Correlation between gene methylation status and clinical features
Colorectal Adenocarcinoma (Primary solid tumor)
17 October 2014  |  analyses__2014_10_17
Maintainer Information
Citation Information
doi:10.7908/C1VM4B31
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/C1VM4B31
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 19848 genes and 13 clinical features across 376 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 10 clinical features related to at least one genes.

  • 52 genes correlated to 'AGE'.

    • GDNF ,  KLF14 ,  XKR6 ,  ELOVL2 ,  EBF4 ,  ...

  • 3070 genes correlated to 'PRIMARY.SITE.OF.DISEASE'.

    • SMPD1 ,  PAPLN ,  FAM13C ,  ORC3L__1 ,  RARS2__1 ,  ...

  • 5 genes correlated to 'NEOPLASM.DISEASESTAGE'.

    • UBE2L6 ,  SP140L ,  C8ORF80 ,  DPCR1 ,  APOL1

  • 2 genes correlated to 'PATHOLOGY.T.STAGE'.

    • SYN2 ,  TIMP4

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

    • UBE2L6 ,  CASP1__1 ,  CASP5 ,  SP140L ,  MARCH8 ,  ...

  • 21 genes correlated to 'GENDER'.

    • GPX1 ,  KIF4B ,  MIR220B ,  TUBB4 ,  PAFAH1B2 ,  ...

  • 2987 genes correlated to 'HISTOLOGICAL.TYPE'.

    • SMPD1 ,  PAPLN ,  C20ORF43__1 ,  FAM13C ,  ORC3L__1 ,  ...

  • 2 genes correlated to 'COMPLETENESS.OF.RESECTION'.

    • BLOC1S3__1 ,  TRAPPC6A

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

    • CASP1__1 ,  UBE2L6 ,  IL12RB1 ,  CASP5 ,  RARRES3 ,  ...

  • 66 genes correlated to 'RACE'.

    • DHRS7 ,  LCE1E ,  GSTCD__1 ,  INTS12__1 ,  F12 ,  ...

  • No genes correlated to 'Time to Death', 'PATHOLOGY.M.STAGE', and 'RADIATIONS.RADIATION.REGIMENINDICATION'.

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=52 older N=52 younger N=0
PRIMARY SITE OF DISEASE Wilcoxon test N=3070 rectum N=3070 colon N=0
NEOPLASM DISEASESTAGE Kruskal-Wallis test N=5        
PATHOLOGY T STAGE Spearman correlation test N=2 higher stage N=2 lower stage N=0
PATHOLOGY N STAGE Spearman correlation test N=36 higher stage N=25 lower stage N=11
PATHOLOGY M STAGE Kruskal-Wallis test   N=0        
GENDER Wilcoxon test N=21 male N=21 female N=0
HISTOLOGICAL TYPE Kruskal-Wallis test N=2987        
RADIATIONS RADIATION REGIMENINDICATION Wilcoxon test   N=0        
COMPLETENESS OF RESECTION Kruskal-Wallis test N=2        
NUMBER OF LYMPH NODES Spearman correlation test N=22 higher number.of.lymph.nodes N=20 lower number.of.lymph.nodes N=2
RACE Kruskal-Wallis test N=66        
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=16.2)
  censored N = 295
  death N = 72
     
  Significant markers N = 0
Clinical variable #2: 'AGE'

52 genes related to 'AGE'.

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

AGE Mean (SD) 64.5 (13)
  Significant markers N = 52
  pos. correlated 52
  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 0.2908 9.583e-09 0.00019
KLF14 0.2782 4.281e-08 0.00085
XKR6 0.2734 7.498e-08 0.00149
ELOVL2 0.2632 2.317e-07 0.0046
EBF4 0.2578 4.169e-07 0.00827
VIM 0.2548 5.914e-07 0.0117
IDO2 0.2536 6.468e-07 0.0128
FOXC2 0.2536 6.494e-07 0.0129
NKX2-2 0.2533 6.659e-07 0.0132
OLIG2 0.2527 7.126e-07 0.0141
Clinical variable #3: 'PRIMARY.SITE.OF.DISEASE'

3070 genes related to 'PRIMARY.SITE.OF.DISEASE'.

