Correlation between gene methylation status and clinical features
Colon Adenocarcinoma (Primary solid tumor)
15 July 2014  |  analyses__2014_07_15
Maintainer Information
Citation Information
doi:10.7908/C19G5KHB
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/C19G5KHB
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 19832 genes and 12 clinical features across 275 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 8 clinical features related to at least one genes.

  • 22 genes correlated to 'AGE'.

    • GDNF ,  C1QL1 ,  KLF14 ,  KIF5C ,  TAC1 ,  ...

  • 2 genes correlated to 'NEOPLASM.DISEASESTAGE'.

    • C8ORF80 ,  UBE2L6

  • 17 genes correlated to 'PATHOLOGY.N.STAGE'.

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

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

    • KIF13B

  • 14 genes correlated to 'GENDER'.

    • GPX1 ,  KIF4B ,  POLDIP3 ,  RNU12 ,  PSRC1 ,  ...

  • 25 genes correlated to 'HISTOLOGICAL.TYPE'.

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

  • 11 genes correlated to 'NUMBER.OF.LYMPH.NODES'.

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

  • 26 genes correlated to 'RACE'.

    • DHRS7 ,  LCE1E ,  XPNPEP1 ,  FAM115C ,  PGBD5 ,  ...

  • 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=22 older N=22 younger N=0
NEOPLASM DISEASESTAGE Kruskal-Wallis test N=2        
PATHOLOGY T STAGE Spearman correlation test   N=0        
PATHOLOGY N STAGE Spearman correlation test N=17 higher stage N=15 lower stage N=2
PATHOLOGY M STAGE Kruskal-Wallis test N=1        
GENDER Wilcoxon test N=14 male N=14 female N=0
HISTOLOGICAL TYPE Wilcoxon test N=25 colon mucinous adenocarcinoma N=25 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=11 higher number.of.lymph.nodes N=11 lower number.of.lymph.nodes N=0
RACE Kruskal-Wallis test N=26        
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=17.9)
  censored N = 214
  death N = 57
     
  Significant markers N = 0
Clinical variable #2: 'AGE'

22 genes related to 'AGE'.

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

AGE Mean (SD) 65.16 (13)
  Significant markers N = 22
  pos. correlated 22
  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 0.3204 5.859e-08 0.00116
C1QL1 0.3042 2.826e-07 0.0056
KLF14 0.2916 9.056e-07 0.018
KIF5C 0.2883 1.21e-06 0.024
TAC1 0.2827 1.975e-06 0.0392
GPR1 0.2815 2.189e-06 0.0434
SHISA3 0.2811 2.275e-06 0.0451
EBF4 0.2752 3.777e-06 0.0749
ZSCAN12 0.2746 3.967e-06 0.0786
ST8SIA4 0.2716 5.104e-06 0.101
Clinical variable #3: 'NEOPLASM.DISEASESTAGE'

2 genes 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 88
  STAGE IIB 5
  STAGE IIC 1
  STAGE III 7
  STAGE IIIA 10
  STAGE IIIB 41
  STAGE IIIC 23
  STAGE IV 20
  STAGE IVA 15
  STAGE IVB 1
     
  Significant markers N = 2
List of 2 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

Table S5.  Get Full Table List of 2 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

ANOVA_P Q
C8ORF80 6.199e-07 0.0123
UBE2L6 4.93e-06 0.0978
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 (0.63)
  N
  0 1
  1 6
  2 42
  3 191
  4 34
     
  Significant markers N = 0
Clinical variable #5: 'PATHOLOGY.N.STAGE'

