Correlation between gene methylation status and clinical features
Colorectal Adenocarcinoma (Primary solid tumor)
15 July 2014  |  analyses__2014_07_15
Maintainer Information
Citation Information
doi:10.7908/C1W37V1M
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/C1W37V1M
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 19868 genes and 13 clinical features across 373 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 11 clinical features related to at least one genes.

  • 82 genes correlated to 'AGE'.

    • GDNF ,  XKR6 ,  KLF14 ,  HPSE2 ,  ELOVL2 ,  ...

  • 3092 genes correlated to 'PRIMARY.SITE.OF.DISEASE'.

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

  • 6 genes correlated to 'NEOPLASM.DISEASESTAGE'.

    • UBE2L6 ,  C8ORF80 ,  SP140L ,  DPCR1 ,  APOL1 ,  ...

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

    • SYN2 ,  TIMP4

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

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

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

    • UBE2L6

  • 29 genes correlated to 'GENDER'.

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

  • 3040 genes correlated to 'HISTOLOGICAL.TYPE'.

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

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

    • BLOC1S3__1 ,  TRAPPC6A

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

    • CASP1__1 ,  UBE2L6 ,  IL12RB1 ,  CASP5 ,  ACTA2__1 ,  ...

  • 44 genes correlated to 'RACE'.

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

  • No genes correlated to 'Time to Death', 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=82 older N=81 younger N=1
PRIMARY SITE OF DISEASE Wilcoxon test N=3092 rectum N=3092 colon N=0
NEOPLASM DISEASESTAGE Kruskal-Wallis test N=6        
PATHOLOGY T STAGE Spearman correlation test N=2 higher stage N=2 lower stage N=0
PATHOLOGY N STAGE Spearman correlation test N=29 higher stage N=20 lower stage N=9
PATHOLOGY M STAGE Kruskal-Wallis test N=1        
GENDER Wilcoxon test N=29 male N=29 female N=0
HISTOLOGICAL TYPE Kruskal-Wallis test N=3040        
RADIATIONS RADIATION REGIMENINDICATION Wilcoxon test   N=0        
COMPLETENESS OF RESECTION Kruskal-Wallis test N=2        
NUMBER OF LYMPH NODES Spearman correlation test N=19 higher number.of.lymph.nodes N=17 lower number.of.lymph.nodes N=2
RACE Kruskal-Wallis test N=44        
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=16.3)
  censored N = 295
  death N = 69
     
  Significant markers N = 0
Clinical variable #2: 'AGE'

82 genes related to 'AGE'.

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

AGE Mean (SD) 64.58 (13)
  Significant markers N = 82
  pos. correlated 81
  neg. correlated 1
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 0.3036 2.274e-09 4.52e-05
XKR6 0.2836 2.602e-08 0.000517
KLF14 0.282 3.146e-08 0.000625
HPSE2 0.2699 1.242e-07 0.00247
ELOVL2 0.2697 1.272e-07 0.00253
EBF4 0.2643 2.31e-07 0.00459
KIAA1755 0.2566 5.27e-07 0.0105
PPM1E 0.2565 5.333e-07 0.0106
PENK 0.2546 6.504e-07 0.0129
IDO2 0.2534 7.346e-07 0.0146
Clinical variable #3: 'PRIMARY.SITE.OF.DISEASE'

3092 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 275
  RECTUM 96
     
  Significant markers N = 3092
  Higher in RECTUM 3092
  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 3208 2.329e-28 4.63e-24 0.8785
PAPLN 3253 4.048e-28 8.04e-24 0.8768
FAM13C 3337 1.128e-27 2.24e-23 0.8736
ORC3L__1 3375 2.196e-27 4.36e-23 0.8717
RARS2__1 3375 2.196e-27 4.36e-23 0.8717
MED27 3590 2.347e-26 4.66e-22 0.864
THOP1 22676 1.135e-25 2.26e-21 0.8589
FLJ13197__1 3926 1.173e-24 2.33e-20 0.8513
KLF3__1 3926 1.173e-24 2.33e-20 0.8513
TEF 4061 5.432e-24 1.08e-19 0.8462
Clinical variable #4: 'NEOPLASM.DISEASESTAGE'

