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 33 genes and 5 clinical features across 248 patients, 10 significant findings detected with Q value < 0.25.

PPP2R1A mutation correlated to 'HISTOLOGICAL.TYPE'.
CTNNB1 mutation correlated to 'HISTOLOGICAL.TYPE'.
PIK3R1 mutation correlated to 'HISTOLOGICAL.TYPE'.
PTEN mutation correlated to 'HISTOLOGICAL.TYPE'.
KRAS mutation correlated to 'AGE' and 'HISTOLOGICAL.TYPE'.
TP53 mutation correlated to 'AGE' and 'HISTOLOGICAL.TYPE'.
CTCF mutation correlated to 'HISTOLOGICAL.TYPE'.
ARID1A mutation correlated to 'HISTOLOGICAL.TYPE'.

Results

Overview of the results

Table 1. Get Full Table Overview of the association between mutation status of 33 genes and 5 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	HISTOLOGICAL TYPE	RADIATIONS RADIATION REGIMENINDICATION	COMPLETENESS OF RESECTION
	nMutated (%)	nWild-Type	logrank test	t-test	Fisher's exact test	Fisher's exact test	Fisher's exact test
KRAS	53 (21%)	195	0.0816 (1.00)	0.000274 (0.043)	0.000253 (0.04)	0.253 (1.00)	0.388 (1.00)
TP53	69 (28%)	179	0.0263 (1.00)	6.15e-06 (0.00099)	8.52e-23 (1.4e-20)	0.371 (1.00)	0.18 (1.00)
PPP2R1A	27 (11%)	221	0.832 (1.00)	0.0374 (1.00)	0.000478 (0.0746)	0.52 (1.00)	1 (1.00)
CTNNB1	74 (30%)	174	0.678 (1.00)	0.0017 (0.264)	1.99e-08 (3.24e-06)	0.381 (1.00)	0.291 (1.00)
PIK3R1	83 (33%)	165	0.963 (1.00)	0.806 (1.00)	1.49e-06 (0.000241)	0.395 (1.00)	0.935 (1.00)
PTEN	161 (65%)	87	0.00636 (0.96)	0.0276 (1.00)	1.23e-23 (2.03e-21)	0.0503 (1.00)	0.0517 (1.00)
CTCF	44 (18%)	204	0.158 (1.00)	0.0349 (1.00)	0.000179 (0.0285)	1 (1.00)	0.866 (1.00)
ARID1A	83 (33%)	165	0.00558 (0.848)	0.00721 (1.00)	0.000113 (0.0181)	0.673 (1.00)	0.257 (1.00)
PIK3CA	132 (53%)	116	0.0344 (1.00)	0.195 (1.00)	0.258 (1.00)	0.593 (1.00)	0.18 (1.00)
PRKAR1B	4 (2%)	244	0.597 (1.00)	0.978 (1.00)	1 (1.00)	0.608 (1.00)	1 (1.00)
FBXW7	39 (16%)	209	0.791 (1.00)	0.904 (1.00)	0.00409 (0.625)	0.855 (1.00)	0.592 (1.00)
SPOP	21 (8%)	227	0.373 (1.00)	0.527 (1.00)	0.842 (1.00)	0.811 (1.00)	0.408 (1.00)
ARID5B	29 (12%)	219	0.792 (1.00)	0.649 (1.00)	0.00928 (1.00)	1 (1.00)	0.161 (1.00)
FGFR2	31 (12%)	217	0.529 (1.00)	0.998 (1.00)	0.701 (1.00)	1 (1.00)	0.337 (1.00)
NFE2L2	15 (6%)	233	0.658 (1.00)	0.191 (1.00)	0.14 (1.00)	0.589 (1.00)	0.789 (1.00)
CCND1	14 (6%)	234	0.564 (1.00)	0.0694 (1.00)	0.171 (1.00)	0.565 (1.00)	0.131 (1.00)
CHD4	35 (14%)	213	0.474 (1.00)	0.418 (1.00)	0.477 (1.00)	0.565 (1.00)	0.967 (1.00)
FAM9A	14 (6%)	234	0.282 (1.00)	0.913 (1.00)	0.437 (1.00)	1 (1.00)	0.859 (1.00)
MORC4	20 (8%)	228	0.117 (1.00)	0.0204 (1.00)	0.269 (1.00)	1 (1.00)	1 (1.00)
CASP8	17 (7%)	231	0.495 (1.00)	0.652 (1.00)	0.491 (1.00)	1 (1.00)	0.67 (1.00)
FOXA2	12 (5%)	236	0.908 (1.00)	0.531 (1.00)	1 (1.00)	0.229 (1.00)	0.58 (1.00)
ABI1	4 (2%)	244	0.615 (1.00)	0.0342 (1.00)	1 (1.00)	0.302 (1.00)	0.282 (1.00)
DNER	18 (7%)	230	0.497 (1.00)	0.0414 (1.00)	0.417 (1.00)	0.44 (1.00)	0.806 (1.00)
BCOR	30 (12%)	218	0.0523 (1.00)	0.0419 (1.00)	0.00741 (1.00)	1 (1.00)	0.337 (1.00)
BRS3	15 (6%)	233	0.141 (1.00)	0.133 (1.00)	0.14 (1.00)	0.4 (1.00)	0.806 (1.00)
SGK1	15 (6%)	233	0.831 (1.00)	0.427 (1.00)	0.47 (1.00)	0.158 (1.00)	0.122 (1.00)
NRAS	9 (4%)	239	0.244 (1.00)	0.616 (1.00)	1 (1.00)	0.722 (1.00)	1 (1.00)
TIAL1	11 (4%)	237	0.282 (1.00)	0.475 (1.00)	0.352 (1.00)	0.753 (1.00)	0.639 (1.00)
SIN3A	21 (8%)	227	0.42 (1.00)	0.256 (1.00)	0.276 (1.00)	0.811 (1.00)	1 (1.00)
SLC48A1	5 (2%)	243	0.467 (1.00)	0.645 (1.00)	0.621 (1.00)	0.663 (1.00)	0.559 (1.00)
RNF43	12 (5%)	236	0.247 (1.00)	0.644 (1.00)	0.289 (1.00)	0.0039 (0.601)	0.689 (1.00)
ZFHX3	44 (18%)	204	0.65 (1.00)	0.765 (1.00)	0.0615 (1.00)	0.73 (1.00)	0.558 (1.00)
RB1	20 (8%)	228	0.331 (1.00)	0.237 (1.00)	0.0685 (1.00)	0.465 (1.00)	0.933 (1.00)

