Correlation between gene methylation status and clinical features
Pan-kidney cohort (KICH+KIRC+KIRP) (Primary solid tumor)
21 August 2015  |  analyses__2015_08_21
Maintainer Information
Citation Information
doi:10.7908/C1GH9H6W
Maintained by Juok Cho (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2015): Correlation between gene methylation status and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C1GH9H6W
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 19909 genes and 14 clinical features across 659 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 10 clinical features related to at least one genes.

  • 30 genes correlated to 'YEARS_TO_BIRTH'.

    • ZNF233 ,  DGKE ,  KLF9 ,  RALGAPA2 ,  TRPM4 ,  ...

  • 30 genes correlated to 'PATHOLOGIC_STAGE'.

    • IRX1 ,  CDO1 ,  SOX30 ,  GPR25 ,  MAFA ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • CDO1 ,  IRX1 ,  SOX30 ,  GPR25 ,  SPAG6 ,  ...

  • 30 genes correlated to 'PATHOLOGY_N_STAGE'.

    • FOXC2 ,  SLC6A3 ,  TLX1 ,  ARL10 ,  C4ORF38 ,  ...

  • 30 genes correlated to 'PATHOLOGY_M_STAGE'.

    • HS3ST2 ,  ADCYAP1 ,  SDR16C5 ,  SOX8 ,  CHRNA3 ,  ...

  • 30 genes correlated to 'GENDER'.

    • ALG11__2 ,  UTP14C ,  TLE1 ,  KIF4B ,  WBP11P1 ,  ...

  • 30 genes correlated to 'KARNOFSKY_PERFORMANCE_SCORE'.

    • PLLP ,  EPS15L1 ,  KIAA1984 ,  SIGIRR ,  CAMK2B ,  ...

  • 30 genes correlated to 'HISTOLOGICAL_TYPE'.

    • CCND1 ,  NOL3 ,  VIM ,  TMCC1 ,  APEH ,  ...

  • 20 genes correlated to 'YEAR_OF_TOBACCO_SMOKING_ONSET'.

    • FAM90A5 ,  LOC349196 ,  LOC100129794 ,  SLC25A21 ,  PCSK4 ,  ...

  • 30 genes correlated to 'RACE'.

    • DHRS7 ,  GSTCD__1 ,  INTS12 ,  RABL2A__1 ,  RPL23AP7__1 ,  ...

  • No genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP', 'RADIATION_THERAPY', 'NUMBER_PACK_YEARS_SMOKED', 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
DAYS_TO_DEATH_OR_LAST_FUP Cox regression test   N=0        
YEARS_TO_BIRTH Spearman correlation test N=30 older N=17 younger N=13
PATHOLOGIC_STAGE Kruskal-Wallis test N=30        
PATHOLOGY_T_STAGE Spearman correlation test N=30 higher stage N=29 lower stage N=1
PATHOLOGY_N_STAGE Spearman correlation test N=30 higher stage N=30 lower stage N=0
PATHOLOGY_M_STAGE Wilcoxon test N=30 class1 N=30 class0 N=0
GENDER Wilcoxon test N=30 male N=30 female N=0
RADIATION_THERAPY Wilcoxon test   N=0        
KARNOFSKY_PERFORMANCE_SCORE Spearman correlation test N=30 higher score N=2 lower score N=28
HISTOLOGICAL_TYPE Kruskal-Wallis test N=30        
NUMBER_PACK_YEARS_SMOKED Spearman correlation test   N=0        
YEAR_OF_TOBACCO_SMOKING_ONSET Spearman correlation test N=20 higher year_of_tobacco_smoking_onset N=16 lower year_of_tobacco_smoking_onset N=4
RACE Kruskal-Wallis test N=30        
ETHNICITY Wilcoxon test   N=0        
Clinical variable #1: 'DAYS_TO_DEATH_OR_LAST_FUP'

No gene related to 'DAYS_TO_DEATH_OR_LAST_FUP'.

Table S1.  Basic characteristics of clinical feature: 'DAYS_TO_DEATH_OR_LAST_FUP'

DAYS_TO_DEATH_OR_LAST_FUP Duration (Months) 0.1-194.8 (median=30.2)
  censored N = 504
  death N = 154
     
  Significant markers N = 0
Clinical variable #2: 'YEARS_TO_BIRTH'

30 genes related to 'YEARS_TO_BIRTH'.

