1.00)	1 (1.00)	0.533 (1.00)	1 (1.00)
SREBF2	3 (1%)	320	1 (1.00)	0.742 (1.00)			0.577 (1.00)	0.214 (1.00)	0.418 (1.00)	0.778 (1.00)
SLC26A11	3 (1%)	320	0.0791 (1.00)	1 (1.00)			0.375 (1.00)	1 (1.00)	0.776 (1.00)	0.398 (1.00)
TSC22D1	3 (1%)	320	1 (1.00)	1 (1.00)			0.751 (1.00)	0.85 (1.00)	1 (1.00)	0.512 (1.00)
ANKRD30A	5 (2%)	318	0.731 (1.00)	0.462 (1.00)			0.75 (1.00)	0.514 (1.00)	0.743 (1.00)	0.744 (1.00)
FAM155A	4 (1%)	319	0.144 (1.00)	0.156 (1.00)	0.778 (1.00)	0.535 (1.00)			0.0361 (1.00)	1 (1.00)
SLA	3 (1%)	320	0.547 (1.00)	0.0627 (1.00)	0.286 (1.00)	0.285 (1.00)	0.174 (1.00)	0.0974 (1.00)	0.0661 (1.00)	0.0243 (1.00)
ZFHX3	10 (3%)	313	0.171 (1.00)	0.616 (1.00)	0.48 (1.00)	0.632 (1.00)	0.583 (1.00)	0.459 (1.00)	0.617 (1.00)	0.721 (1.00)
ARMCX3	3 (1%)	320	0.547 (1.00)	0.742 (1.00)			0.657 (1.00)	0.132 (1.00)	0.533 (1.00)	0.2 (1.00)
SLC25A45	3 (1%)	320	0.135 (1.00)	1 (1.00)					0.209 (1.00)	0.292 (1.00)
COL5A3	6 (2%)	317	0.752 (1.00)	0.317 (1.00)	0.778 (1.00)	0.758 (1.00)	0.0513 (1.00)	0.518 (1.00)	0.875 (1.00)	0.596 (1.00)
CDC27	3 (1%)	320	1 (1.00)	1 (1.00)			0.375 (1.00)	0.17 (1.00)	0.776 (1.00)	0.398 (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 = 3.88e-49 (Fisher's exact test), Q value = 1.1e-46

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

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	106	39	74	96
BRAF MUTATED	5	22	60	91
BRAF WILD-TYPE	101	17	14	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 = 7.76e-49 (Fisher's exact test), Q value = 2.2e-46

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

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	97	125	29	64
BRAF MUTATED	1	112	17	48
BRAF WILD-TYPE	96	13	12	16

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 = 2.35e-40 (Fisher's exact test), Q value = 6.6e-38

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	106	114	102
BRAF MUTATED	7	98	77
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 = 3.32e-43 (Fisher's exact test), Q value = 9.3e-41

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	94	116	112
BRAF MUTATED	1	92	89
BRAF WILD-TYPE	93	24	23

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 = 0.059

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 = 4e-04

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 = 1.71e-05 (Fisher's exact test), Q value = 0.0045

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

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	106	39	74	96
HRAS MUTATED	12	0	0	0
HRAS WILD-TYPE	94	39	74	96

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 = 5.23e-06 (Fisher's exact test), Q value = 0.0014

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

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	97	125	29	64
HRAS MUTATED	12	0	0	0
HRAS WILD-TYPE	85	125	29	64

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 = 1.69e-06 (Fisher's exact test), Q value = 0.00045

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	106	114	102
HRAS MUTATED	12	0	0
HRAS WILD-TYPE	94	114	102

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 = 9.25e-06 (Fisher's exact test), Q value = 0.0025

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	94	116	112
HRAS MUTATED	11	0	1
HRAS WILD-TYPE	83	116	111

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 = 1.63e-12 (Fisher's exact test), Q value = 4.5e-10

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

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	106	39	74	96
NRAS MUTATED	26	0	0	0
NRAS WILD-TYPE	80	39	74	96

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 = 1.11e-13 (Fisher's exact test), Q value = 3.1e-11

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

nPatients	CLUS_1	CLUS_2	CLUS_3	CLUS_4
ALL	97	125	29	64
NRAS MUTATED	26	0	0	0
NRAS WILD-TYPE	71	125	29	64

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 = 1.87e-12 (Fisher's exact test), Q value = 5.1e-10

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	106	114	102
NRAS MUTATED	25	0	1
NRAS WILD-TYPE	81	114	101

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 = 3.3e-12 (Fisher's exact test), Q value = 9e-10

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	94	116	112
NRAS MUTATED	24	1	1
NRAS WILD-TYPE	70	115	111

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.

Download Results

This is an experimental feature. The full results of the analysis summarized in this report can be downloaded from the TCGA Data Coordination Center.

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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