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 27 genes and 14 clinical features across 241 patients, 8 significant findings detected with Q value < 0.25.

BRAF mutation correlated to 'HISTOLOGICAL.TYPE', 'EXTRATHYROIDAL.EXTENSION', and 'LYMPH.NODE.METASTASIS'.
HRAS mutation correlated to 'HISTOLOGICAL.TYPE'.
NRAS mutation correlated to 'HISTOLOGICAL.TYPE'.
CCDC15 mutation correlated to 'LYMPH.NODE.METASTASIS'.
ATAD2 mutation correlated to 'NUMBER.OF.LYMPH.NODES' and 'TUMOR.SIZE'.

Results

Overview of the results

Table 1. Get Full Table Overview of the association between mutation status of 27 genes and 14 clinical features. Shown in the table are P values (Q values). Thresholded by Q value < 0.25, 8 significant findings detected.


		Clinical Features	AGE	GENDER	HISTOLOGICAL TYPE	RADIATIONS RADIATION REGIMENINDICATION	RADIATIONEXPOSURE	DISTANT METASTASIS	EXTRATHYROIDAL EXTENSION	LYMPH NODE METASTASIS	COMPLETENESS OF RESECTION	NUMBER OF LYMPH NODES	TUMOR STAGECODE	NEOPLASM DISEASESTAGE	MULTIFOCALITY	TUMOR SIZE
	nMutated (%)	nWild-Type	t-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	Chi-square test	Fisher's exact test	t-test	t-test	Chi-square test	Fisher's exact test	t-test
BRAF	135 (56%)	106	0.547 (1.00)	0.375 (1.00)	1.91e-20 (6.32e-18)	0.014 (1.00)	1 (1.00)	0.43 (1.00)	3.27e-07 (0.000107)	0.00057 (0.186)	0.513 (1.00)	0.0873 (1.00)		0.0492 (1.00)	1 (1.00)	0.0585 (1.00)
ATAD2	3 (1%)	238	0.6 (1.00)	0.571 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	0.539 (1.00)	1 (1.00)	9.63e-13 (3.18e-10)		0.669 (1.00)	0.249 (1.00)	3.16e-25 (1.05e-22)
HRAS	10 (4%)	231	0.712 (1.00)	0.72 (1.00)	0.000208 (0.0682)	1 (1.00)	1 (1.00)	0.133 (1.00)	1 (1.00)	0.23 (1.00)	0.115 (1.00)	0.808 (1.00)		0.0312 (1.00)	0.342 (1.00)	0.412 (1.00)
NRAS	21 (9%)	220	0.623 (1.00)	0.436 (1.00)	5.23e-08 (1.72e-05)	0.607 (1.00)	1 (1.00)	0.28 (1.00)	0.0208 (1.00)	0.00306 (0.987)	1 (1.00)	0.0122 (1.00)		0.0402 (1.00)	0.366 (1.00)	0.974 (1.00)
CCDC15	5 (2%)	236	0.147 (1.00)	1 (1.00)	0.394 (1.00)	1 (1.00)	1 (1.00)	0.215 (1.00)	1 (1.00)	0.000611 (0.198)	1 (1.00)	0.196 (1.00)		0.641 (1.00)	0.19 (1.00)	0.384 (1.00)
EMG1	5 (2%)	236	0.954 (1.00)	0.332 (1.00)	0.353 (1.00)	1 (1.00)	1 (1.00)	0.44 (1.00)	1 (1.00)	0.865 (1.00)	0.159 (1.00)	0.0759 (1.00)		0.32 (1.00)	0.668 (1.00)	0.249 (1.00)
RPTN	7 (3%)	234	0.94 (1.00)	1 (1.00)	0.345 (1.00)	1 (1.00)	1 (1.00)	0.502 (1.00)	0.701 (1.00)	0.0198 (1.00)	1 (1.00)	0.139 (1.00)		0.581 (1.00)	1 (1.00)	0.589 (1.00)
EIF1AX	3 (1%)	238	0.429 (1.00)	0.163 (1.00)	0.0756 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	0.0645 (1.00)	0.196 (1.00)			0.724 (1.00)	1 (1.00)	0.3 (1.00)
ZNF845	5 (2%)	236	0.869 (1.00)	1 (1.00)	0.394 (1.00)	1 (1.00)	0.178 (1.00)	0.673 (1.00)	1 (1.00)	0.541 (1.00)	1 (1.00)	0.965 (1.00)		0.246 (1.00)	1 (1.00)	0.882 (1.00)