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

YEARS_TO_BIRTH Mean (SD) 60.5 (13)
  Significant markers N = 30
  pos. correlated 17
  neg. correlated 13
List of top 10 genes differentially expressed by 'YEARS_TO_BIRTH'

Table S3.  Get Full Table List of top 10 genes significantly correlated to 'YEARS_TO_BIRTH' by Spearman correlation test

SpearmanCorr corrP Q
ZNF233 0.2682 3.057e-12 6.09e-08
DGKE 0.2564 2.808e-11 2.8e-07
KLF9 -0.2432 2.934e-10 1.16e-06
RALGAPA2 0.243 3.017e-10 1.16e-06
TRPM4 0.2422 3.473e-10 1.16e-06
REC8 0.2422 3.486e-10 1.16e-06
ARHGAP1 -0.2406 4.599e-10 1.31e-06
ITGAE -0.2377 7.496e-10 1.87e-06
SLC25A22 -0.2342 1.347e-09 2.76e-06
DDO -0.234 1.387e-09 2.76e-06
Clinical variable #3: 'PATHOLOGIC_STAGE'

30 genes related to 'PATHOLOGIC_STAGE'.

Table S4.  Basic characteristics of clinical feature: 'PATHOLOGIC_STAGE'

PATHOLOGIC_STAGE Labels N
  STAGE I 345
  STAGE II 75
  STAGE III 138
  STAGE IV 79
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'PATHOLOGIC_STAGE'

Table S5.  Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGIC_STAGE'

kruskal_wallis_P Q
IRX1 5.523e-32 1.1e-27
CDO1 7.577e-31 7.54e-27
SOX30 3.068e-28 2.04e-24
GPR25 3.74e-27 1.86e-23
MAFA 1.074e-26 4.27e-23
SPAG6 2.952e-26 9.8e-23
NEIL1 8.901e-26 2.53e-22
SOX8 7.553e-25 1.88e-21
ADCYAP1 1.199e-24 2.47e-21
RRM2 1.24e-24 2.47e-21
Clinical variable #4: 'PATHOLOGY_T_STAGE'

30 genes related to 'PATHOLOGY_T_STAGE'.

Table S6.  Basic characteristics of clinical feature: 'PATHOLOGY_T_STAGE'

PATHOLOGY_T_STAGE Mean (SD) 1.76 (0.93)
  N
  T1 366
  T2 92
  T3 187
  T4 12
     
  Significant markers N = 30
  pos. correlated 29
  neg. correlated 1
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
CDO1 0.459 1.509e-35 3e-31
IRX1 0.4532 1.346e-34 1.34e-30
SOX30 0.428 1.197e-30 7.95e-27
GPR25 0.4207 1.457e-29 7.25e-26
SPAG6 0.4138 1.47e-28 5.85e-25
ZNF132 0.4126 2.153e-28 7.15e-25
USP44 0.4054 2.234e-27 6.35e-24
MAFA 0.4033 4.288e-27 1.07e-23
RRM2 -0.4008 9.645e-27 2.13e-23
ABCC8 0.3917 1.591e-25 3.17e-22
Clinical variable #5: 'PATHOLOGY_N_STAGE'

30 genes related to 'PATHOLOGY_N_STAGE'.

Table S8.  Basic characteristics of clinical feature: 'PATHOLOGY_N_STAGE'

PATHOLOGY_N_STAGE Mean (SD) 0.18 (0.45)
  N
  N0 220
  N1 34
  N2 7
     
  Significant markers N = 30
  pos. correlated 30
  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
FOXC2 0.4416 6.951e-14 1.08e-09
SLC6A3 0.4385 1.083e-13 1.08e-09
TLX1 0.4341 2.037e-13 1.35e-09
ARL10 0.4221 1.065e-12 5.3e-09
C4ORF38 0.4185 1.729e-12 5.74e-09
WWC2 0.4185 1.729e-12 5.74e-09
C2ORF55 0.4164 2.28e-12 6.29e-09
DENND1C 0.4156 2.528e-12 6.29e-09
FOXE1 0.3951 3.501e-11 7.75e-08
FGF5 0.3934 4.333e-11 8.63e-08
Clinical variable #6: 'PATHOLOGY_M_STAGE'

30 genes related to 'PATHOLOGY_M_STAGE'.

