Correlation between gene methylation status and clinical features
Kidney Renal Papillary Cell Carcinoma (Primary solid tumor)
15 July 2014  |  analyses__2014_07_15
Maintainer Information
Citation Information
doi:10.7908/C1NC5ZXB
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/C1NC5ZXB
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 19873 genes and 11 clinical features across 186 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 8 clinical features related to at least one genes.

  • 26 genes correlated to 'AGE'.

    • ARHGAP1 ,  TNFAIP6 ,  ELOVL2 ,  SLCO2A1 ,  PDE10A ,  ...

  • 642 genes correlated to 'NEOPLASM.DISEASESTAGE'.

    • DLEU2 ,  ECEL1 ,  CPA5 ,  DLX6 ,  DLX6AS ,  ...

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

    • DLX6 ,  DLX6AS ,  OTX1 ,  NSD1 ,  GPR150 ,  ...

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

    • KLK7 ,  PLEKHF2 ,  SLC13A5 ,  MEOX2 ,  ABCC8 ,  ...

  • 93 genes correlated to 'PATHOLOGY.M.STAGE'.

    • ZNF18 ,  C7ORF36 ,  GABARAPL2 ,  CHD1 ,  PIGH ,  ...

  • 58 genes correlated to 'GENDER'.

    • ALG11__2 ,  UTP14C ,  PRKRIR ,  FDPS ,  RUSC1__1 ,  ...

  • 18 genes correlated to 'KARNOFSKY.PERFORMANCE.SCORE'.

    • CHAF1B ,  AOC3 ,  SCARF1 ,  MIP ,  MKL1 ,  ...

  • 16 genes correlated to 'RACE'.

    • DHRS7 ,  DARC ,  C14ORF167 ,  DHRS4 ,  RCBTB2 ,  ...

  • No genes correlated to 'Time to Death', 'NUMBERPACKYEARSSMOKED', and 'ETHNICITY'.

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=26 older N=12 younger N=14
NEOPLASM DISEASESTAGE Kruskal-Wallis test N=642        
PATHOLOGY T STAGE Spearman correlation test N=921 higher stage N=724 lower stage N=197
PATHOLOGY N STAGE Spearman correlation test N=20 higher stage N=20 lower stage N=0
PATHOLOGY M STAGE Kruskal-Wallis test N=93        
GENDER Wilcoxon test N=58 male N=58 female N=0
KARNOFSKY PERFORMANCE SCORE Spearman correlation test N=18 higher score N=14 lower score N=4
NUMBERPACKYEARSSMOKED Spearman correlation test   N=0        
RACE Kruskal-Wallis test N=16        
ETHNICITY Wilcoxon test   N=0        
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 (Years) 2-5925 (median=445.5)
  censored N = 156
  death N = 6
     
  Significant markers N = 0
Clinical variable #2: 'AGE'

26 genes related to 'AGE'.

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

AGE Mean (SD) 60.31 (12)
  Significant markers N = 26
  pos. correlated 12
  neg. correlated 14
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
ARHGAP1 -0.3884 5.545e-08 0.0011
TNFAIP6 0.3639 4.103e-07 0.00815
ELOVL2 0.3576 6.697e-07 0.0133
SLCO2A1 0.3556 7.812e-07 0.0155
PDE10A 0.3523 1.002e-06 0.0199
CTSD -0.3465 1.549e-06 0.0308
HCCA2__5 -0.3465 1.549e-06 0.0308
ATP6V0C -0.3418 2.185e-06 0.0434
AAK1 -0.3318 4.465e-06 0.0887
ARGFXP2 -0.3301 5.019e-06 0.0997
Clinical variable #3: 'NEOPLASM.DISEASESTAGE'

642 genes related to 'NEOPLASM.DISEASESTAGE'.

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

NEOPLASM.DISEASESTAGE Labels N
  STAGE I 119
  STAGE II 9
  STAGE III 42
  STAGE IV 11
     
  Significant markers N = 642
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
DLEU2 6.936e-11 1.38e-06
ECEL1 8.034e-11 1.6e-06
CPA5 9.105e-11 1.81e-06
DLX6 1.031e-10 2.05e-06
DLX6AS 1.031e-10 2.05e-06
TMEM132B 1.032e-10 2.05e-06
NSD1 1.305e-10 2.59e-06
IRX1 3.795e-10 7.54e-06
ZSCAN1 4.909e-10 9.75e-06
OTX1 5.723e-10 1.14e-05
Clinical variable #4: 'PATHOLOGY.T.STAGE'

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

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

PATHOLOGY.T.STAGE Mean (SD) 1.6 (0.9)
  N
  1 125
  2 12
  3 47
  4 2
     
  Significant markers N = 921
  pos. correlated 724
  neg. correlated 197
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
DLX6 0.5095 1.111e-13 2.21e-09
DLX6AS 0.5095 1.111e-13 2.21e-09
OTX1 0.4945 7.299e-13 1.45e-08
NSD1 0.4846 2.407e-12 4.78e-08
GPR150 0.4825 3.087e-12 6.13e-08
C6ORF195 0.4755 6.973e-12 1.39e-07
FLOT2 0.4754 7.055e-12 1.4e-07
DLEU2 -0.4735 8.723e-12 1.73e-07
CPA5 0.4721 1.033e-11 2.05e-07
ECEL1 0.4695 1.387e-11 2.76e-07
Clinical variable #5: 'PATHOLOGY.N.STAGE'

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

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

PATHOLOGY.N.STAGE Mean (SD) 0.49 (0.63)
  N
  0 32
  1 19
  2 4
     
  Significant markers N = 20
  pos. correlated 20
  neg. correlated 0
List of top 10 genes differentially expressed by 'PATHOLOGY.N.STAGE'

