Correlation between gene methylation status and clinical features

Colon Adenocarcinoma (Primary solid tumor)

17 October 2014 | analyses__2014_10_17

Maintainer Information

Citation Information

Maintained by Juok Cho (Broad Institute)

Cite as Broad Institute TCGA Genome Data Analysis Center (2014): Correlation between gene methylation status and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C1JH3K1T

Overview

Introduction

This pipeline uses various statistical tests to identify genes whose promoter methylation levels correlated to selected clinical features.

Summary

Testing the association between 19885 genes and 12 clinical features across 278 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 8 clinical features related to at least one genes.

14 genes correlated to 'AGE'.

GDNF , C1QL1 , VENTX , KLF14 , GPR1 , ...

1 gene correlated to 'NEOPLASM.DISEASESTAGE'.

UBE2L6

21 genes correlated to 'PATHOLOGY.N.STAGE'.

CASP1__1 , UBE2L6 , APOL1 , CASP5 , IL12RB1 , ...

1 gene correlated to 'PATHOLOGY.M.STAGE'.

KIF13B

15 genes correlated to 'GENDER'.

GPX1 , KIF4B , POLDIP3 , RNU12 , MIR220B , ...

15 genes correlated to 'HISTOLOGICAL.TYPE'.

RALGPS1__1 , POFUT1 , PDE4B , POLR1D , BCL2L1 , ...

12 genes correlated to 'NUMBER.OF.LYMPH.NODES'.

CASP1__1 , UBE2L6 , IL12RB1 , APOL1 , SRBD1 , ...

35 genes correlated to 'RACE'.

DHRS7 , CN5H6.4 , GTSE1 , XPNPEP1 , GSTCD__1 , ...

No genes correlated to 'Time to Death', 'PATHOLOGY.T.STAGE', 'RADIATIONS.RADIATION.REGIMENINDICATION', and 'COMPLETENESS.OF.RESECTION'.

Results

Overview of the results

Complete statistical result table is provided in Supplement Table 1

Table 1. Get Full Table This table shows the clinical features, statistical methods used, and the number of genes that are significantly associated with each clinical feature at P value < 0.05 and Q value < 0.3.

Clinical feature	Statistical test	Significant genes	Associated with		Associated with
Time to Death	Cox regression test	N=0
AGE	Spearman correlation test	N=14	older	N=14	younger	N=0
NEOPLASM DISEASESTAGE	Kruskal-Wallis test	N=1
PATHOLOGY T STAGE	Spearman correlation test	N=0
PATHOLOGY N STAGE	Spearman correlation test	N=21	higher stage	N=17	lower stage	N=4
PATHOLOGY M STAGE	Kruskal-Wallis test	N=1
GENDER	Wilcoxon test	N=15	male	N=15	female	N=0
HISTOLOGICAL TYPE	Wilcoxon test	N=15	colon mucinous adenocarcinoma	N=15	colon adenocarcinoma	N=0
RADIATIONS RADIATION REGIMENINDICATION	Wilcoxon test	N=0
COMPLETENESS OF RESECTION	Kruskal-Wallis test	N=0
NUMBER OF LYMPH NODES	Spearman correlation test	N=12	higher number.of.lymph.nodes	N=12	lower number.of.lymph.nodes	N=0
RACE	Kruskal-Wallis test	N=35

Clinical variable #1: 'Time to Death'

No gene related to 'Time to Death'.

Table S1. Basic characteristics of clinical feature: 'Time to Death'


Time to Death	Duration (Months)	0.1-140.4 (median=17.8)
	censored	N = 214
	death	N = 60

	Significant markers	N = 0

Clinical variable #2: 'AGE'

14 genes related to 'AGE'.

Table S2. Basic characteristics of clinical feature: 'AGE'


AGE	Mean (SD)	65.05 (13)
	Significant markers	N = 14
	pos. correlated	14
	neg. correlated	0

List of top 10 genes differentially expressed by 'AGE'

Table S3. Get Full Table List of top 10 genes significantly correlated to 'AGE' by Spearman correlation test

	SpearmanCorr	corrP	Q
GDNF	0.3033	2.639e-07	0.00525
C1QL1	0.2938	6.444e-07	0.0128
VENTX	0.2749	3.424e-06	0.0681
KLF14	0.2744	3.564e-06	0.0709
GPR1	0.2705	4.948e-06	0.0984
TAC1	0.2703	5.047e-06	0.1
EBF4	0.2681	6.035e-06	0.12
SLC26A8	0.2647	7.999e-06	0.159
CCL2	0.2612	1.064e-05	0.211
ZSCAN12	0.2609	1.086e-05	0.216

Clinical variable #3: 'NEOPLASM.DISEASESTAGE'

One gene related to 'NEOPLASM.DISEASESTAGE'.