TG	12 (5%)	229	0.952 (1.00)	1 (1.00)	0.0205 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	0.775 (1.00)	0.919 (1.00)	0.823 (1.00)	0.622 (1.00)		0.969 (1.00)	0.774 (1.00)	0.873 (1.00)
PRB2	3 (1%)	238	0.277 (1.00)	1 (1.00)	0.601 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	0.576 (1.00)	0.644 (1.00)	1 (1.00)			0.724 (1.00)	1 (1.00)	0.396 (1.00)
R3HDM2	4 (2%)	237	0.991 (1.00)	1 (1.00)	0.364 (1.00)	1 (1.00)	1 (1.00)	0.66 (1.00)	0.597 (1.00)	0.613 (1.00)	1 (1.00)			0.924 (1.00)	1 (1.00)	0.468 (1.00)
PPTC7	3 (1%)	238	0.74 (1.00)	0.163 (1.00)	0.601 (1.00)	1 (1.00)	1 (1.00)	0.589 (1.00)	1 (1.00)	0.863 (1.00)	1 (1.00)	0.00108 (0.349)		0.93 (1.00)	1 (1.00)	0.844 (1.00)
LYPD3	3 (1%)	238	0.271 (1.00)	1 (1.00)	0.0998 (1.00)	1 (1.00)	1 (1.00)	0.589 (1.00)	0.576 (1.00)	0.863 (1.00)	0.196 (1.00)	0.623 (1.00)		0.93 (1.00)	0.249 (1.00)	0.00362 (1.00)
TMEM90B	3 (1%)	238	0.413 (1.00)	0.571 (1.00)	0.216 (1.00)	1 (1.00)	1 (1.00)	0.589 (1.00)	0.175 (1.00)	0.863 (1.00)	1 (1.00)	0.623 (1.00)		0.468 (1.00)	0.249 (1.00)
ZNF799	4 (2%)	237	0.559 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	0.597 (1.00)	0.0332 (1.00)	1 (1.00)			0.73 (1.00)	0.344 (1.00)
PPM1D	5 (2%)	236	0.53 (1.00)	1 (1.00)	0.869 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	0.384 (1.00)	0.223 (1.00)	1 (1.00)	0.0772 (1.00)		0.0443 (1.00)	1 (1.00)	0.736 (1.00)
KRAS	3 (1%)	238	0.873 (1.00)	0.571 (1.00)	0.149 (1.00)	1 (1.00)	1 (1.00)	0.589 (1.00)		0.863 (1.00)				0.93 (1.00)	1 (1.00)
SLC5A11	3 (1%)	238	0.273 (1.00)	0.571 (1.00)	0.601 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	0.727 (1.00)	1 (1.00)			0.93 (1.00)	0.602 (1.00)
PRG4	3 (1%)	238	0.666 (1.00)	1 (1.00)	0.216 (1.00)	1 (1.00)	1 (1.00)	0.106 (1.00)	1 (1.00)	0.403 (1.00)	1 (1.00)	0.825 (1.00)		0.93 (1.00)	0.249 (1.00)	0.0214 (1.00)
SLC26A11	3 (1%)	238	0.406 (1.00)	0.163 (1.00)	0.291 (1.00)	1 (1.00)	1 (1.00)	0.106 (1.00)	1 (1.00)	0.863 (1.00)	1 (1.00)	0.433 (1.00)		0.669 (1.00)	1 (1.00)	0.211 (1.00)
ANKRD30A	3 (1%)	238	0.298 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	0.589 (1.00)		0.677 (1.00)		0.987 (1.00)		0.425 (1.00)	1 (1.00)
FAM155A	3 (1%)	238	0.165 (1.00)	1 (1.00)	0.216 (1.00)	1 (1.00)	1 (1.00)	0.294 (1.00)	1 (1.00)	0.863 (1.00)	1 (1.00)	0.785 (1.00)		0.93 (1.00)	0.249 (1.00)
ZFHX3	5 (2%)	236	0.97 (1.00)	1 (1.00)	0.315 (1.00)	0.227 (1.00)	1 (1.00)	1 (1.00)	0.147 (1.00)	0.238 (1.00)	0.555 (1.00)	0.402 (1.00)		0.341 (1.00)	0.0621 (1.00)	0.576 (1.00)
ARMCX3	3 (1%)	238	0.534 (1.00)	0.571 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	1 (1.00)	0.539 (1.00)	1 (1.00)			0.669 (1.00)	0.602 (1.00)	0.0389 (1.00)
COL5A3	5 (2%)	236	0.413 (1.00)	0.332 (1.00)	0.753 (1.00)	1 (1.00)	1 (1.00)	0.44 (1.00)	1 (1.00)	0.883 (1.00)	0.555 (1.00)	0.282 (1.00)		0.641 (1.00)	0.374 (1.00)	0.274 (1.00)
CDC27	3 (1%)	238	0.787 (1.00)	0.571 (1.00)	1 (1.00)	1 (1.00)	0.136 (1.00)	0.589 (1.00)	0.576 (1.00)	0.539 (1.00)	1 (1.00)			0.779 (1.00)	1 (1.00)

