Correlation between gene methylation status and clinical features

Kidney Chromophobe (Primary solid tumor)

23 September 2013 | analyses__2013_09_23

Maintainer Information

Citation Information

Maintained by Juok Cho (Broad Institute)

Cite as Broad Institute TCGA Genome Data Analysis Center (2013): Correlation between gene methylation status and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C1XK8CWJ

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 19761 genes and 10 clinical features across 61 samples, statistically thresholded by Q value < 0.05, 5 clinical features related to at least one genes.

1 gene correlated to 'Time to Death'.

MAEL

58 genes correlated to 'NEOPLASM.DISEASESTAGE'.

C20ORF46 , LOC643719 , FAM135B , FOXC1 , WTIP , ...

1 gene correlated to 'PATHOLOGY.T.STAGE'.

LRPAP1

53 genes correlated to 'PATHOLOGY.M.STAGE'.

DOK5 , GRID1 , QRFPR , NPY , SHE , ...

1 gene correlated to 'NUMBERPACKYEARSSMOKED'.

GRHL1

No genes correlated to 'AGE', 'PATHOLOGY.N.STAGE', 'GENDER', 'KARNOFSKY.PERFORMANCE.SCORE', and 'YEAROFTOBACCOSMOKINGONSET'.

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 Q value < 0.05.

Clinical feature	Statistical test	Significant genes	Associated with		Associated with
Time to Death	Cox regression test	N=1	shorter survival	N=0	longer survival	N=1
AGE	Spearman correlation test	N=0
NEOPLASM DISEASESTAGE	ANOVA test	N=58
PATHOLOGY T STAGE	Spearman correlation test	N=1	higher stage	N=1	lower stage	N=0
PATHOLOGY N STAGE	Spearman correlation test	N=0
PATHOLOGY M STAGE	ANOVA test	N=53
GENDER	t test	N=0
KARNOFSKY PERFORMANCE SCORE	Spearman correlation test	N=0
NUMBERPACKYEARSSMOKED	Spearman correlation test	N=1	higher numberpackyearssmoked	N=1	lower numberpackyearssmoked	N=0
YEAROFTOBACCOSMOKINGONSET	Spearman correlation test	N=0

Clinical variable #1: 'Time to Death'

One gene related to 'Time to Death'.

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


Time to Death	Duration (Months)	0.6-151.9 (median=63.1)
	censored	N = 54
	death	N = 6

	Significant markers	N = 1
	associated with shorter survival	0
	associated with longer survival	1

List of one gene significantly associated with 'Time to Death' by Cox regression test

Table S2. Get Full Table List of one gene significantly associated with 'Time to Death' by Cox regression test

	HazardRatio	Wald_P	Q	C_index
MAEL	0	1.097e-06	0.022	0.191

Figure S1. Get High-res Image As an example, this figure shows the association of MAEL to 'Time to Death'. four curves present the cumulative survival rates of 4 quartile subsets of patients. P value = 1.1e-06 with univariate Cox regression analysis using continuous log-2 expression values.

Clinical variable #2: 'AGE'

No gene related to 'AGE'.

Table S3. Basic characteristics of clinical feature: 'AGE'


AGE	Mean (SD)	50.9 (15)
	Significant markers	N = 0

Clinical variable #3: 'NEOPLASM.DISEASESTAGE'

58 genes related to 'NEOPLASM.DISEASESTAGE'.

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


NEOPLASM.DISEASESTAGE	Labels	N
	STAGE I	20
	STAGE II	23
	STAGE III	12
	STAGE IV	6

	Significant markers	N = 58

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
C20ORF46	2.395e-11	4.73e-07
LOC643719	1.629e-10	3.22e-06
FAM135B	1.722e-10	3.4e-06
FOXC1	2.308e-10	4.56e-06
WTIP	7.149e-10	1.41e-05
TASP1	1.473e-09	2.91e-05
TSPYL5	1.527e-09	3.02e-05
FAM78B	6.063e-09	0.00012
ADCY1	1.818e-08	0.000359
C8ORF47	2.104e-08	0.000416

Figure S2. Get High-res Image As an example, this figure shows the association of C20ORF46 to 'NEOPLASM.DISEASESTAGE'. P value = 2.4e-11 with ANOVA analysis.