Table S4. Basic characteristics of clinical feature: 'NEOPLASM.DISEASESTAGE'


NEOPLASM.DISEASESTAGE	Labels	N
	STAGE I	41
	STAGE IA	1
	STAGE II	14
	STAGE IIA	89
	STAGE IIB	5
	STAGE IIC	1
	STAGE III	7
	STAGE IIIA	9
	STAGE IIIB	43
	STAGE IIIC	23
	STAGE IV	20
	STAGE IVA	16
	STAGE IVB	1

	Significant markers	N = 1

List of one gene differentially expressed by 'NEOPLASM.DISEASESTAGE'

Table S5. Get Full Table List of one gene differentially expressed by 'NEOPLASM.DISEASESTAGE'

	ANOVA_P	Q
UBE2L6	2.223e-06	0.0442

Clinical variable #4: 'PATHOLOGY.T.STAGE'

No gene related to 'PATHOLOGY.T.STAGE'.

Table S6. Basic characteristics of clinical feature: 'PATHOLOGY.T.STAGE'


PATHOLOGY.T.STAGE	Mean (SD)	2.92 (0.61)
		N
	1	7
	2	42
	3	193
	4	35

	Significant markers	N = 0

Clinical variable #5: 'PATHOLOGY.N.STAGE'

21 genes related to 'PATHOLOGY.N.STAGE'.

Table S7. Basic characteristics of clinical feature: 'PATHOLOGY.N.STAGE'


PATHOLOGY.N.STAGE	Mean (SD)	0.57 (0.75)
		N
	0	163
	1	70
	2	44

	Significant markers	N = 21
	pos. correlated	17
	neg. correlated	4

List of top 10 genes differentially expressed by 'PATHOLOGY.N.STAGE'

Table S8. Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY.N.STAGE' by Spearman correlation test

	SpearmanCorr	corrP	Q
CASP1__1	0.3613	5.798e-10	1.15e-05
UBE2L6	0.3399	6.444e-09	0.000128
APOL1	0.336	9.822e-09	0.000195
CASP5	0.312	1.139e-07	0.00227
IL12RB1	0.308	1.697e-07	0.00337
PKN2	0.2925	7.214e-07	0.0143
SP140L	0.2868	1.21e-06	0.024
MED18	0.2821	1.839e-06	0.0366
PFKFB2	0.2818	1.884e-06	0.0375
RARRES3	0.2816	1.908e-06	0.0379

Clinical variable #6: 'PATHOLOGY.M.STAGE'

One gene related to 'PATHOLOGY.M.STAGE'.

Table S9. Basic characteristics of clinical feature: 'PATHOLOGY.M.STAGE'


PATHOLOGY.M.STAGE	Labels	N
	M0	190
	M1	28
	M1A	7
	M1B	1
	MX	47

	Significant markers	N = 1

List of one gene differentially expressed by 'PATHOLOGY.M.STAGE'

Table S10. Get Full Table List of one gene differentially expressed by 'PATHOLOGY.M.STAGE'

	ANOVA_P	Q
KIF13B	5.672e-06	0.113

Clinical variable #7: 'GENDER'

15 genes related to 'GENDER'.

Table S11. Basic characteristics of clinical feature: 'GENDER'


GENDER	Labels	N
	FEMALE	126
	MALE	152

	Significant markers	N = 15
	Higher in MALE	15
	Higher in FEMALE	0

List of top 10 genes differentially expressed by 'GENDER'

Table S12. Get Full Table List of top 10 genes differentially expressed by 'GENDER'. 0 significant gene(s) located in sex chromosomes is(are) filtered out.

	W(pos if higher in 'MALE')	wilcoxontestP	Q	AUC
GPX1	3111	3.404e-22	6.77e-18	0.8376
KIF4B	3748	2.48e-18	4.93e-14	0.8043
POLDIP3	3958	3.82e-17	7.59e-13	0.7933
RNU12	3958	3.82e-17	7.59e-13	0.7933
MIR220B	14423	3.789e-13	7.53e-09	0.7531
TUBB4	14423	3.789e-13	7.53e-09	0.7531
PSRC1	5087	1.739e-11	3.46e-07	0.7344
PAFAH1B2	5175	4.266e-11	8.48e-07	0.7298
ZNF839	5832	2.024e-08	0.000402	0.6955
FASTKD2__1	6045	1.218e-07	0.00242	0.6844

Clinical variable #8: 'HISTOLOGICAL.TYPE'

15 genes related to 'HISTOLOGICAL.TYPE'.

Table S13. Basic characteristics of clinical feature: 'HISTOLOGICAL.TYPE'


HISTOLOGICAL.TYPE	Labels	N
	COLON ADENOCARCINOMA	244
	COLON MUCINOUS ADENOCARCINOMA	34

	Significant markers	N = 15
	Higher in COLON MUCINOUS ADENOCARCINOMA	15
	Higher in COLON ADENOCARCINOMA	0

List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

Table S14. Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

	W(pos if higher in 'COLON MUCINOUS ADENOCARCINOMA')	wilcoxontestP	Q	AUC
RALGPS1__1	6315	8.097e-07	0.0161	0.7612
POFUT1	6280	1.214e-06	0.0241	0.757
PDE4B	2047	1.729e-06	0.0344	0.7533
POLR1D	6207	2.771e-06	0.0551	0.7482
BCL2L1	6186	3.496e-06	0.0695	0.7457
MYST4	2111	3.535e-06	0.0703	0.7455
GFOD2	6172	4.077e-06	0.081	0.744
CPPED1	6144	5.529e-06	0.11	0.7406
SPDYC	2177	7.232e-06	0.144	0.7376
REV1	6090	9.838e-06	0.196	0.7341

Clinical variable #9: 'RADIATIONS.RADIATION.REGIMENINDICATION'

No gene related to 'RADIATIONS.RADIATION.REGIMENINDICATION'.

