Correlation between gene methylation status and clinical features
Pan-kidney cohort (KICH+KIRC+KIRP) (Primary solid tumor)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
doi:10.7908/C1XK8DMC
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/C1XK8DMC
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 13 clinical features across 636 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 ,  ARHGAP1 ,  DDO ,  ...

  • 30 genes correlated to 'NEOPLASM_DISEASESTAGE'.

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

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

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

  • 30 genes correlated to 'PATHOLOGY_N_STAGE'.

    • ARL10 ,  FOXC2 ,  SLC6A3 ,  DENND1C ,  TLX1 ,  ...

  • 30 genes correlated to 'PATHOLOGY_M_STAGE'.

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

  • 30 genes correlated to 'GENDER'.

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

  • 30 genes correlated to 'KARNOFSKY_PERFORMANCE_SCORE'.

    • DCLRE1A ,  NHLRC2 ,  HSPB9 ,  KAT2A ,  C10ORF93 ,  ...

  • 30 genes correlated to 'HISTOLOGICAL_TYPE'.

    • CCND1 ,  NOL3 ,  ZNF704 ,  VIM ,  APEH ,  ...

  • 23 genes correlated to 'YEAR_OF_TOBACCO_SMOKING_ONSET'.

    • FAM90A5 ,  LOC349196 ,  TRAP1 ,  HYAL4 ,  LOC100129794 ,  ...

  • 30 genes correlated to 'RACE'.

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

  • No genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP', '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=14 younger N=16
NEOPLASM_DISEASESTAGE 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
KARNOFSKY_PERFORMANCE_SCORE Spearman correlation test N=30 higher score N=12 lower score N=18
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=23 higher year_of_tobacco_smoking_onset N=18 lower year_of_tobacco_smoking_onset N=5
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=26.2)
  censored N = 494
  death N = 141
     
  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 14
  neg. correlated 16
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 0.2655 1.209e-11 2.41e-07
DGKE 0.2583 4.466e-11 4.45e-07
KLF9 -0.2525 1.239e-10 8.22e-07
ARHGAP1 -0.246 3.789e-10 1.89e-06
DDO -0.2437 5.495e-10 2.12e-06
REC8 0.2428 6.4e-10 2.12e-06
MRPS33 0.2398 1.054e-09 3e-06
RALGAPA2 0.2373 1.575e-09 3.75e-06
TRPM4 0.2368 1.731e-09 3.75e-06
DUSP23 -0.2362 1.885e-09 3.75e-06
Clinical variable #3: 'NEOPLASM_DISEASESTAGE'

30 genes related to 'NEOPLASM_DISEASESTAGE'.

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

NEOPLASM_DISEASESTAGE Labels N
  STAGE I 338
  STAGE II 74
  STAGE III 137
  STAGE IV 75
     
  Significant markers N = 30
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'

kruskal_wallis_P Q
IRX1 8.634e-31 1.72e-26
CDO1 3.009e-30 3e-26
SOX30 5.053e-27 3.35e-23
GPR25 1.425e-26 7.09e-23
MAFA 4.722e-26 1.79e-22
SPAG6 5.388e-26 1.79e-22
NEIL1 1.054e-24 3e-21
SOX8 1.646e-24 4.1e-21
ADCYAP1 6.05e-24 1.32e-20
RRM2 6.626e-24 1.32e-20
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) 1.77 (0.93)
  N
  T1 348
  T2 88
  T3 180
  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 0.4591 4.688e-34 9.33e-30
IRX1 0.4501 1.185e-32 1.18e-28
SOX30 0.4256 5.16e-29 3.42e-25
GPR25 0.4163 1.039e-27 5.03e-24
SPAG6 0.4156 1.264e-27 5.03e-24
ZNF132 0.4036 5.306e-26 1.76e-22
RRM2 -0.4012 1.096e-25 3.12e-22
ABCC8 0.3976 3.191e-25 7.94e-22
MAFA 0.3931 1.224e-24 2.47e-21
USP44 0.393 1.243e-24 2.47e-21
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 (0.44)
  N
  N0 214
  N1 33
  N2 6
     
  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
ARL10 0.4184 3.831e-12 6.92e-08
FOXC2 0.4116 9.151e-12 6.92e-08
SLC6A3 0.4106 1.042e-11 6.92e-08
DENND1C 0.404 2.362e-11 9.72e-08
TLX1 0.4037 2.466e-11 9.72e-08
C2ORF55 0.4023 2.929e-11 9.72e-08
C4ORF38 0.3921 1.005e-10 2.5e-07
WWC2 0.3921 1.005e-10 2.5e-07
SLC10A4 0.3792 4.462e-10 9.87e-07
CPAMD8 0.3688 1.431e-09 2.85e-06
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 349
  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
ADCYAP1 16804 2.406e-11 2.76e-07 0.7643
HS3ST2 16786 2.771e-11 2.76e-07 0.7635
SDR16C5 16655 7.632e-11 4.28e-07 0.7575
SOX8 16630 9.237e-11 4.28e-07 0.7564
CHRNA3 16610 1.075e-10 4.28e-07 0.7554
DRD1 16580 1.35e-10 4.48e-07 0.7541
ZC3HAV1L 5466 2.103e-10 5.98e-07 0.7514
CDO1 16500 2.46e-10 6.12e-07 0.7504
ZNF229 16454 3.46e-10 7.33e-07 0.7484
RRM2 5549 3.894e-10 7.33e-07 0.7476
Clinical variable #7: 'GENDER'

30 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 209
  MALE 427
     
  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 84745 6.968e-76 6.94e-72 0.9496
UTP14C 84745 6.968e-76 6.94e-72 0.9496
TLE1 15039 4.509e-42 2.99e-38 0.8315
KIF4B 19085 8.696e-32 4.33e-28 0.7861
WBP11P1 68154 3.031e-27 1.21e-23 0.7637
FRG1B 21476 2.073e-26 6.88e-23 0.7594
C5ORF27 21525 2.639e-26 7.51e-23 0.7588
SCGB1D2 22218 7.581e-25 1.89e-21 0.751
FKBP5 24045 3.275e-21 7.25e-18 0.7306
PEMT 24966 1.71e-19 3.41e-16 0.7202
Clinical variable #8: 'KARNOFSKY_PERFORMANCE_SCORE'

30 genes related to 'KARNOFSKY_PERFORMANCE_SCORE'.

