Correlation between gene mutation status and selected clinical features

Colorectal Adenocarcinoma (Primary solid tumor)

15 January 2014 | analyses__2014_01_15

Maintainer Information

Citation Information

doi:10.7908/C1930RKM

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

Cite as Broad Institute TCGA Genome Data Analysis Center (2014): Correlation between gene mutation status and selected clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C1930RKM

Overview

Introduction

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

Summary

Testing the association between mutation status of 24 genes and 11 clinical features across 223 patients, 8 significant findings detected with Q value < 0.25.

BRAF mutation correlated to 'HISTOLOGICAL.TYPE'.
TP53 mutation correlated to 'HISTOLOGICAL.TYPE'.
PIK3CA mutation correlated to 'NUMBER.OF.LYMPH.NODES'.
ACVR2A mutation correlated to 'NUMBER.OF.LYMPH.NODES'.
CRTC1 mutation correlated to 'NUMBER.OF.LYMPH.NODES'.
KRTAP5-5 mutation correlated to 'NUMBER.OF.LYMPH.NODES'.
PCBP1 mutation correlated to 'NEOPLASM.DISEASESTAGE'.
GGT1 mutation correlated to 'NUMBER.OF.LYMPH.NODES'.

Results

Overview of the results

Table 1. Get Full Table Overview of the association between mutation status of 24 genes and 11 clinical features. Shown in the table are P values (Q values). Thresholded by Q value < 0.25, 8 significant findings detected.