6 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 108
  STAGE IIB 7
  STAGE IIC 3
  STAGE III 11
  STAGE IIIA 19
  STAGE IIIB 54
  STAGE IIIC 34
  STAGE IV 26
  STAGE IVA 24
  STAGE IVB 1
     
  Significant markers N = 6
List of 6 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

Table S7.  Get Full Table List of 6 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

ANOVA_P Q
UBE2L6 1.065e-08 0.000212
C8ORF80 1.04e-06 0.0207
SP140L 1.543e-06 0.0307
DPCR1 8.124e-06 0.161
APOL1 1.174e-05 0.233
CASP1__1 1.206e-05 0.24
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) 2.91 (0.63)
  N
  0 1
  1 10
  2 55
  3 260
  4 45
     
  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 0.2489 1.204e-06 0.0239
TIMP4 0.2489 1.204e-06 0.0239
Clinical variable #6: 'PATHOLOGY.N.STAGE'

29 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
  0 205
  1 99
  2 65
     
  Significant markers N = 29
  pos. correlated 20
  neg. correlated 9
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 0.345 9.367e-12 1.86e-07
CASP1__1 0.3358 3.533e-11 7.02e-07
CASP5 0.3134 7.459e-10 1.48e-05
SP140L 0.3046 2.316e-09 4.6e-05
MARCH8 0.2894 1.499e-08 0.000298
APOL1 0.2877 1.832e-08 0.000364
IL12RB1 0.2875 1.874e-08 0.000372
C8ORF80 0.2727 1.032e-07 0.00205
ASPHD2 0.2706 1.296e-07 0.00257
UBA7 0.2701 1.365e-07 0.00271
Clinical variable #7: 'PATHOLOGY.M.STAGE'

One 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 8
  M1B 1
  MX 59
     
  Significant markers N = 1
List of one gene differentially expressed by 'PATHOLOGY.M.STAGE'

Table S13.  Get Full Table List of one gene differentially expressed by 'PATHOLOGY.M.STAGE'

ANOVA_P Q
UBE2L6 1.248e-05 0.248
Clinical variable #8: 'GENDER'

29 genes related to 'GENDER'.

Table S14.  Basic characteristics of clinical feature: 'GENDER'

GENDER Labels N
  FEMALE 170
  MALE 203
     
  Significant markers N = 29
  Higher in MALE 29
  Higher in FEMALE 0
List of top 10 genes differentially expressed by 'GENDER'

Table S15.  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 6149 9.306e-27 1.85e-22 0.8218
KIF4B 6808 7.282e-24 1.45e-19 0.8027
POLDIP3 6958 3.138e-23 6.23e-19 0.7984
RNU12 6958 3.138e-23 6.23e-19 0.7984
MIR220B 26290 3.002e-18 5.96e-14 0.7618
TUBB4 26290 3.002e-18 5.96e-14 0.7618
UBAP2 9924 1.568e-12 3.11e-08 0.7124
PAFAH1B2 10217 1.154e-11 2.29e-07 0.7039
YARS2 11471 2.452e-08 0.000487 0.6676
UGDH 11477 2.535e-08 0.000503 0.6674
Clinical variable #9: 'HISTOLOGICAL.TYPE'

3040 genes related to 'HISTOLOGICAL.TYPE'.