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

KARNOFSKY_PERFORMANCE_SCORE Mean (SD) 92.43 (9.7)
  Significant markers N = 30
  pos. correlated 12
  neg. correlated 18
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
DCLRE1A 0.398 2.179e-05 0.121
NHLRC2 0.398 2.179e-05 0.121
HSPB9 -0.3935 2.757e-05 0.121
KAT2A -0.3935 2.757e-05 0.121
C10ORF93 -0.3861 4.003e-05 0.121
IRAK4__1 0.3827 4.727e-05 0.121
PUS7L 0.3827 4.727e-05 0.121
NAB2 -0.3821 4.875e-05 0.121
LDHD -0.374 7.253e-05 0.121
SHROOM1 0.3733 7.488e-05 0.121
Clinical variable #9: 'HISTOLOGICAL_TYPE'

30 genes related to 'HISTOLOGICAL_TYPE'.

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

HISTOLOGICAL_TYPE Labels N
  KIDNEY CHROMOPHOBE 66
  KIDNEY CLEAR CELL RENAL CARCINOMA 315
  KIDNEY PAPILLARY RENAL CELL CARCINOMA 255
     
  Significant markers N = 30
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'

kruskal_wallis_P Q
CCND1 4.571e-93 9.1e-89
NOL3 2.318e-90 2.31e-86
ZNF704 4.271e-89 2.83e-85
VIM 7.036e-89 3.5e-85
APEH 9.729e-89 3.87e-85
FTO 1.337e-88 4.35e-85
KSR1 1.531e-88 4.35e-85
TMCC1 2.709e-88 6.74e-85
UBE2N 3.391e-88 7.5e-85
ZNF395 7.26e-88 1.45e-84
Clinical variable #10: 'NUMBER_PACK_YEARS_SMOKED'

No gene related to 'NUMBER_PACK_YEARS_SMOKED'.

Table S18.  Basic characteristics of clinical feature: 'NUMBER_PACK_YEARS_SMOKED'

NUMBER_PACK_YEARS_SMOKED Mean (SD) 31.14 (26)
  Significant markers N = 0
Clinical variable #11: 'YEAR_OF_TOBACCO_SMOKING_ONSET'

23 genes related to 'YEAR_OF_TOBACCO_SMOKING_ONSET'.

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

YEAR_OF_TOBACCO_SMOKING_ONSET Mean (SD) 1973.13 (16)
  Significant markers N = 23
  pos. correlated 18
  neg. correlated 5
List of top 10 genes differentially expressed by 'YEAR_OF_TOBACCO_SMOKING_ONSET'

Table S20.  Get Full Table List of top 10 genes significantly correlated to 'YEAR_OF_TOBACCO_SMOKING_ONSET' by Spearman correlation test

SpearmanCorr corrP Q
FAM90A5 -0.5274 4.522e-06 0.045
LOC349196 -0.5274 4.522e-06 0.045
TRAP1 0.5059 3.188e-05 0.19
HYAL4 0.4802 3.915e-05 0.19
LOC100129794 0.4711 5.74e-05 0.19
SLC25A21 0.4711 5.74e-05 0.19
PCSK4 0.461 8.652e-05 0.215
REEP6 0.461 8.652e-05 0.215
CHDH__1 0.4511 0.0001278 0.254
IL17RB 0.4511 0.0001278 0.254
Clinical variable #12: 'RACE'

30 genes related to 'RACE'.

Table S21.  Basic characteristics of clinical feature: 'RACE'

RACE Labels N
  AMERICAN INDIAN OR ALASKA NATIVE 2
  ASIAN 8
  BLACK OR AFRICAN AMERICAN 102
  WHITE 504
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'RACE'

Table S22.  Get Full Table List of top 10 genes differentially expressed by 'RACE'

kruskal_wallis_P Q
DHRS7 5.361e-27 1.07e-22
GSTCD__1 1.225e-19 8.13e-16
INTS12 1.225e-19 8.13e-16
RABL2A__1 4.453e-18 1.77e-14
RPL23AP7__1 4.453e-18 1.77e-14
C18ORF54 5.61e-16 1.86e-12
CCDC117 5.399e-15 1.54e-11
DARC 6.485e-15 1.61e-11
DDX55 8.426e-15 1.86e-11
PPPDE2 2.669e-14 4.83e-11
Clinical variable #13: 'ETHNICITY'

No gene related to 'ETHNICITY'.

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

ETHNICITY Labels N
  HISPANIC OR LATINO 26
  NOT HISPANIC OR LATINO 493
     
  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 = 636

  • Number of genes = 19909

  • Number of clinical features = 13

Selected clinical features

  • For clinical features selected for this analysis and their value conozzle.versions, please find a documentation on selected CDEs .

  • 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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