'BRAF MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 1.91e-20 (Fisher's exact test), Q value = 6.3e-18

Table S1. Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients	OTHER	THYROID PAPILLARY CARCINOMA - CLASSICAL/USUAL	THYROID PAPILLARY CARCINOMA - FOLLICULAR (>= 99% FOLLICULAR PATTERNED)	THYROID PAPILLARY CARCINOMA - TALL CELL (>= 50% TALL CELL FEATURES)
ALL	19	128	71	23
BRAF MUTATED	4	98	12	21
BRAF WILD-TYPE	15	30	59	2

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

'BRAF MUTATION STATUS' versus 'EXTRATHYROIDAL.EXTENSION'

P value = 3.27e-07 (Fisher's exact test), Q value = 0.00011

Table S2. Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #7: 'EXTRATHYROIDAL.EXTENSION'

nPatients	MINIMAL (T3)	MODERATE/ADVANCED (T4A)	NONE
ALL	54	3	173
BRAF MUTATED	46	3	82
BRAF WILD-TYPE	8	0	91

Figure S2. Get High-res Image Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #7: 'EXTRATHYROIDAL.EXTENSION'

'BRAF MUTATION STATUS' versus 'LYMPH.NODE.METASTASIS'

P value = 0.00057 (Chi-square test), Q value = 0.19

Table S3. Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #8: 'LYMPH.NODE.METASTASIS'

nPatients	N0	N1	N1A	N1B	NX
ALL	119	11	51	31	29
BRAF MUTATED	55	8	41	18	13
BRAF WILD-TYPE	64	3	10	13	16

Figure S3. Get High-res Image Gene #1: 'BRAF MUTATION STATUS' versus Clinical Feature #8: 'LYMPH.NODE.METASTASIS'

'HRAS MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 0.000208 (Fisher's exact test), Q value = 0.068