Table S4.  Basic characteristics of clinical feature: 'PRIMARY.SITE.OF.DISEASE'

PRIMARY.SITE.OF.DISEASE Labels N
  COLON 278
  RECTUM 96
     
  Significant markers N = 3070
  Higher in RECTUM 3070
  Higher in COLON 0
List of top 10 genes differentially expressed by 'PRIMARY.SITE.OF.DISEASE'

Table S5.  Get Full Table List of top 10 genes differentially expressed by 'PRIMARY.SITE.OF.DISEASE'

W(pos if higher in 'RECTUM') wilcoxontestP Q AUC
SMPD1 3230 1.671e-28 3.32e-24 0.879
PAPLN 3273 2.823e-28 5.6e-24 0.8774
FAM13C 3377 9.948e-28 1.97e-23 0.8735
ORC3L__1 3403 1.667e-27 3.31e-23 0.872
RARS2__1 3403 1.667e-27 3.31e-23 0.872
MED27 3665 3.043e-26 6.04e-22 0.8627
THOP1 22926 9.42e-26 1.87e-21 0.859
FLJ13197__1 3960 9.134e-25 1.81e-20 0.8516
KLF3__1 3960 9.134e-25 1.81e-20 0.8516
PRKAR2B 4031 2.523e-24 5.01e-20 0.8484
Clinical variable #4: 'NEOPLASM.DISEASESTAGE'

5 genes related to 'NEOPLASM.DISEASESTAGE'.

Table S6.  Basic characteristics of clinical feature: 'NEOPLASM.DISEASESTAGE'

NEOPLASM.DISEASESTAGE Labels N
  STAGE I 52
  STAGE IA 1
  STAGE II 20
  STAGE IIA 109
  STAGE IIB 7
  STAGE IIC 3
  STAGE III 11
  STAGE IIIA 18
  STAGE IIIB 56
  STAGE IIIC 34
  STAGE IV 26
  STAGE IVA 25
  STAGE IVB 1
     
  Significant markers N = 5
List of 5 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

Table S7.  Get Full Table List of 5 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

ANOVA_P Q
UBE2L6 6.512e-09 0.000129
SP140L 8.422e-07 0.0167
C8ORF80 1.563e-06 0.031
DPCR1 5.759e-06 0.114
APOL1 9.044e-06 0.179
Clinical variable #5: 'PATHOLOGY.T.STAGE'

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

Table S8.  Basic characteristics of clinical feature: 'PATHOLOGY.T.STAGE'

PATHOLOGY.T.STAGE Mean (SD) 2.92 (0.62)
  N
  1 11
  2 55
  3 262
  4 46
     
  Significant markers N = 2
  pos. correlated 2
  neg. correlated 0
List of 2 genes differentially expressed by 'PATHOLOGY.T.STAGE'

Table S9.  Get Full Table List of 2 genes significantly correlated to 'PATHOLOGY.T.STAGE' by Spearman correlation test

SpearmanCorr corrP Q
SYN2 0.2446 1.697e-06 0.0337
TIMP4 0.2446 1.697e-06 0.0337
Clinical variable #6: 'PATHOLOGY.N.STAGE'

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

Table S10.  Basic characteristics of clinical feature: 'PATHOLOGY.N.STAGE'

PATHOLOGY.N.STAGE Mean (SD) 0.62 (0.77)
  N
  0 206
  1 100
  2 66
     
  Significant markers N = 36
  pos. correlated 25
  neg. correlated 11
List of top 10 genes differentially expressed by 'PATHOLOGY.N.STAGE'

Table S11.  Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY.N.STAGE' by Spearman correlation test

SpearmanCorr corrP Q
UBE2L6 0.3513 3.025e-12 6e-08
CASP1__1 0.3425 1.123e-11 2.23e-07
CASP5 0.316 4.505e-10 8.94e-06
SP140L 0.3087 1.185e-09 2.35e-05
MARCH8 0.2962 5.694e-09 0.000113
APOL1 0.2962 5.75e-09 0.000114
IL12RB1 0.2928 8.623e-09 0.000171
RARRES3 0.2873 1.678e-08 0.000333
C8ORF80 0.279 4.437e-08 0.00088
UBA7 0.2749 7.127e-08 0.00141
Clinical variable #7: 'PATHOLOGY.M.STAGE'

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

Table S12.  Basic characteristics of clinical feature: 'PATHOLOGY.M.STAGE'

PATHOLOGY.M.STAGE Labels N
  M0 260
  M1 38
  M1A 9
  M1B 1
  MX 61
     
  Significant markers N = 0
Clinical variable #8: 'GENDER'

21 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 170
  MALE 206
     
  Significant markers N = 21
  Higher in MALE 21
  Higher in FEMALE 0
List of top 10 genes differentially expressed by 'GENDER'

Table S14.  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 6197 4.052e-27 8.04e-23 0.823
KIF4B 6864 3.344e-24 6.64e-20 0.804
MIR220B 26477 1.248e-17 2.48e-13 0.7561
TUBB4 26477 1.248e-17 2.48e-13 0.7561
PAFAH1B2 10391 1.148e-11 2.28e-07 0.7033
ZNF839 11664 2.505e-08 0.000497 0.6669
UGDH 11841 6.51e-08 0.00129 0.6619
DDX43 11974 1.31e-07 0.0026 0.6581
WBP11P1 22694 7.741e-07 0.0154 0.648
RWDD2B 12428 1.269e-06 0.0252 0.6451
Clinical variable #9: 'HISTOLOGICAL.TYPE'

2987 genes related to 'HISTOLOGICAL.TYPE'.

