Correlation between gene mutation status and selected clinical features

Overview

Introduction

This pipeline computes the correlation between significantly recurrent gene mutations and selected clinical features.

Summary

Testing the association between mutation status of 11 genes and 17 clinical features across 395 patients, 10 significant findings detected with Q value < 0.25.

BRAF mutation correlated to 'NEOPLASM.DISEASESTAGE', 'PATHOLOGY.T.STAGE', 'PATHOLOGY.N.STAGE', 'HISTOLOGICAL.TYPE', and 'EXTRATHYROIDAL.EXTENSION'.
NRAS mutation correlated to 'PATHOLOGY.N.STAGE' and 'HISTOLOGICAL.TYPE'.
DNMT3A mutation correlated to 'Time to Death'.
ITGAL mutation correlated to 'NEOPLASM.DISEASESTAGE' and 'EXTRATHYROIDAL.EXTENSION'.

Results

Overview of the results

Table 1. Get Full Table Overview of the association between mutation status of 11 genes and 17 clinical features. Shown in the table are P values (Q values). Thresholded by Q value < 0.25, 10 significant findings detected.


		Clinical Features	Time to Death	AGE	NEOPLASM DISEASESTAGE	PATHOLOGY T STAGE	PATHOLOGY N STAGE	PATHOLOGY M STAGE	GENDER	HISTOLOGICAL TYPE	RADIATIONS RADIATION REGIMENINDICATION	RADIATIONEXPOSURE	EXTRATHYROIDAL EXTENSION	COMPLETENESS OF RESECTION	NUMBER OF LYMPH NODES	MULTIFOCALITY	TUMOR SIZE	RACE	ETHNICITY
	nMutated (%)	nWild-Type	logrank test	Wilcoxon-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	Wilcoxon-test	Fisher's exact test	Wilcoxon-test	Fisher's exact test	Fisher's exact test
BRAF	237 (60%)	158	0.912 (1.00)	0.518 (1.00)	0.00099 (0.17)	0.00042 (0.0731)	0.000205 (0.0359)	0.116 (1.00)	0.347 (1.00)	1e-05 (0.00179)	0.0322 (1.00)	0.593 (1.00)	1e-05 (0.00179)	0.379 (1.00)	0.00787 (1.00)	0.835 (1.00)	0.179 (1.00)	0.887 (1.00)	0.554 (1.00)
NRAS	34 (9%)	361	0.463 (1.00)	0.505 (1.00)	0.0344 (1.00)	0.161 (1.00)	0.000142 (0.025)	0.562 (1.00)	0.84 (1.00)	7e-05 (0.0124)	0.61 (1.00)	1 (1.00)	0.19 (1.00)	0.657 (1.00)	0.00167 (0.284)	0.369 (1.00)	0.503 (1.00)	0.0943 (1.00)	0.0647 (1.00)
ITGAL	4 (1%)	391	0.067 (1.00)	0.0162 (1.00)	0.00053 (0.0917)	0.145 (1.00)	0.347 (1.00)	1 (1.00)	0.0531 (1.00)	0.708 (1.00)	1 (1.00)	1 (1.00)	0.00142 (0.243)	0.102 (1.00)		0.626 (1.00)	0.446 (1.00)	1 (1.00)	0.271 (1.00)
DNMT3A	3 (1%)	392	0 (0)	0.137 (1.00)	0.0626 (1.00)	0.167 (1.00)	1 (1.00)	1 (1.00)	0.573 (1.00)	0.656 (1.00)	1 (1.00)	0.125 (1.00)	0.261 (1.00)	0.424 (1.00)	0.755 (1.00)	1 (1.00)		1 (1.00)	1 (1.00)
HRAS	14 (4%)	381	0.507 (1.00)	0.313 (1.00)	0.366 (1.00)	0.377 (1.00)	0.389 (1.00)	0.26 (1.00)	0.76 (1.00)	0.0228 (1.00)	1 (1.00)	1 (1.00)	0.69 (1.00)	0.203 (1.00)	0.762 (1.00)	0.793 (1.00)	0.725 (1.00)	0.102 (1.00)	0.617 (1.00)
EIF1AX	6 (2%)	389	0.0942 (1.00)	0.0573 (1.00)	0.924 (1.00)	1 (1.00)	0.625 (1.00)	0.475 (1.00)	0.177 (1.00)	0.0713 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	0.284 (1.00)	0.491 (1.00)	0.668 (1.00)	0.472 (1.00)		1 (1.00)
NUP93	4 (1%)	391	0.91 (1.00)	0.522 (1.00)	0.638 (1.00)	0.734 (1.00)	0.347 (1.00)	0.657 (1.00)	1 (1.00)	0.0138 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	0.521 (1.00)	0.365 (1.00)	0.343 (1.00)	1 (1.00)	0.198 (1.00)	1 (1.00)
PPM1D	5 (1%)	390	0.923 (1.00)	0.16 (1.00)	0.241 (1.00)	0.315 (1.00)	1 (1.00)	1 (1.00)	0.606 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	0.114 (1.00)	0.361 (1.00)		1 (1.00)	0.517 (1.00)	1 (1.00)	1 (1.00)
KRAS	4 (1%)	391	0.873 (1.00)	0.469 (1.00)	1 (1.00)	0.209 (1.00)	0.625 (1.00)	1 (1.00)	0.576 (1.00)	0.467 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	0.425 (1.00)	0.313 (1.00)	1 (1.00)	0.74 (1.00)		1 (1.00)
DLC1	4 (1%)	391	0.0772 (1.00)	0.793 (1.00)	0.737 (1.00)	1 (1.00)	0.604 (1.00)	0.659 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	0.389 (1.00)	0.523 (1.00)	0.405 (1.00)	0.626 (1.00)	0.573 (1.00)	1 (1.00)	0.271 (1.00)
NLRP6	3 (1%)	392	0.65 (1.00)	0.418 (1.00)	0.794 (1.00)	0.168 (1.00)	0.604 (1.00)	0.134 (1.00)	1 (1.00)	0.657 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	0.33 (1.00)	0.6 (1.00)			1 (1.00)