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

One gene related to 'PATHOLOGY.T.STAGE'.

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


PATHOLOGY.T.STAGE	Mean (SD)	2 (0.86)
		N
	1	20
	2	23
	3	16
	4	2

	Significant markers	N = 1
	pos. correlated	1
	neg. correlated	0

List of one gene significantly correlated to 'PATHOLOGY.T.STAGE' by Spearman correlation test

Table S7. Get Full Table List of one gene significantly correlated to 'PATHOLOGY.T.STAGE' by Spearman correlation test

	SpearmanCorr	corrP	Q
LRPAP1	0.5662	1.976e-06	0.0391

Figure S3. Get High-res Image As an example, this figure shows the association of LRPAP1 to 'PATHOLOGY.T.STAGE'. P value = 1.98e-06 with Spearman correlation analysis.

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)	0.16 (0.48)
		N
	0	38
	1	3
	2	2

	Significant markers	N = 0

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

53 genes related to 'PATHOLOGY.M.STAGE'.

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


PATHOLOGY.M.STAGE	Labels	N
	M0	29
	M1	2
	MX	9

	Significant markers	N = 53

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

Table S10. Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGY.M.STAGE'

	ANOVA_P	Q
DOK5	4.96e-28	9.8e-24
GRID1	1.179e-27	2.33e-23
QRFPR	4.775e-20	9.43e-16
NPY	4.681e-19	9.25e-15
SHE	1.691e-16	3.34e-12
TDRD10	1.691e-16	3.34e-12
CPNE9	4.934e-16	9.75e-12
IL11	2.65e-14	5.24e-10
FSTL3	1.449e-13	2.86e-09
KCTD15	4.694e-13	9.27e-09

Figure S4. Get High-res Image As an example, this figure shows the association of DOK5 to 'PATHOLOGY.M.STAGE'. P value = 4.96e-28 with ANOVA analysis.

Clinical variable #7: 'GENDER'

No gene related to 'GENDER'.

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


GENDER	Labels	N
	FEMALE	23
	MALE	38

	Significant markers	N = 0

Clinical variable #8: 'KARNOFSKY.PERFORMANCE.SCORE'

No gene related to 'KARNOFSKY.PERFORMANCE.SCORE'.

Table S12. Basic characteristics of clinical feature: 'KARNOFSKY.PERFORMANCE.SCORE'


KARNOFSKY.PERFORMANCE.SCORE	Mean (SD)	89.09 (9.4)
	Score	N
	70	1
	80	2
	90	5
	100	3

	Significant markers	N = 0

Clinical variable #9: 'NUMBERPACKYEARSSMOKED'

One gene related to 'NUMBERPACKYEARSSMOKED'.

Table S13. Basic characteristics of clinical feature: 'NUMBERPACKYEARSSMOKED'


NUMBERPACKYEARSSMOKED	Mean (SD)	27.5 (22)
	Significant markers	N = 1
	pos. correlated	1
	neg. correlated	0

List of one gene significantly correlated to 'NUMBERPACKYEARSSMOKED' by Spearman correlation test

Table S14. Get Full Table List of one gene significantly correlated to 'NUMBERPACKYEARSSMOKED' by Spearman correlation test

	SpearmanCorr	corrP	Q
GRHL1	0.9726	2.369e-06	0.0468

Figure S5. Get High-res Image As an example, this figure shows the association of GRHL1 to 'NUMBERPACKYEARSSMOKED'. P value = 2.37e-06 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #10: 'YEAROFTOBACCOSMOKINGONSET'

No gene related to 'YEAROFTOBACCOSMOKINGONSET'.

Table S15. Basic characteristics of clinical feature: 'YEAROFTOBACCOSMOKINGONSET'


YEAROFTOBACCOSMOKINGONSET	Mean (SD)	1973.75 (15)
	Significant markers	N = 0

Methods & Data

Input

Expresson data file = KICH-TP.meth.by_min_expr_corr.data.txt
Clinical data file = KICH-TP.clin.merged.picked.txt
Number of patients = 61
Number of genes = 19761
Number of clinical features = 10

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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