Correlation between gene methylation status and clinical features

Stomach 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/C1VQ31MP

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 19730 genes and 12 clinical features across 319 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 6 clinical features related to at least one genes.

215 genes correlated to 'AGE'.

CDCA5 , ZFPL1 , OBFC2B , SLC26A3 , SPRR1A , ...

171 genes correlated to 'NEOPLASM.DISEASESTAGE'.

TRNT1 , ZFP42 , SMAD1 , EED , SNORA25 , ...

821 genes correlated to 'PATHOLOGY.T.STAGE'.

FAM3C , CEP152 , RPL24 , FBXO33 , PIGY , ...

7 genes correlated to 'GENDER'.

ALG11__1 , UTP14C , KIF4B , CDH15 , NLRP2 , ...

513 genes correlated to 'HISTOLOGICAL.TYPE'.

ASB14 , C3ORF26 , FILIP1L , OVOL1 , NGEF , ...

352 genes correlated to 'RACE'.

GRAPL , GTF2IRD2B , CRYZ__1 , TYW3__1 , PYCRL , ...

No genes correlated to 'Time to Death', 'PATHOLOGY.N.STAGE', 'PATHOLOGY.M.STAGE', 'RADIATIONS.RADIATION.REGIMENINDICATION', 'COMPLETENESS.OF.RESECTION', and 'NUMBER.OF.LYMPH.NODES'.

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=215	older	N=4	younger	N=211
NEOPLASM DISEASESTAGE	Kruskal-Wallis test	N=171
PATHOLOGY T STAGE	Spearman correlation test	N=821	higher stage	N=305	lower stage	N=516
PATHOLOGY N STAGE	Spearman correlation test	N=0
PATHOLOGY M STAGE	Kruskal-Wallis test	N=0
GENDER	Wilcoxon test	N=7	male	N=7	female	N=0
HISTOLOGICAL TYPE	Kruskal-Wallis test	N=513
RADIATIONS RADIATION REGIMENINDICATION	Wilcoxon test	N=0
COMPLETENESS OF RESECTION	Kruskal-Wallis test	N=0
NUMBER OF LYMPH NODES	Spearman correlation test	N=0
RACE	Kruskal-Wallis test	N=352

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)	0.1-122.3 (median=11.3)
	censored	N = 218
	death	N = 90

	Significant markers	N = 0

Clinical variable #2: 'AGE'

215 genes related to 'AGE'.

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


AGE	Mean (SD)	65.6 (11)
	Significant markers	N = 215
	pos. correlated	4
	neg. correlated	211

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
CDCA5	-0.3158	1.182e-08	0.000233
ZFPL1	-0.3158	1.182e-08	0.000233
OBFC2B	-0.2988	7.427e-08	0.00147
SLC26A3	-0.2974	8.586e-08	0.00169
SPRR1A	-0.2947	1.143e-07	0.00225
STARD10	-0.2916	1.562e-07	0.00308
RPL35	-0.2887	2.109e-07	0.00416
PRTN3	-0.2882	2.22e-07	0.00438
BOP1	-0.2879	2.273e-07	0.00448
HSF1	-0.2879	2.273e-07	0.00448

Clinical variable #3: 'NEOPLASM.DISEASESTAGE'

171 genes related to 'NEOPLASM.DISEASESTAGE'.

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


NEOPLASM.DISEASESTAGE	Labels	N
	STAGE I	2
	STAGE IA	11
	STAGE IB	33
	STAGE II	26
	STAGE IIA	37
	STAGE IIB	47
	STAGE III	2
	STAGE IIIA	64
	STAGE IIIB	46
	STAGE IIIC	32
	STAGE IV	19

	Significant markers	N = 171

List of top 10 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

Table S5. Get Full Table List of top 10 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

	ANOVA_P	Q
TRNT1	6.369e-09	0.000126
ZFP42	3.76e-08	0.000742
SMAD1	4.584e-08	0.000904
EED	6.644e-08	0.00131
SNORA25	7.424e-08	0.00146
SNORA32	7.424e-08	0.00146
SNORD6	7.424e-08	0.00146
MGEA5	1.727e-07	0.00341
PRKAR1A	2.657e-07	0.00524
NIT1__1	3.539e-07	0.00698

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

821 genes related to 'PATHOLOGY.T.STAGE'.

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


PATHOLOGY.T.STAGE	Mean (SD)	2.92 (0.84)
		N
	1	18
	2	72
	3	148
	4	81

	Significant markers	N = 821
	pos. correlated	305
	neg. correlated	516

List of top 10 genes differentially expressed by 'PATHOLOGY.T.STAGE'

Table S7. Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY.T.STAGE' by Spearman correlation test

	SpearmanCorr	corrP	Q
FAM3C	-0.3511	1.104e-10	2.18e-06
CEP152	-0.3482	1.6e-10	3.16e-06
RPL24	-0.3478	1.672e-10	3.3e-06
FBXO33	-0.3332	1.037e-09	2.05e-05
PIGY	-0.3313	1.306e-09	2.58e-05
LRRC40	-0.3311	1.343e-09	2.65e-05
SFRS11	-0.3311	1.343e-09	2.65e-05
FEM1B	-0.3309	1.368e-09	2.7e-05
C4ORF29	-0.3294	1.652e-09	3.26e-05
MFSD8	-0.3294	1.652e-09	3.26e-05

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

No gene related to 'PATHOLOGY.N.STAGE'.