		Clinical Features	Time to Death	AGE	PRIMARY SITE OF DISEASE	NEOPLASM DISEASESTAGE	PATHOLOGY T STAGE	PATHOLOGY N STAGE	PATHOLOGY M STAGE	GENDER	HISTOLOGICAL TYPE	COMPLETENESS OF RESECTION	NUMBER OF LYMPH NODES
	nMutated (%)	nWild-Type	logrank test	t-test	Fisher's exact test	Chi-square 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	t-test
BRAF	22 (10%)	201	0.667 (1.00)	0.0902 (1.00)	0.0261 (1.00)	0.154 (1.00)	0.0799 (1.00)	0.904 (1.00)	0.395 (1.00)	0.0703 (1.00)	9.61e-06 (0.00245)	0.612 (1.00)	0.589 (1.00)
TP53	119 (53%)	104	0.485 (1.00)	0.0778 (1.00)	0.013 (1.00)	0.344 (1.00)	0.928 (1.00)	0.258 (1.00)	0.885 (1.00)	0.285 (1.00)	0.000164 (0.0415)	0.566 (1.00)	0.43 (1.00)
PIK3CA	33 (15%)	190	0.925 (1.00)	0.0966 (1.00)	0.226 (1.00)	0.0202 (1.00)	0.916 (1.00)	0.022 (1.00)	0.133 (1.00)	0.851 (1.00)	0.0297 (1.00)	0.304 (1.00)	1.26e-05 (0.00321)
ACVR2A	9 (4%)	214	0.217 (1.00)	0.443 (1.00)	0.281 (1.00)	0.492 (1.00)	0.905 (1.00)	0.353 (1.00)	1 (1.00)	0.0912 (1.00)	0.704 (1.00)	1 (1.00)	3.99e-08 (1.03e-05)
CRTC1	6 (3%)	217		0.0354 (1.00)	0.669 (1.00)	0.266 (1.00)	0.205 (1.00)	0.536 (1.00)	0.609 (1.00)	0.43 (1.00)	0.745 (1.00)	1 (1.00)	0.000473 (0.119)
KRTAP5-5	4 (2%)	219		0.912 (1.00)	0.589 (1.00)	0.0263 (1.00)	0.431 (1.00)	0.479 (1.00)	1 (1.00)	1 (1.00)	0.773 (1.00)	1 (1.00)	3.21e-11 (8.31e-09)
PCBP1	6 (3%)	217	0.541 (1.00)	0.777 (1.00)	1 (1.00)	5.52e-06 (0.00141)	0.508 (1.00)	0.536 (1.00)	0.0311 (1.00)	0.685 (1.00)	1 (1.00)	1 (1.00)	0.0129 (1.00)
GGT1	3 (1%)	220		0.957 (1.00)	0.554 (1.00)	0.929 (1.00)	0.704 (1.00)	0.567 (1.00)	1 (1.00)	0.609 (1.00)	0.715 (1.00)	1 (1.00)	3.24e-11 (8.37e-09)
APC	160 (72%)	63	0.5 (1.00)	0.293 (1.00)	0.0232 (1.00)	0.953 (1.00)	0.945 (1.00)	0.865 (1.00)	0.609 (1.00)	0.0531 (1.00)	0.128 (1.00)	0.186 (1.00)	0.899 (1.00)
FBXW7	38 (17%)	185	0.977 (1.00)	0.0623 (1.00)	0.34 (1.00)	0.0561 (1.00)	0.117 (1.00)	0.745 (1.00)	0.00355 (0.889)	0.374 (1.00)	0.0316 (1.00)	0.0346 (1.00)	0.855 (1.00)
NRAS	20 (9%)	203	0.145 (1.00)	0.0391 (1.00)	0.623 (1.00)	0.414 (1.00)	0.292 (1.00)	0.0366 (1.00)	0.542 (1.00)	0.0357 (1.00)	1 (1.00)	0.471 (1.00)	0.0251 (1.00)
KRAS	96 (43%)	127	0.0338 (1.00)	0.141 (1.00)	0.0272 (1.00)	0.739 (1.00)	0.296 (1.00)	0.291 (1.00)	0.172 (1.00)	0.591 (1.00)	0.0856 (1.00)	0.0365 (1.00)	0.194 (1.00)
SMAD4	26 (12%)	197	0.613 (1.00)	0.951 (1.00)	1 (1.00)	0.97 (1.00)	0.87 (1.00)	1 (1.00)	0.796 (1.00)	0.838 (1.00)	0.0143 (1.00)	0.831 (1.00)	0.318 (1.00)
FAM123B	25 (11%)	198	0.801 (1.00)	0.896 (1.00)	0.499 (1.00)	0.888 (1.00)	0.705 (1.00)	0.316 (1.00)	0.782 (1.00)	1 (1.00)	0.856 (1.00)	0.646 (1.00)	0.498 (1.00)
SMAD2	15 (7%)	208	0.98 (1.00)	0.689 (1.00)	0.78 (1.00)	0.00267 (0.671)	0.373 (1.00)	0.27 (1.00)	1 (1.00)	0.291 (1.00)	0.38 (1.00)	0.748 (1.00)	0.0341 (1.00)
TCF7L2	18 (8%)	205	0.243 (1.00)	0.385 (1.00)	0.785 (1.00)	0.865 (1.00)	0.337 (1.00)	0.943 (1.00)	0.737 (1.00)	0.624 (1.00)	0.481 (1.00)	0.575 (1.00)	0.108 (1.00)
SOX9	10 (4%)	213	0.68 (1.00)	0.274 (1.00)	0.181 (1.00)	0.309 (1.00)	0.155 (1.00)	0.902 (1.00)	1 (1.00)	0.526 (1.00)	0.608 (1.00)	1 (1.00)	0.203 (1.00)
ELF3	6 (3%)	217	0.616 (1.00)	0.197 (1.00)	0.375 (1.00)	0.974 (1.00)	0.205 (1.00)	1 (1.00)	1 (1.00)	0.685 (1.00)	0.831 (1.00)	0.595 (1.00)	0.626 (1.00)
TNFRSF10C	6 (3%)	217		0.854 (1.00)	0.181 (1.00)	0.337 (1.00)	0.0712 (1.00)	0.195 (1.00)	0.064 (1.00)	0.685 (1.00)	0.423 (1.00)	0.0799 (1.00)	0.184 (1.00)
KIAA1804	15 (7%)	208	0.251 (1.00)	0.78 (1.00)	0.0181 (1.00)	0.843 (1.00)	0.732 (1.00)	0.345 (1.00)	1 (1.00)	0.425 (1.00)	0.0223 (1.00)	0.748 (1.00)	0.0129 (1.00)
PTEN	7 (3%)	216	0.49 (1.00)	0.0292 (1.00)	0.679 (1.00)	0.247 (1.00)	0.175 (1.00)	1 (1.00)	1 (1.00)	0.713 (1.00)	0.223 (1.00)	0.595 (1.00)	0.14 (1.00)
ACOT4	3 (1%)	220		0.0271 (1.00)	0.554 (1.00)	0.986 (1.00)	0.0642 (1.00)	1 (1.00)	0.376 (1.00)	1 (1.00)	0.379 (1.00)	0.361 (1.00)	0.653 (1.00)
MYO1B	13 (6%)	210	0.318 (1.00)	0.611 (1.00)	1 (1.00)	0.263 (1.00)	0.683 (1.00)	0.53 (1.00)	0.267 (1.00)	0.778 (1.00)	0.308 (1.00)	0.458 (1.00)	0.123 (1.00)
ACVR1B	14 (6%)	209	0.775 (1.00)	0.809 (1.00)	0.0692 (1.00)	0.268 (1.00)	0.0397 (1.00)	1 (1.00)	0.717 (1.00)	1 (1.00)	0.021 (1.00)	1 (1.00)	0.477 (1.00)