'PPP2R1A MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 0.000478 (Fisher's exact test), Q value = 0.075

Table S1. Gene #1: 'PPP2R1A MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients	ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA	MIXED SEROUS AND ENDOMETRIOID	SEROUS ENDOMETRIAL ADENOCARCINOMA
ALL	200	4	44
PPP2R1A MUTATED	14	1	12
PPP2R1A WILD-TYPE	186	3	32

Figure S1. Get High-res Image Gene #1: 'PPP2R1A MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

'CTNNB1 MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 1.99e-08 (Fisher's exact test), Q value = 3.2e-06

Table S2. Gene #3: 'CTNNB1 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients	ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA	MIXED SEROUS AND ENDOMETRIOID	SEROUS ENDOMETRIAL ADENOCARCINOMA
ALL	200	4	44
CTNNB1 MUTATED	74	0	0
CTNNB1 WILD-TYPE	126	4	44

Figure S2. Get High-res Image Gene #3: 'CTNNB1 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

'PIK3R1 MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 1.49e-06 (Fisher's exact test), Q value = 0.00024

Table S3. Gene #4: 'PIK3R1 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients	ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA	MIXED SEROUS AND ENDOMETRIOID	SEROUS ENDOMETRIAL ADENOCARCINOMA
ALL	200	4	44
PIK3R1 MUTATED	80	1	2
PIK3R1 WILD-TYPE	120	3	42