Table S8. Basic characteristics of clinical feature: 'PATHOLOGY.N.STAGE'


PATHOLOGY.N.STAGE	Mean (SD)	1.26 (1.1)
		N
	0	110
	1	81
	2	62
	3	65

	Significant markers	N = 0

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

No gene related to 'PATHOLOGY.M.STAGE'.

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


PATHOLOGY.M.STAGE	Labels	N
	M0	289
	M1	15
	MX	15

	Significant markers	N = 0

Clinical variable #7: 'GENDER'

7 genes related to 'GENDER'.

Table S10. Basic characteristics of clinical feature: 'GENDER'


GENDER	Labels	N
	FEMALE	122
	MALE	197

	Significant markers	N = 7
	Higher in MALE	7
	Higher in FEMALE	0

List of 7 genes differentially expressed by 'GENDER'

Table S11. Get Full Table List of 7 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
ALG11__1	22518	2.655e-39	5.24e-35	0.9369
UTP14C	22518	2.655e-39	5.24e-35	0.9369
KIF4B	4129	6.693e-23	1.32e-18	0.8282
CDH15	16083	3.809e-07	0.00751	0.6692
NLRP2	15599	7.687e-06	0.152	0.649
RIMBP3	15581	8.538e-06	0.168	0.6483
DDX43	8468	9.315e-06	0.184	0.6477

Clinical variable #8: 'HISTOLOGICAL.TYPE'

513 genes related to 'HISTOLOGICAL.TYPE'.

Table S12. Basic characteristics of clinical feature: 'HISTOLOGICAL.TYPE'


HISTOLOGICAL.TYPE	Labels	N
	STOMACH ADENOCARCINOMA DIFFUSE TYPE	59
	STOMACH ADENOCARCINOMA NOT OTHERWISE SPECIFIED (NOS)	128
	STOMACH INTESTINAL ADENOCARCINOMA NOT OTHERWISE SPECIFIED (NOS)	50
	STOMACH INTESTINAL ADENOCARCINOMA TUBULAR TYPE	50
	STOMACH INTESTINAL ADENOCARCINOMA MUCINOUS TYPE	19
	STOMACH INTESTINAL ADENOCARCINOMA PAPILLARY TYPE	7
	STOMACH ADENOCARCINOMA SIGNET RING TYPE	6

	Significant markers	N = 513

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

Table S13. Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

	ANOVA_P	Q
ASB14	2.963e-10	5.85e-06
C3ORF26	1.233e-09	2.43e-05
FILIP1L	1.233e-09	2.43e-05
OVOL1	4.109e-09	8.11e-05
NGEF	4.242e-09	8.37e-05
VIL1	5.549e-09	0.000109
KRT23	5.657e-09	0.000112
SERPINB12	7.237e-09	0.000143
SLC23A1	9.35e-09	0.000184
COX8C	1.149e-08	0.000227

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

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

Table S14. Basic characteristics of clinical feature: 'RADIATIONS.RADIATION.REGIMENINDICATION'


RADIATIONS.RADIATION.REGIMENINDICATION	Labels	N
	NO	6
	YES	313

	Significant markers	N = 0

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

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

Table S15. Basic characteristics of clinical feature: 'COMPLETENESS.OF.RESECTION'


COMPLETENESS.OF.RESECTION	Labels	N
	R0	280
	R1	13
	R2	7

	Significant markers	N = 0

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

No gene related to 'NUMBER.OF.LYMPH.NODES'.

Table S16. Basic characteristics of clinical feature: 'NUMBER.OF.LYMPH.NODES'


NUMBER.OF.LYMPH.NODES	Mean (SD)	4.98 (7.5)
	Significant markers	N = 0

Clinical variable #12: 'RACE'

352 genes related to 'RACE'.

Table S17. Basic characteristics of clinical feature: 'RACE'


RACE	Labels	N
	ASIAN	88
	BLACK OR AFRICAN AMERICAN	6
	NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER	1
	WHITE	196

	Significant markers	N = 352

List of top 10 genes differentially expressed by 'RACE'

Table S18. Get Full Table List of top 10 genes differentially expressed by 'RACE'

	ANOVA_P	Q
GRAPL	2.998e-13	5.91e-09
GTF2IRD2B	2.716e-11	5.36e-07
CRYZ__1	2.875e-11	5.67e-07
TYW3__1	2.875e-11	5.67e-07
PYCRL	1.609e-10	3.17e-06
LOC100271836	7.077e-10	1.4e-05
PM20D1	9.857e-10	1.94e-05
C11ORF58	1.229e-09	2.42e-05
TRMT11	2.994e-09	5.91e-05
PIGY	3.125e-09	6.16e-05

Methods & Data

Input

Expresson data file = STAD-TP.meth.by_min_clin_corr.data.txt
Clinical data file = STAD-TP.merged_data.txt
Number of patients = 319
Number of genes = 19730
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)

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