'BRAF MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 9.61e-06 (Fisher's exact test), Q value = 0.0024

Table S1. Gene #4: 'BRAF MUTATION STATUS' versus Clinical Feature #9: 'HISTOLOGICAL.TYPE'

nPatients	COLON ADENOCARCINOMA	COLON MUCINOUS ADENOCARCINOMA	RECTAL ADENOCARCINOMA	RECTAL MUCINOUS ADENOCARCINOMA
ALL	130	22	57	8
BRAF MUTATED	10	10	1	1
BRAF WILD-TYPE	120	12	56	7

Figure S1. Get High-res Image Gene #4: 'BRAF MUTATION STATUS' versus Clinical Feature #9: 'HISTOLOGICAL.TYPE'

'TP53 MUTATION STATUS' versus 'HISTOLOGICAL.TYPE'

P value = 0.000164 (Fisher's exact test), Q value = 0.042

Table S2. Gene #6: 'TP53 MUTATION STATUS' versus Clinical Feature #9: 'HISTOLOGICAL.TYPE'

nPatients	COLON ADENOCARCINOMA	COLON MUCINOUS ADENOCARCINOMA	RECTAL ADENOCARCINOMA	RECTAL MUCINOUS ADENOCARCINOMA
ALL	130	22	57	8
TP53 MUTATED	68	4	41	4
TP53 WILD-TYPE	62	18	16	4

Figure S2. Get High-res Image Gene #6: 'TP53 MUTATION STATUS' versus Clinical Feature #9: 'HISTOLOGICAL.TYPE'

'PIK3CA MUTATION STATUS' versus 'NUMBER.OF.LYMPH.NODES'

P value = 1.26e-05 (t-test), Q value = 0.0032

Table S3. Gene #9: 'PIK3CA MUTATION STATUS' versus Clinical Feature #11: 'NUMBER.OF.LYMPH.NODES'

	nPatients	Mean (Std.Dev)
ALL	222	2.3 (4.8)
PIK3CA MUTATED	33	0.5 (1.4)
PIK3CA WILD-TYPE	189	2.6 (5.1)

Figure S3. Get High-res Image Gene #9: 'PIK3CA MUTATION STATUS' versus Clinical Feature #11: 'NUMBER.OF.LYMPH.NODES'

'ACVR2A MUTATION STATUS' versus 'NUMBER.OF.LYMPH.NODES'