Table S16.  Basic characteristics of clinical feature: 'HISTOLOGICAL.TYPE'

HISTOLOGICAL.TYPE Labels N
  COLON ADENOCARCINOMA 242
  COLON MUCINOUS ADENOCARCINOMA 33
  RECTAL ADENOCARCINOMA 90
  RECTAL MUCINOUS ADENOCARCINOMA 6
     
  Significant markers N = 3040
List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

Table S17.  Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

ANOVA_P Q
SMPD1 3.8e-27 7.55e-23
PAPLN 1.124e-26 2.23e-22
C20ORF43__1 4.329e-26 8.6e-22
FAM13C 5.065e-26 1.01e-21
ORC3L__1 9.24e-26 1.84e-21
RARS2__1 9.24e-26 1.84e-21
MED27 1.286e-24 2.55e-20
THOP1 1.322e-24 2.63e-20
CYP19A1 2.685e-23 5.33e-19
FOXC1 3.01e-23 5.98e-19
Clinical variable #10: 'RADIATIONS.RADIATION.REGIMENINDICATION'

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

Table S18.  Basic characteristics of clinical feature: 'RADIATIONS.RADIATION.REGIMENINDICATION'

RADIATIONS.RADIATION.REGIMENINDICATION Labels N
  NO 8
  YES 365
     
  Significant markers N = 0
Clinical variable #11: 'COMPLETENESS.OF.RESECTION'

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

Table S19.  Basic characteristics of clinical feature: 'COMPLETENESS.OF.RESECTION'

COMPLETENESS.OF.RESECTION Labels N
  R0 242
  R1 4
  R2 6
  RX 28
     
  Significant markers N = 2
List of 2 genes differentially expressed by 'COMPLETENESS.OF.RESECTION'

Table S20.  Get Full Table List of 2 genes differentially expressed by 'COMPLETENESS.OF.RESECTION'

ANOVA_P Q
BLOC1S3__1 1.238e-05 0.246
TRAPPC6A 1.238e-05 0.246
Clinical variable #12: 'NUMBER.OF.LYMPH.NODES'

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

Table S21.  Basic characteristics of clinical feature: 'NUMBER.OF.LYMPH.NODES'

NUMBER.OF.LYMPH.NODES Mean (SD) 2.23 (4.8)
  Significant markers N = 19
  pos. correlated 17
  neg. correlated 2
List of top 10 genes differentially expressed by 'NUMBER.OF.LYMPH.NODES'

Table S22.  Get Full Table List of top 10 genes significantly correlated to 'NUMBER.OF.LYMPH.NODES' by Spearman correlation test

SpearmanCorr corrP Q
CASP1__1 0.3419 9.938e-11 1.97e-06
UBE2L6 0.3332 3.114e-10 6.19e-06
IL12RB1 0.2914 4.663e-08 0.000926
CASP5 0.2878 6.867e-08 0.00136
ACTA2__1 0.2725 3.465e-07 0.00688
FAS 0.2725 3.465e-07 0.00688
MARCH8 0.2723 3.555e-07 0.00706
SP140L 0.2705 4.269e-07 0.00848
APOL1 0.2647 7.637e-07 0.0152
C8ORF80 0.2595 1.273e-06 0.0253
Clinical variable #13: 'RACE'

44 genes related to 'RACE'.

Table S23.  Basic characteristics of clinical feature: 'RACE'

RACE Labels N
  AMERICAN INDIAN OR ALASKA NATIVE 1
  ASIAN 12
  BLACK OR AFRICAN AMERICAN 45
  WHITE 282
     
  Significant markers N = 44
List of top 10 genes differentially expressed by 'RACE'

Table S24.  Get Full Table List of top 10 genes differentially expressed by 'RACE'

ANOVA_P Q
DHRS7 2.227e-12 4.42e-08
LCE1E 1.24e-10 2.46e-06
GSTCD__1 2.518e-09 5e-05
INTS12__1 2.518e-09 5e-05
F12 1.853e-08 0.000368
CPS1 1.899e-08 0.000377
LANCL1 1.899e-08 0.000377
UBTF 3.568e-08 0.000709
TRIM73 5.091e-08 0.00101
TRIM74 5.091e-08 0.00101
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 = 373

  • Number of genes = 19868

  • 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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