Correlation between gene mutation status and molecular subtypes

Thyroid Adenocarcinoma (Primary solid tumor)

22 February 2013 | analyses__2013_02_22

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): Correlation between gene mutation status and molecular subtypes. Broad Institute of MIT and Harvard. doi:10.7908/C1S75DK3

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	0.00338 (0.874)	1.08e-37 (2.98e-35)	3.6e-07 (9.6e-05)	3.71e-13 (1.01e-10)	4.03e-46 (1.12e-43)	1.56e-39 (4.29e-37)	1.34e-43 (3.7e-41)	2.16e-45 (6e-43)
HRAS	12 (4%)	311	0.000107 (0.0279)	2.48e-06 (0.000658)	0.000224 (0.0582)	0.00349 (0.9)	1.37e-05 (0.00361)	6.79e-06 (0.00179)	1.49e-06 (0.000397)	3.38e-07 (9.06e-05)
NRAS	26 (8%)	297	0.0098 (1.00)	6.63e-14 (1.82e-11)	1 (1.00)	0.000209 (0.0545)	4.7e-11 (1.26e-08)	4.03e-11 (1.09e-08)	1.64e-12 (4.43e-10)	1.76e-13 (4.8e-11)
EMG1	6 (2%)	317	0.557 (1.00)	0.862 (1.00)	0.267 (1.00)	0.147 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	0.166 (1.00)
PTTG1IP	4 (1%)	319	1 (1.00)	1 (1.00)			0.242 (1.00)	0.252 (1.00)	0.471 (1.00)	0.0379 (1.00)
RPTN	8 (2%)	315	1 (1.00)	0.688 (1.00)	0.327 (1.00)	0.485 (1.00)	0.0249 (1.00)	0.415 (1.00)	0.741 (1.00)	1 (1.00)
EIF1AX	5 (2%)	318	1 (1.00)	0.028 (1.00)	0.444 (1.00)	0.115 (1.00)	0.0621 (1.00)	0.0109 (1.00)	0.0616 (1.00)	0.234 (1.00)
CCDC15	5 (2%)	318	1 (1.00)	0.17 (1.00)	1 (1.00)	0.778 (1.00)	0.132 (1.00)	0.136 (1.00)	0.628 (1.00)	0.527 (1.00)
ZNF845	6 (2%)	317	0.557 (1.00)	0.615 (1.00)	0.64 (1.00)	0.35 (1.00)	0.943 (1.00)	0.166 (1.00)	0.38 (1.00)	0.327 (1.00)
ZNF878	4 (1%)	319	1 (1.00)	0.456 (1.00)			0.0454 (1.00)	0.833 (1.00)	0.694 (1.00)	1 (1.00)
TG	16 (5%)	307	1 (1.00)	0.0255 (1.00)	0.286 (1.00)	0.273 (1.00)	0.406 (1.00)	0.293 (1.00)	0.0426 (1.00)	0.0244 (1.00)
PRB2	6 (2%)	317	1 (1.00)	0.615 (1.00)	0.0809 (1.00)	1 (1.00)	0.474 (1.00)	0.723 (1.00)	0.525 (1.00)	0.594 (1.00)
R3HDM2	4 (1%)	319	0.0134 (1.00)	0.0495 (1.00)			0.0699 (1.00)	0.0388 (1.00)	0.0202 (1.00)	0.00788 (1.00)
IL32	3 (1%)	320	1 (1.00)	0.39 (1.00)			1 (1.00)	0.78 (1.00)	0.206 (1.00)	0.641 (1.00)
TMCO2	3 (1%)	320	1 (1.00)	0.545 (1.00)	0.778 (1.00)	0.185 (1.00)	0.492 (1.00)	0.303 (1.00)	0.413 (1.00)	0.779 (1.00)
PPTC7	3 (1%)	320	0.079 (1.00)	0.0835 (1.00)			0.172 (1.00)	0.0916 (1.00)	0.306 (1.00)	0.395 (1.00)
MUC7	5 (2%)	318	1 (1.00)	0.274 (1.00)	0.684 (1.00)	0.778 (1.00)	0.805 (1.00)	0.848 (1.00)	0.453 (1.00)	0.632 (1.00)
LYPD3	3 (1%)	320	0.55 (1.00)	0.545 (1.00)			0.492 (1.00)	0.303 (1.00)	0.65 (1.00)	0.779 (1.00)
TMEM90B	3 (1%)	320	0.136 (1.00)	1 (1.00)			1 (1.00)	0.78 (1.00)	1 (1.00)	1 (1.00)
ZNF799	5 (2%)	318	0.473 (1.00)	0.834 (1.00)	0.51 (1.00)	1 (1.00)	0.592 (1.00)	0.848 (1.00)	0.453 (1.00)	1 (1.00)
PPM1D	5 (2%)	318	1 (1.00)	1 (1.00)	0.778 (1.00)	0.35 (1.00)	0.693 (1.00)	0.848 (1.00)	0.868 (1.00)	0.281 (1.00)
MAP3K3	4 (1%)	319	0.381 (1.00)	0.276 (1.00)	0.393 (1.00)	0.147 (1.00)	0.274 (1.00)	0.184 (1.00)	0.471 (1.00)	0.391 (1.00)
TROAP	3 (1%)	320	1 (1.00)	0.39 (1.00)	0.778 (1.00)	1 (1.00)	0.746 (1.00)	1 (1.00)	0.306 (1.00)	0.395 (1.00)
SYNPO2L	3 (1%)	320	0.55 (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)	0.612 (1.00)			0.808 (1.00)	1 (1.00)	0.694 (1.00)	1 (1.00)
KRAS	3 (1%)	320	1 (1.00)	0.0835 (1.00)			0.172 (1.00)	0.0916 (1.00)	0.0642 (1.00)	0.0267 (1.00)
SLC5A11	3 (1%)	320	0.55 (1.00)	0.716 (1.00)					0.306 (1.00)	0.395 (1.00)
PRG4	4 (1%)	319	0.232 (1.00)	0.362 (1.00)			0.0128 (1.00)	0.142 (1.00)	0.471 (1.00)	0.558 (1.00)
SCUBE2	3 (1%)	320		0.246 (1.00)			0.314 (1.00)	0.303 (1.00)	0.65 (1.00)	0.511 (1.00)
ZNF479	3 (1%)	320	1 (1.00)	0.39 (1.00)			1 (1.00)	0.78 (1.00)	1 (1.00)	1 (1.00)
SREBF2	3 (1%)	320	1 (1.00)	0.39 (1.00)			0.568 (1.00)	1 (1.00)	0.413 (1.00)	0.779 (1.00)
SLC26A11	3 (1%)	320	0.079 (1.00)	1 (1.00)			0.368 (1.00)	0.78 (1.00)	0.777 (1.00)	0.292 (1.00)
TSC22D1	3 (1%)	320	1 (1.00)	1 (1.00)			0.746 (1.00)	1 (1.00)	1 (1.00)	0.641 (1.00)
ANKRD30A	5 (2%)	318	1 (1.00)	0.43 (1.00)			0.749 (1.00)	0.507 (1.00)	0.742 (1.00)	0.865 (1.00)
FAM155A	4 (1%)	319	0.144 (1.00)	0.612 (1.00)	0.778 (1.00)	1 (1.00)			0.332 (1.00)	0.832 (1.00)
SLA	3 (1%)	320	0.55 (1.00)	0.0835 (1.00)	0.29 (1.00)	0.35 (1.00)	0.172 (1.00)	0.0916 (1.00)	0.0642 (1.00)	0.0267 (1.00)
ZFHX3	10 (3%)	313	0.178 (1.00)	0.737 (1.00)	0.483 (1.00)	0.533 (1.00)	0.794 (1.00)	0.437 (1.00)	0.615 (1.00)	0.727 (1.00)
ARMCX3	3 (1%)	320	0.55 (1.00)	0.39 (1.00)			0.646 (1.00)	0.213 (1.00)	0.528 (1.00)	0.199 (1.00)
SLC25A45	3 (1%)	320	0.136 (1.00)	1 (1.00)					0.206 (1.00)	0.641 (1.00)
COL5A3	6 (2%)	317	0.758 (1.00)	1 (1.00)	0.778 (1.00)	1 (1.00)	0.044 (1.00)	0.753 (1.00)	0.876 (1.00)	0.519 (1.00)
CDC27	3 (1%)	320	1 (1.00)	1 (1.00)			0.368 (1.00)	0.0446 (1.00)	0.777 (1.00)	1 (1.00)