Table S10.  Basic characteristics of clinical feature: 'PATHOLOGY_M_STAGE'

PATHOLOGY_M_STAGE Labels N
  class0 352
  class1 63
     
  Significant markers N = 30
  Higher in class1 30
  Higher in class0 0
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'

W(pos if higher in 'class1') wilcoxontestP Q AUC
HS3ST2 16941 2.474e-11 2.85e-07 0.7639
ADCYAP1 16922 2.868e-11 2.85e-07 0.7631
SDR16C5 16799 7.37e-11 4.29e-07 0.7575
SOX8 16757 1.013e-10 4.29e-07 0.7556
CHRNA3 16744 1.117e-10 4.29e-07 0.7551
DRD1 16718 1.358e-10 4.29e-07 0.7539
ZC3HAV1L 5472 1.508e-10 4.29e-07 0.7532
CDO1 16617 2.875e-10 6.75e-07 0.7493
ZNF229 16609 3.05e-10 6.75e-07 0.749
RRM2 5598 3.828e-10 7.45e-07 0.7476
Clinical variable #7: 'GENDER'

30 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 214
  MALE 445
     
  Significant markers N = 30
  Higher in MALE 30
  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 90327 9.94e-78 9.89e-74 0.9485
UTP14C 90327 9.94e-78 9.89e-74 0.9485
TLE1 15759 4.839e-44 3.21e-40 0.8345
KIF4B 19986 1.48e-33 7.37e-30 0.7901
WBP11P1 72869 2.604e-28 1.04e-24 0.7652
FRG1B 22587 7.775e-28 2.58e-24 0.7628
C5ORF27 22811 2.277e-27 6.48e-24 0.7605
SCGB1D2 23111 9.457e-27 2.35e-23 0.7573
FKBP5 25308 1.903e-22 4.21e-19 0.7342
PEMT 26413 1.969e-20 3.92e-17 0.7226
Clinical variable #8: 'RADIATION_THERAPY'

No gene related to 'RADIATION_THERAPY'.

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

RADIATION_THERAPY Labels N
  NO 377
  YES 3
     
  Significant markers N = 0
Clinical variable #9: 'KARNOFSKY_PERFORMANCE_SCORE'

30 genes related to 'KARNOFSKY_PERFORMANCE_SCORE'.

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

KARNOFSKY_PERFORMANCE_SCORE Mean (SD) 89.85 (18)
  Significant markers N = 30
  pos. correlated 2
  neg. correlated 28
List of top 10 genes differentially expressed by 'KARNOFSKY_PERFORMANCE_SCORE'

Table S16.  Get Full Table List of top 10 genes significantly correlated to 'KARNOFSKY_PERFORMANCE_SCORE' by Spearman correlation test

SpearmanCorr corrP Q
PLLP -0.428 2.771e-07 0.00382
EPS15L1 -0.4233 3.839e-07 0.00382
KIAA1984 -0.4147 6.949e-07 0.00461
SIGIRR -0.4026 1.56e-06 0.00622
CAMK2B -0.4025 1.562e-06 0.00622
C1ORF210 -0.3883 3.864e-06 0.00998
C11ORF92 -0.3852 4.692e-06 0.00998
C11ORF93 -0.3852 4.692e-06 0.00998
LHFPL2 0.3844 4.913e-06 0.00998
C4ORF36 -0.3841 5.015e-06 0.00998
Clinical variable #10: 'HISTOLOGICAL_TYPE'

30 genes related to 'HISTOLOGICAL_TYPE'.

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

HISTOLOGICAL_TYPE Labels N
  KIDNEY CHROMOPHOBE 66
  KIDNEY CLEAR CELL RENAL CARCINOMA 319
  KIDNEY PAPILLARY RENAL CELL CARCINOMA 274
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'HISTOLOGICAL_TYPE'

Table S18.  Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL_TYPE'

kruskal_wallis_P Q
CCND1 1.573e-96 3.13e-92
NOL3 8.298e-93 8.26e-89
VIM 4.272e-91 2.32e-87
TMCC1 4.664e-91 2.32e-87
APEH 7.316e-91 2.67e-87
KSR1 8.038e-91 2.67e-87
ZNF704 1.276e-90 3.63e-87
ZNF395 5.414e-90 1.3e-86
FTO 5.868e-90 1.3e-86
NDUFA4L2 1.11e-89 2.21e-86
Clinical variable #11: 'NUMBER_PACK_YEARS_SMOKED'

No gene related to 'NUMBER_PACK_YEARS_SMOKED'.