17 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
  0 162
  1 69
  2 43
     
  Significant markers N = 17
  pos. correlated 15
  neg. correlated 2
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 0.3522 2.024e-09 4.01e-05
UBE2L6 0.3306 2.07e-08 0.000411
APOL1 0.3249 3.742e-08 0.000742
CASP5 0.3081 1.944e-07 0.00385
IL12RB1 0.3001 4.155e-07 0.00824
PKN2 0.2832 1.893e-06 0.0375
SP140L 0.2809 2.312e-06 0.0458
ASPHD2 0.2759 3.551e-06 0.0704
MED18 0.2737 4.284e-06 0.0849
UBA7 0.2718 5.012e-06 0.0993
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 6
  M1B 1
  MX 45
     
  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 5.026e-06 0.0997
Clinical variable #7: 'GENDER'

14 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 126
  MALE 149
     
  Significant markers N = 14
  Higher in MALE 14
  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 3074 7.516e-22 1.49e-17 0.8363
KIF4B 3712 5.849e-18 1.16e-13 0.8023
POLDIP3 3887 5.804e-17 1.15e-12 0.793
RNU12 3887 5.804e-17 1.15e-12 0.793
PSRC1 4902 8.822e-12 1.75e-07 0.7389
PAFAH1B2 5086 5.969e-11 1.18e-06 0.7291
UBAP2 5630 1.086e-08 0.000215 0.7001
ZNF839 5752 3.184e-08 0.000631 0.6936
FASTKD2__1 5998 2.514e-07 0.00498 0.6805
MDH1B__1 5998 2.514e-07 0.00498 0.6805
Clinical variable #8: 'HISTOLOGICAL.TYPE'

25 genes related to 'HISTOLOGICAL.TYPE'.

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

HISTOLOGICAL.TYPE Labels N
  COLON ADENOCARCINOMA 242
  COLON MUCINOUS ADENOCARCINOMA 33
     
  Significant markers N = 25
  Higher in COLON MUCINOUS ADENOCARCINOMA 25
  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
PDE4B 1861 6.578e-07 0.013 0.767
RALGPS1__1 6121 6.902e-07 0.0137 0.7665
POLR1D 6090 9.993e-07 0.0198 0.7626
BCL2L1 6034 1.925e-06 0.0382 0.7556
POFUT1 6034 1.925e-06 0.0382 0.7556
GFOD2 6012 2.48e-06 0.0492 0.7528
REV1 6009 2.566e-06 0.0509 0.7524
PRSS3 5997 2.943e-06 0.0583 0.7509
ABHD12B 5951 4.937e-06 0.0979 0.7452
C19ORF44__1 5929 6.299e-06 0.125 0.7424
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 272
     
  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 176
  R1 2
  R2 4
  RX 23
     
  Significant markers N = 0
Clinical variable #11: 'NUMBER.OF.LYMPH.NODES'

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

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

NUMBER.OF.LYMPH.NODES Mean (SD) 1.92 (4.4)
  Significant markers N = 11
  pos. correlated 11
  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 0.3697 1.4e-09 2.78e-05
UBE2L6 0.3358 4.664e-08 0.000925
IL12RB1 0.307 6.694e-07 0.0133
APOL1 0.3004 1.185e-06 0.0235
SRBD1 0.2954 1.809e-06 0.0359
CSGALNACT1 0.2899 2.871e-06 0.0569
CASP5 0.2867 3.73e-06 0.074
C8ORF80 0.2792 6.798e-06 0.135
MAST3 0.2787 7.097e-06 0.141
MARCH8 0.2745 9.792e-06 0.194
Clinical variable #12: 'RACE'

26 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 40
  WHITE 205
     
  Significant markers N = 26
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 2.982e-11 5.91e-07
LCE1E 5.923e-08 0.00117
XPNPEP1 7.667e-08 0.00152
FAM115C 9.393e-08 0.00186
PGBD5 1.742e-07 0.00345
CPS1 3.414e-07 0.00677
LANCL1 3.414e-07 0.00677
GSTCD__1 3.537e-07 0.00701
INTS12__1 3.537e-07 0.00701
UBTF 1.552e-06 0.0308
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 = 275

  • Number of genes = 19832

  • 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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