Table S4. Gene #3: 'HRAS MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients	OTHER	THYROID PAPILLARY CARCINOMA - CLASSICAL/USUAL	THYROID PAPILLARY CARCINOMA - FOLLICULAR (>= 99% FOLLICULAR PATTERNED)	THYROID PAPILLARY CARCINOMA - TALL CELL (>= 50% TALL CELL FEATURES)
ALL	19	128	71	23
HRAS MUTATED	2	0	8	0
HRAS WILD-TYPE	17	128	63	23

Figure S4. Get High-res Image Gene #3: 'HRAS MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

'NRAS MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 5.23e-08 (Fisher's exact test), Q value = 1.7e-05

Table S5. Gene #4: 'NRAS MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients	OTHER	THYROID PAPILLARY CARCINOMA - CLASSICAL/USUAL	THYROID PAPILLARY CARCINOMA - FOLLICULAR (>= 99% FOLLICULAR PATTERNED)	THYROID PAPILLARY CARCINOMA - TALL CELL (>= 50% TALL CELL FEATURES)
ALL	19	128	71	23
NRAS MUTATED	2	1	18	0
NRAS WILD-TYPE	17	127	53	23

Figure S5. Get High-res Image Gene #4: 'NRAS MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

'CCDC15 MUTATION STATUS' versus 'LYMPH.NODE.METASTASIS'

P value = 0.000611 (Chi-square test), Q value = 0.2

Table S6. Gene #7: 'CCDC15 MUTATION STATUS' versus Clinical Feature #8: 'LYMPH.NODE.METASTASIS'

nPatients	N0	N1	N1A	N1B	NX
ALL	119	11	51	31	29
CCDC15 MUTATED	1	2	0	2	0
CCDC15 WILD-TYPE	118	9	51	29	29

Figure S6. Get High-res Image Gene #7: 'CCDC15 MUTATION STATUS' versus Clinical Feature #8: 'LYMPH.NODE.METASTASIS'

'ATAD2 MUTATION STATUS' versus 'NUMBER.OF.LYMPH.NODES'

P value = 9.63e-13 (t-test), Q value = 3.2e-10

Table S7. Gene #17: 'ATAD2 MUTATION STATUS' versus Clinical Feature #10: 'NUMBER.OF.LYMPH.NODES'

	nPatients	Mean (Std.Dev)
ALL	191	2.6 (4.7)
ATAD2 MUTATED	3	0.0 (0.0)
ATAD2 WILD-TYPE	188	2.7 (4.8)

Figure S7. Get High-res Image Gene #17: 'ATAD2 MUTATION STATUS' versus Clinical Feature #10: 'NUMBER.OF.LYMPH.NODES'

'ATAD2 MUTATION STATUS' versus 'TUMOR.SIZE'

P value = 3.16e-25 (t-test), Q value = 1.1e-22

Table S8. Gene #17: 'ATAD2 MUTATION STATUS' versus Clinical Feature #14: 'TUMOR.SIZE'

	nPatients	Mean (Std.Dev)
ALL	192	2.8 (1.5)
ATAD2 MUTATED	3	1.3 (0.1)
ATAD2 WILD-TYPE	189	2.8 (1.5)

Figure S8. Get High-res Image Gene #17: 'ATAD2 MUTATION STATUS' versus Clinical Feature #14: 'TUMOR.SIZE'

Methods & Data

Input

Mutation data file = THCA-TP.mutsig.cluster.txt
Clinical data file = THCA-TP.clin.merged.picked.txt
Number of patients = 241
Number of significantly mutated genes = 27
Number of selected clinical features = 14
Exclude genes that fewer than K tumors have mutations, K = 3

Student's t-test analysis

For continuous numerical clinical features, two-tailed Student's t test with unequal variance (Lehmann and Romano 2005) was applied to compare the clinical values between tumors with and without gene mutations using 't.test' 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

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] Lehmann and Romano, Testing Statistical Hypotheses (3E ed.), New York: Springer. ISBN 0387988645 (2005)

[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] Greenwood and Nikulin, A guide to chi-squared testing, Wiley, New York. ISBN 047155779X (1996)

[4] 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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