Table S15. Basic characteristics of clinical feature: 'RADIATIONS.RADIATION.REGIMENINDICATION'


RADIATIONS.RADIATION.REGIMENINDICATION	Labels	N
	NO	3
	YES	275

	Significant markers	N = 0

Clinical variable #10: 'COMPLETENESS.OF.RESECTION'

No gene related to 'COMPLETENESS.OF.RESECTION'.

Table S16. Basic characteristics of clinical feature: 'COMPLETENESS.OF.RESECTION'


COMPLETENESS.OF.RESECTION	Labels	N
	R0	179
	R1	2
	R2	4
	RX	23

	Significant markers	N = 0

Clinical variable #11: 'NUMBER.OF.LYMPH.NODES'

12 genes related to 'NUMBER.OF.LYMPH.NODES'.

Table S17. Basic characteristics of clinical feature: 'NUMBER.OF.LYMPH.NODES'


NUMBER.OF.LYMPH.NODES	Mean (SD)	1.93 (4.4)
	Significant markers	N = 12
	pos. correlated	12
	neg. correlated	0

List of top 10 genes differentially expressed by 'NUMBER.OF.LYMPH.NODES'

Table S18. Get Full Table List of top 10 genes significantly correlated to 'NUMBER.OF.LYMPH.NODES' by Spearman correlation test

	SpearmanCorr	corrP	Q
CASP1__1	0.3805	3.312e-10	6.59e-06
UBE2L6	0.3465	1.328e-08	0.000264
IL12RB1	0.316	2.561e-07	0.00509
APOL1	0.3142	3e-07	0.00596
SRBD1	0.3007	9.966e-07	0.0198
CSGALNACT1	0.2953	1.584e-06	0.0315
CASP5	0.2918	2.137e-06	0.0425
MARCH8	0.2869	3.21e-06	0.0638
CARD16	0.2813	5.048e-06	0.1
CASP1	0.2813	5.048e-06	0.1

Clinical variable #12: 'RACE'

35 genes related to 'RACE'.

Table S19. Basic characteristics of clinical feature: 'RACE'


RACE	Labels	N
	AMERICAN INDIAN OR ALASKA NATIVE	1
	ASIAN	11
	BLACK OR AFRICAN AMERICAN	43
	WHITE	205

	Significant markers	N = 35

List of top 10 genes differentially expressed by 'RACE'

Table S20. Get Full Table List of top 10 genes differentially expressed by 'RACE'

	ANOVA_P	Q
DHRS7	1.335e-11	2.66e-07
CN5H6.4	5.198e-09	0.000103
GTSE1	5.198e-09	0.000103
XPNPEP1	6.412e-08	0.00127
GSTCD__1	7.057e-08	0.0014
INTS12__1	7.057e-08	0.0014
FAM115C	1.176e-07	0.00234
CPS1	1.297e-07	0.00258
LANCL1	1.297e-07	0.00258
PGBD5	1.664e-07	0.00331

Methods & Data

Input

Expresson data file = COAD-TP.meth.by_min_clin_corr.data.txt
Clinical data file = COAD-TP.merged_data.txt
Number of patients = 278
Number of genes = 19885
Number of clinical features = 12

Survival analysis

For survival clinical features, Wald's test in univariate Cox regression analysis with proportional hazards model (Andersen and Gill 1982) was used to estimate the P values using the 'coxph' function in R. Kaplan-Meier survival curves were plot using the four quartile subgroups of patients based on expression levels

Correlation analysis

For continuous numerical clinical features, Spearman's rank correlation coefficients (Spearman 1904) and two-tailed P values were estimated using 'cor.test' function in R

ANOVA analysis

For multi-class clinical features (ordinal or nominal), one-way analysis of variance (Howell 2002) was applied to compare the log2-expression levels between different clinical classes using 'anova' function in R

Student's t-test analysis

For two-class clinical features, two-tailed Student's t test with unequal variance (Lehmann and Romano 2005) was applied to compare the log2-expression levels between the two clinical classes using 't.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] Andersen and Gill, Cox's regression model for counting processes, a large sample study, Annals of Statistics 10(4):1100-1120 (1982)

[2] Spearman, C, The proof and measurement of association between two things, Amer. J. Psychol 15:72-101 (1904)

[3] Howell, D, Statistical Methods for Psychology. (5th ed.), Duxbury Press:324-5 (2002)

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

[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)

Made with Nozzle