P value = 3.99e-08 (t-test), Q value = 1e-05

Table S4. Gene #12: 'ACVR2A MUTATION STATUS' versus Clinical Feature #11: 'NUMBER.OF.LYMPH.NODES'

	nPatients	Mean (Std.Dev)
ALL	222	2.3 (4.8)
ACVR2A MUTATED	9	0.2 (0.4)
ACVR2A WILD-TYPE	213	2.3 (4.9)

Figure S4. Get High-res Image Gene #12: 'ACVR2A MUTATION STATUS' versus Clinical Feature #11: 'NUMBER.OF.LYMPH.NODES'

'CRTC1 MUTATION STATUS' versus 'NUMBER.OF.LYMPH.NODES'

P value = 0.000473 (t-test), Q value = 0.12

Table S5. Gene #15: 'CRTC1 MUTATION STATUS' versus Clinical Feature #11: 'NUMBER.OF.LYMPH.NODES'

	nPatients	Mean (Std.Dev)
ALL	222	2.3 (4.8)
CRTC1 MUTATED	6	0.3 (0.8)
CRTC1 WILD-TYPE	216	2.3 (4.9)

Figure S5. Get High-res Image Gene #15: 'CRTC1 MUTATION STATUS' versus Clinical Feature #11: 'NUMBER.OF.LYMPH.NODES'

'KRTAP5-5 MUTATION STATUS' versus 'NUMBER.OF.LYMPH.NODES'

P value = 3.21e-11 (t-test), Q value = 8.3e-09

Table S6. Gene #18: 'KRTAP5-5 MUTATION STATUS' versus Clinical Feature #11: 'NUMBER.OF.LYMPH.NODES'

	nPatients	Mean (Std.Dev)
ALL	222	2.3 (4.8)
KRTAP5-5 MUTATED	4	0.0 (0.0)
KRTAP5-5 WILD-TYPE	218	2.3 (4.8)

Figure S6. Get High-res Image Gene #18: 'KRTAP5-5 MUTATION STATUS' versus Clinical Feature #11: 'NUMBER.OF.LYMPH.NODES'

'PCBP1 MUTATION STATUS' versus 'NEOPLASM.DISEASESTAGE'

P value = 5.52e-06 (Chi-square test), Q value = 0.0014

Table S7. Gene #22: 'PCBP1 MUTATION STATUS' versus Clinical Feature #4: 'NEOPLASM.DISEASESTAGE'

nPatients	STAGE I	STAGE II	STAGE IIA	STAGE IIB	STAGE III	STAGE IIIA	STAGE IIIB	STAGE IIIC	STAGE IV	STAGE IVA
ALL	49	20	57	4	18	2	20	20	30	1
PCBP1 MUTATED	2	0	3	0	0	0	0	0	0	1
PCBP1 WILD-TYPE	47	20	54	4	18	2	20	20	30	0

Figure S7. Get High-res Image Gene #22: 'PCBP1 MUTATION STATUS' versus Clinical Feature #4: 'NEOPLASM.DISEASESTAGE'

'GGT1 MUTATION STATUS' versus 'NUMBER.OF.LYMPH.NODES'

P value = 3.24e-11 (t-test), Q value = 8.4e-09

Table S8. Gene #23: 'GGT1 MUTATION STATUS' versus Clinical Feature #11: 'NUMBER.OF.LYMPH.NODES'

	nPatients	Mean (Std.Dev)
ALL	222	2.3 (4.8)
GGT1 MUTATED	3	0.0 (0.0)
GGT1 WILD-TYPE	219	2.3 (4.8)

Figure S8. Get High-res Image Gene #23: 'GGT1 MUTATION STATUS' versus Clinical Feature #11: 'NUMBER.OF.LYMPH.NODES'

Methods & Data

Input

Mutation data file = transformed.cor.cli.txt
Clinical data file = COADREAD-TP.merged_data.txt
Number of patients = 223
Number of significantly mutated genes = 24
Number of selected clinical features = 11
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

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.

Download Results

In addition to the links below, the full results of the analysis summarized in this report can also be downloaded programmatically using firehose_get, or interactively from either the Broad GDAC website or TCGA Data Coordination Center Portal.

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

[5] 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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