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

NUMBER_PACK_YEARS_SMOKED Mean (SD) 31.27 (25)
  Significant markers N = 0
Clinical variable #12: 'YEAR_OF_TOBACCO_SMOKING_ONSET'

20 genes related to 'YEAR_OF_TOBACCO_SMOKING_ONSET'.

Table S20.  Basic characteristics of clinical feature: 'YEAR_OF_TOBACCO_SMOKING_ONSET'

YEAR_OF_TOBACCO_SMOKING_ONSET Mean (SD) 1973.03 (16)
  Significant markers N = 20
  pos. correlated 16
  neg. correlated 4
List of top 10 genes differentially expressed by 'YEAR_OF_TOBACCO_SMOKING_ONSET'

Table S21.  Get Full Table List of top 10 genes significantly correlated to 'YEAR_OF_TOBACCO_SMOKING_ONSET' by Spearman correlation test

SpearmanCorr corrP Q
FAM90A5 -0.5352 1.273e-06 0.0127
LOC349196 -0.5352 1.273e-06 0.0127
LOC100129794 0.4467 8.365e-05 0.281
SLC25A21 0.4467 8.365e-05 0.281
PCSK4 0.4398 0.000111 0.281
REEP6 0.4398 0.000111 0.281
WBSCR26 0.4394 0.0001125 0.281
TRAP1 0.4544 0.000127 0.281
ALLC -0.4307 0.000159 0.281
HYAL4 0.4266 0.0001864 0.281
Clinical variable #13: 'RACE'

30 genes related to 'RACE'.

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

RACE Labels N
  AMERICAN INDIAN OR ALASKA NATIVE 2
  ASIAN 8
  BLACK OR AFRICAN AMERICAN 107
  WHITE 522
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'RACE'

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

kruskal_wallis_P Q
DHRS7 4.123e-29 8.21e-25
GSTCD__1 1.03e-19 6.83e-16
INTS12 1.03e-19 6.83e-16
RABL2A__1 1.833e-19 7.3e-16
RPL23AP7__1 1.833e-19 7.3e-16
C18ORF54 1.063e-15 3.5e-12
DARC 1.23e-15 3.5e-12
DDX55 1.941e-15 4.83e-12
NDUFA7__1 2.564e-15 5.1e-12
RPS28__1 2.564e-15 5.1e-12
Clinical variable #14: 'ETHNICITY'

No gene related to 'ETHNICITY'.

Table S24.  Basic characteristics of clinical feature: 'ETHNICITY'

ETHNICITY Labels N
  HISPANIC OR LATINO 26
  NOT HISPANIC OR LATINO 518
     
  Significant markers N = 0
Methods & Data
Input

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

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

  • Number of patients = 659

  • Number of genes = 19909

  • Number of clinical features = 14

Selected clinical features

  • Further details on clinical features selected for this analysis, please find a documentation on selected CDEs (Clinical Data Elements). The first column of the file is a formula to convert values and the second column is a clinical parameter name.

  • Survival time data

    • Survival time data is a combined value of days_to_death and days_to_last_followup. For each patient, it creates a combined value 'days_to_death_or_last_fup' using conversion process below.

      • if 'vital_status'==1(dead), 'days_to_last_followup' is always NA. Thus, uses 'days_to_death' value for 'days_to_death_or_fup'

      • if 'vital_status'==0(alive),

        • if 'days_to_death'==NA & 'days_to_last_followup'!=NA, uses 'days_to_last_followup' value for 'days_to_death_or_fup'

        • if 'days_to_death'!=NA, excludes this case in survival analysis and report the case.

      • if 'vital_status'==NA,excludes this case in survival analysis and report the case.

    • cf. In certain diesase types such as SKCM, days_to_death parameter is replaced with time_from_specimen_dx or time_from_specimen_procurement_to_death .

  • This analysis excluded clinical variables that has only NA values.

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

Wilcoxon rank sum test (Mann-Whitney U test)

For two groups (mutant or wild-type) of continuous type of clinical data, wilcoxon rank sum test (Mann and Whitney, 1947) was applied to compare their mean difference using 'wilcox.test(continuous.clinical ~ as.factor(group), exact=FALSE)' function in R. This test is equivalent to the Mann-Whitney test.

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] Mann and Whitney, On a Test of Whether one of Two Random Variables is Stochastically Larger than the Other, Annals of Mathematical Statistics 18 (1), 50-60 (1947)
[4] 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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