Table S9.  Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY.N.STAGE' by Spearman correlation test

SpearmanCorr corrP Q
KLK7 0.6088 8.166e-07 0.0162
PLEKHF2 0.605 9.968e-07 0.0198
SLC13A5 0.6025 1.136e-06 0.0226
MEOX2 0.5973 1.477e-06 0.0293
ABCC8 0.5895 2.184e-06 0.0434
HOXA13 0.5891 2.229e-06 0.0443
WNT1 0.5858 2.627e-06 0.0522
ZNF702P 0.5839 2.87e-06 0.057
LBXCOR1 0.5811 3.294e-06 0.0654
KLK4 0.5728 4.884e-06 0.097
Clinical variable #6: 'PATHOLOGY.M.STAGE'

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

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

PATHOLOGY.M.STAGE Labels N
  M0 74
  M1 7
  MX 97
     
  Significant markers N = 93
List of top 10 genes differentially expressed by 'PATHOLOGY.M.STAGE'

Table S11.  Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGY.M.STAGE'

ANOVA_P Q
ZNF18 8.8e-09 0.000175
C7ORF36 1.091e-08 0.000217
GABARAPL2 3.415e-08 0.000679
CHD1 1.571e-07 0.00312
PIGH 2.942e-07 0.00585
PPIE 3.091e-07 0.00614
DCTN2 3.537e-07 0.00703
HIST1H3A 3.743e-07 0.00744
HIST1H4A 3.743e-07 0.00744
PRKACA 5.753e-07 0.0114
Clinical variable #7: 'GENDER'

58 genes related to 'GENDER'.

Table S12.  Basic characteristics of clinical feature: 'GENDER'

GENDER Labels N
  FEMALE 55
  MALE 131
     
  Significant markers N = 58
  Higher in MALE 58
  Higher in FEMALE 0
List of top 10 genes differentially expressed by 'GENDER'

Table S13.  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
ALG11__2 6579 6.597e-19 1.31e-14 0.9131
UTP14C 6579 6.597e-19 1.31e-14 0.9131
PRKRIR 6395 7.924e-17 1.57e-12 0.8876
FDPS 6356 2.104e-16 4.18e-12 0.8822
RUSC1__1 6356 2.104e-16 4.18e-12 0.8822
MYST2 6261 2.148e-15 4.27e-11 0.869
WBP11P1 6130 4.646e-14 9.23e-10 0.8508
NARFL 1411 6.203e-11 1.23e-06 0.8042
C5ORF27 1464 1.764e-10 3.5e-06 0.7968
PEMT 1549 8.96e-10 1.78e-05 0.785
Clinical variable #8: 'KARNOFSKY.PERFORMANCE.SCORE'

18 genes related to 'KARNOFSKY.PERFORMANCE.SCORE'.

Table S14.  Basic characteristics of clinical feature: 'KARNOFSKY.PERFORMANCE.SCORE'

KARNOFSKY.PERFORMANCE.SCORE Mean (SD) 93.21 (10)
  Score N
  40 1
  70 1
  80 4
  90 19
  100 28
     
  Significant markers N = 18
  pos. correlated 14
  neg. correlated 4
List of top 10 genes differentially expressed by 'KARNOFSKY.PERFORMANCE.SCORE'

Table S15.  Get Full Table List of top 10 genes significantly correlated to 'KARNOFSKY.PERFORMANCE.SCORE' by Spearman correlation test

SpearmanCorr corrP Q
CHAF1B 0.6152 9.505e-07 0.0189
AOC3 0.6045 1.636e-06 0.0325
SCARF1 0.5939 2.761e-06 0.0549
MIP 0.5913 3.137e-06 0.0623
MKL1 0.5789 5.598e-06 0.111
MYH16 0.5747 6.774e-06 0.135
APOBEC3H 0.5737 7.113e-06 0.141
FAM38A 0.5732 7.258e-06 0.144
NPHP4 -0.5713 7.917e-06 0.157
ZNF610 -0.5712 7.949e-06 0.158
Clinical variable #9: 'NUMBERPACKYEARSSMOKED'

No gene related to 'NUMBERPACKYEARSSMOKED'.

Table S16.  Basic characteristics of clinical feature: 'NUMBERPACKYEARSSMOKED'

NUMBERPACKYEARSSMOKED Mean (SD) 28.86 (34)
  Significant markers N = 0
Clinical variable #10: 'RACE'

16 genes related to 'RACE'.

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

RACE Labels N
  AMERICAN INDIAN OR ALASKA NATIVE 2
  ASIAN 5
  BLACK OR AFRICAN AMERICAN 42
  WHITE 123
     
  Significant markers N = 16
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
DHRS7 2.994e-13 5.95e-09
DARC 4.912e-08 0.000976
C14ORF167 8.973e-08 0.00178
DHRS4 8.973e-08 0.00178
RCBTB2 1.104e-07 0.00219
CS 5.892e-07 0.0117
AQP6 6.025e-07 0.012
RABL2A 9.121e-07 0.0181
RPL23AP7 9.121e-07 0.0181
GRAPL 1.044e-06 0.0207
Clinical variable #11: 'ETHNICITY'

No gene related to 'ETHNICITY'.

Table S19.  Basic characteristics of clinical feature: 'ETHNICITY'

ETHNICITY Labels N
  HISPANIC OR LATINO 9
  NOT HISPANIC OR LATINO 141
     
  Significant markers N = 0
Methods & Data
Input

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

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

  • Number of patients = 186

  • Number of genes = 19873

  • Number of clinical features = 11

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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