'BRAF MUTATION STATUS' versus 'NEOPLASM.DISEASESTAGE'

P value = 0.00099 (Fisher's exact test), Q value = 0.17

Table S1. Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #3: 'NEOPLASM.DISEASESTAGE'

nPatients	STAGE I	STAGE II	STAGE III	STAGE IV	STAGE IVA	STAGE IVC
ALL	225	44	83	2	33	6
BRAF MUTATED	129	18	59	0	26	4
BRAF WILD-TYPE	96	26	24	2	7	2

Figure S1. Get High-res Image Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #3: 'NEOPLASM.DISEASESTAGE'

'BRAF MUTATION STATUS' versus 'PATHOLOGY.T.STAGE'

P value = 0.00042 (Fisher's exact test), Q value = 0.073

Table S2. Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #4: 'PATHOLOGY.T.STAGE'

nPatients	T1	T2	T3	T4
ALL	115	137	126	15
BRAF MUTATED	67	67	89	13
BRAF WILD-TYPE	48	70	37	2

Figure S2. Get High-res Image Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #4: 'PATHOLOGY.T.STAGE'

'BRAF MUTATION STATUS' versus 'PATHOLOGY.N.STAGE'

P value = 0.000205 (Fisher's exact test), Q value = 0.036

Table S3. Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #5: 'PATHOLOGY.N.STAGE'

nPatients	0	1
ALL	187	167
BRAF MUTATED	97	119
BRAF WILD-TYPE	90	48

Figure S3. Get High-res Image Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #5: 'PATHOLOGY.N.STAGE'

'BRAF MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 1e-05 (Fisher's exact test), Q value = 0.0018

Table S4. Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #8: 'HISTOLOGICAL.TYPE'

nPatients	OTHER SPECIFY	THYROID PAPILLARY CARCINOMA - CLASSICAL/USUAL	THYROID PAPILLARY CARCINOMA - FOLLICULAR (>= 99% FOLLICULAR PATTERNED)	THYROID PAPILLARY CARCINOMA - TALL CELL (>= 50% TALL CELL FEATURES)
ALL	6	277	83	29
BRAF MUTATED	3	192	15	27
BRAF WILD-TYPE	3	85	68	2

Figure S4. Get High-res Image Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #8: 'HISTOLOGICAL.TYPE'

'BRAF MUTATION STATUS' versus 'EXTRATHYROIDAL.EXTENSION'

P value = 1e-05 (Fisher's exact test), Q value = 0.0018

Table S5. Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #11: 'EXTRATHYROIDAL.EXTENSION'

nPatients	MINIMAL (T3)	MODERATE/ADVANCED (T4A)	NONE	VERY ADVANCED (T4B)
ALL	102	11	267	1
BRAF MUTATED	80	11	140	0
BRAF WILD-TYPE	22	0	127	1