'BRAF MUTATION STATUS' versus 'METHLYATION_CNMF'

P value = 1.08e-37 (Fisher's exact test), Q value = 3e-35

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	105	44	174
BRAF MUTATED	10	25	148
BRAF WILD-TYPE	95	19	26

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 = 3.6e-07 (Fisher's exact test), Q value = 9.6e-05

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	63	75	79
BRAF MUTATED	19	57	42
BRAF WILD-TYPE	44	18	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 = 3.71e-13 (Fisher's exact test), Q value = 1e-10

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	27	95	95
BRAF MUTATED	11	78	29
BRAF WILD-TYPE	16	17	66

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 = 1.34e-43 (Fisher's exact test), Q value = 3.7e-41

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	105	116	101
BRAF MUTATED	5	101	76
BRAF WILD-TYPE	100	15	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 = 2.16e-45 (Fisher's exact test), Q value = 6e-43

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	97	122	103
BRAF MUTATED	1	97	84
BRAF WILD-TYPE	96	25	19

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 = 0.000107 (Fisher's exact test), Q value = 0.028

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	26	244	48
HRAS MUTATED	0	4	8
HRAS WILD-TYPE	26	240	40

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 = 2.48e-06 (Fisher's exact test), Q value = 0.00066

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	105	44	174
HRAS MUTATED	12	0	0
HRAS WILD-TYPE	93	44	174

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 = 0.000224 (Fisher's exact test), Q value = 0.058

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	63	75	79
HRAS MUTATED	9	2	0
HRAS WILD-TYPE	54	73	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 = 1.49e-06 (Fisher's exact test), Q value = 4e-04

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	105	116	101
HRAS MUTATED	12	0	0
HRAS WILD-TYPE	93	116	101

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 = 3.38e-07 (Fisher's exact test), Q value = 9.1e-05

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	97	122	103
HRAS MUTATED	12	0	0
HRAS WILD-TYPE	85	122	103

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 = 6.63e-14 (Fisher's exact test), Q value = 1.8e-11

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	105	44	174
NRAS MUTATED	26	0	0
NRAS WILD-TYPE	79	44	174

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 = 0.000209 (Fisher's exact test), Q value = 0.054

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	27	95	95
NRAS MUTATED	5	0	9
NRAS WILD-TYPE	22	95	86

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 = 1.64e-12 (Fisher's exact test), Q value = 4.4e-10

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	105	116	101
NRAS MUTATED	25	0	1
NRAS WILD-TYPE	80	116	100

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 = 1.76e-13 (Fisher's exact test), Q value = 4.8e-11

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

nPatients	CLUS_1	CLUS_2	CLUS_3
ALL	97	122	103
NRAS MUTATED	25	1	0
NRAS WILD-TYPE	72	121	103

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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