Table S15.  Basic characteristics of clinical feature: 'HISTOLOGICAL.TYPE'

HISTOLOGICAL.TYPE Labels N
  COLON ADENOCARCINOMA 244
  COLON MUCINOUS ADENOCARCINOMA 34
  RECTAL ADENOCARCINOMA 90
  RECTAL MUCINOUS ADENOCARCINOMA 6
     
  Significant markers N = 2987
List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

Table S16.  Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

ANOVA_P Q
SMPD1 2.541e-27 5.04e-23
PAPLN 7.671e-27 1.52e-22
C20ORF43__1 2.146e-26 4.26e-22
FAM13C 4.031e-26 8e-22
ORC3L__1 6.332e-26 1.26e-21
RARS2__1 6.332e-26 1.26e-21
THOP1 9.051e-25 1.8e-20
MED27 1.533e-24 3.04e-20
PRKAR2B 7.129e-24 1.41e-19
CYP19A1 1.579e-23 3.13e-19
Clinical variable #10: 'RADIATIONS.RADIATION.REGIMENINDICATION'

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

Table S17.  Basic characteristics of clinical feature: 'RADIATIONS.RADIATION.REGIMENINDICATION'

RADIATIONS.RADIATION.REGIMENINDICATION Labels N
  NO 8
  YES 368
     
  Significant markers N = 0
Clinical variable #11: 'COMPLETENESS.OF.RESECTION'

2 genes related to 'COMPLETENESS.OF.RESECTION'.

Table S18.  Basic characteristics of clinical feature: 'COMPLETENESS.OF.RESECTION'

COMPLETENESS.OF.RESECTION Labels N
  R0 245
  R1 4
  R2 6
  RX 28
     
  Significant markers N = 2
List of 2 genes differentially expressed by 'COMPLETENESS.OF.RESECTION'

Table S19.  Get Full Table List of 2 genes differentially expressed by 'COMPLETENESS.OF.RESECTION'

ANOVA_P Q
BLOC1S3__1 1.167e-05 0.232
TRAPPC6A 1.167e-05 0.232
Clinical variable #12: 'NUMBER.OF.LYMPH.NODES'

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

Table S20.  Basic characteristics of clinical feature: 'NUMBER.OF.LYMPH.NODES'

NUMBER.OF.LYMPH.NODES Mean (SD) 2.23 (4.8)
  Significant markers N = 22
  pos. correlated 20
  neg. correlated 2
List of top 10 genes differentially expressed by 'NUMBER.OF.LYMPH.NODES'

Table S21.  Get Full Table List of top 10 genes significantly correlated to 'NUMBER.OF.LYMPH.NODES' by Spearman correlation test

SpearmanCorr corrP Q
CASP1__1 0.3499 2.765e-11 5.49e-07
UBE2L6 0.3407 9.604e-11 1.91e-06
IL12RB1 0.2974 2.063e-08 0.000409
CASP5 0.2911 4.167e-08 0.000827
RARRES3 0.2904 4.531e-08 0.000899
MARCH8 0.2806 1.319e-07 0.00262
APOL1 0.2751 2.359e-07 0.00468
SP140L 0.275 2.37e-07 0.0047
ACTA2__1 0.2742 2.581e-07 0.00512
FAS 0.2742 2.581e-07 0.00512
Clinical variable #13: 'RACE'

66 genes related to 'RACE'.

Table S22.  Basic characteristics of clinical feature: 'RACE'

RACE Labels N
  AMERICAN INDIAN OR ALASKA NATIVE 1
  ASIAN 12
  BLACK OR AFRICAN AMERICAN 48
  WHITE 282
     
  Significant markers N = 66
List of top 10 genes differentially expressed by 'RACE'

Table S23.  Get Full Table List of top 10 genes differentially expressed by 'RACE'

ANOVA_P Q
DHRS7 1.086e-12 2.16e-08
LCE1E 4.345e-10 8.62e-06
GSTCD__1 4.475e-10 8.88e-06
INTS12__1 4.475e-10 8.88e-06
F12 1.527e-09 3.03e-05
CPS1 6.849e-09 0.000136
LANCL1 6.849e-09 0.000136
IL20 9.071e-09 0.00018
DNAJC10 1.323e-08 0.000262
UBTF 2.494e-08 0.000495
Methods & Data
Input

  • Expresson data file = COADREAD-TP.meth.by_min_clin_corr.data.txt

  • Clinical data file = COADREAD-TP.merged_data.txt

  • Number of patients = 376

  • Number of genes = 19848

  • Number of clinical features = 13

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

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

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

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] Lehmann and Romano, Testing Statistical Hypotheses (3E ed.), New York: Springer. ISBN 0387988645 (2005)
[4] Howell, D, Statistical Methods for Psychology. (5th ed.), Duxbury Press:324-5 (2002)
[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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