Figure S5. Get High-res Image Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #11: 'EXTRATHYROIDAL.EXTENSION'

'NRAS MUTATION STATUS' versus 'PATHOLOGY.N.STAGE'

P value = 0.000142 (Fisher's exact test), Q value = 0.025

Table S6. Gene #2: 'NRAS MUTATION STATUS' versus Clinical Feature #5: 'PATHOLOGY.N.STAGE'

nPatients	0	1
ALL	187	167
NRAS MUTATED	27	5
NRAS WILD-TYPE	160	162

Figure S6. Get High-res Image Gene #2: 'NRAS MUTATION STATUS' versus Clinical Feature #5: 'PATHOLOGY.N.STAGE'

'NRAS MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 7e-05 (Fisher's exact test), Q value = 0.012

Table S7. Gene #2: 'NRAS MUTATION STATUS' versus Clinical Feature #8: 'HISTOLOGICAL.TYPE'

nPatients	OTHER SPECIFY	THYROID PAPILLARY CARCINOMA - CLASSICAL/USUAL	THYROID PAPILLARY CARCINOMA - FOLLICULAR (>= 99% FOLLICULAR PATTERNED)	THYROID PAPILLARY CARCINOMA - TALL CELL (>= 50% TALL CELL FEATURES)
ALL	6	277	83	29
NRAS MUTATED	0	15	19	0
NRAS WILD-TYPE	6	262	64	29

Figure S7. Get High-res Image Gene #2: 'NRAS MUTATION STATUS' versus Clinical Feature #8: 'HISTOLOGICAL.TYPE'

'DNMT3A MUTATION STATUS' versus 'Time to Death'

P value = 0 (logrank test), Q value = 0

Table S8. Gene #7: 'DNMT3A MUTATION STATUS' versus Clinical Feature #1: 'Time to Death'

	nPatients	nDeath	Duration Range (Median), Month
ALL	393	13	0.0 - 158.8 (16.1)
DNMT3A MUTATED	3	1	1.0 - 7.7 (6.8)
DNMT3A WILD-TYPE	390	12	0.0 - 158.8 (16.3)

Figure S8. Get High-res Image Gene #7: 'DNMT3A MUTATION STATUS' versus Clinical Feature #1: 'Time to Death'

'ITGAL MUTATION STATUS' versus 'NEOPLASM.DISEASESTAGE'

P value = 0.00053 (Fisher's exact test), Q value = 0.092

Table S9. Gene #10: 'ITGAL MUTATION STATUS' versus Clinical Feature #3: 'NEOPLASM.DISEASESTAGE'

nPatients	STAGE I	STAGE II	STAGE III	STAGE IV	STAGE IVA	STAGE IVC
ALL	225	44	83	2	33	6
ITGAL MUTATED	0	1	0	1	2	0
ITGAL WILD-TYPE	225	43	83	1	31	6

Figure S9. Get High-res Image Gene #10: 'ITGAL MUTATION STATUS' versus Clinical Feature #3: 'NEOPLASM.DISEASESTAGE'

'ITGAL MUTATION STATUS' versus 'EXTRATHYROIDAL.EXTENSION'

P value = 0.00142 (Fisher's exact test), Q value = 0.24

Table S10. Gene #10: 'ITGAL MUTATION STATUS' versus Clinical Feature #11: 'EXTRATHYROIDAL.EXTENSION'

nPatients	MINIMAL (T3)	MODERATE/ADVANCED (T4A)	NONE	VERY ADVANCED (T4B)
ALL	102	11	267	1
ITGAL MUTATED	0	1	2	1
ITGAL WILD-TYPE	102	10	265	0

Figure S10. Get High-res Image Gene #10: 'ITGAL MUTATION STATUS' versus Clinical Feature #11: 'EXTRATHYROIDAL.EXTENSION'

Methods & Data

Input

Mutation data file = transformed.cor.cli.txt
Clinical data file = THCA-TP.merged_data.txt
Number of patients = 395
Number of significantly mutated genes = 11
Number of selected clinical features = 17
Exclude genes that fewer than K tumors have mutations, K = 3

Survival analysis

For survival clinical features, the Kaplan-Meier survival curves of tumors with and without gene mutations were plotted and the statistical significance P values were estimated by logrank test (Bland and Altman 2004) using the 'survdiff' function in R

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] Bland and Altman, Statistics notes: The logrank test, BMJ 328(7447):1073 (2004)

[2] 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)

[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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