Figure S3. Get High-res Image Gene #4: 'PIK3R1 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

'PTEN MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 1.23e-23 (Fisher's exact test), Q value = 2e-21

Table S4. Gene #6: 'PTEN MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients	ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA	MIXED SEROUS AND ENDOMETRIOID	SEROUS ENDOMETRIAL ADENOCARCINOMA
ALL	200	4	44
PTEN MUTATED	159	1	1
PTEN WILD-TYPE	41	3	43

Figure S4. Get High-res Image Gene #6: 'PTEN MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

'KRAS MUTATION STATUS' versus 'AGE'

P value = 0.000274 (t-test), Q value = 0.043

Table S5. Gene #7: 'KRAS MUTATION STATUS' versus Clinical Feature #2: 'AGE'

	nPatients	Mean (Std.Dev)
ALL	248	63.1 (11.1)
KRAS MUTATED	53	58.8 (8.7)
KRAS WILD-TYPE	195	64.3 (11.4)

Figure S5. Get High-res Image Gene #7: 'KRAS MUTATION STATUS' versus Clinical Feature #2: 'AGE'

'KRAS MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 0.000253 (Fisher's exact test), Q value = 0.04

Table S6. Gene #7: 'KRAS MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients	ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA	MIXED SEROUS AND ENDOMETRIOID	SEROUS ENDOMETRIAL ADENOCARCINOMA
ALL	200	4	44
KRAS MUTATED	52	0	1
KRAS WILD-TYPE	148	4	43

Figure S6. Get High-res Image Gene #7: 'KRAS MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

'TP53 MUTATION STATUS' versus 'AGE'

P value = 6.15e-06 (t-test), Q value = 0.00099

Table S7. Gene #8: 'TP53 MUTATION STATUS' versus Clinical Feature #2: 'AGE'

	nPatients	Mean (Std.Dev)
ALL	248	63.1 (11.1)
TP53 MUTATED	69	67.9 (9.4)
TP53 WILD-TYPE	179	61.3 (11.2)

Figure S7. Get High-res Image Gene #8: 'TP53 MUTATION STATUS' versus Clinical Feature #2: 'AGE'

'TP53 MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 8.52e-23 (Fisher's exact test), Q value = 1.4e-20

Table S8. Gene #8: 'TP53 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients	ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA	MIXED SEROUS AND ENDOMETRIOID	SEROUS ENDOMETRIAL ADENOCARCINOMA
ALL	200	4	44
TP53 MUTATED	27	3	39
TP53 WILD-TYPE	173	1	5

Figure S8. Get High-res Image Gene #8: 'TP53 MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

'CTCF MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 0.000179 (Fisher's exact test), Q value = 0.028

Table S9. Gene #10: 'CTCF MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients	ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA	MIXED SEROUS AND ENDOMETRIOID	SEROUS ENDOMETRIAL ADENOCARCINOMA
ALL	200	4	44
CTCF MUTATED	44	0	0
CTCF WILD-TYPE	156	4	44

Figure S9. Get High-res Image Gene #10: 'CTCF MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

'ARID1A MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 0.000113 (Fisher's exact test), Q value = 0.018

Table S10. Gene #11: 'ARID1A MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

nPatients	ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA	MIXED SEROUS AND ENDOMETRIOID	SEROUS ENDOMETRIAL ADENOCARCINOMA
ALL	200	4	44
ARID1A MUTATED	78	1	4
ARID1A WILD-TYPE	122	3	40

Figure S10. Get High-res Image Gene #11: 'ARID1A MUTATION STATUS' versus Clinical Feature #3: 'HISTOLOGICAL.TYPE'

Methods & Data

Input

Mutation data file = transformed.cor.cli.txt
Clinical data file = UCEC-TP.merged_data.txt
Number of patients = 248
Number of significantly mutated genes = 33
Number of selected clinical features = 5
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

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

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

[3] 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)

[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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