Correlation between gene methylation status and clinical features
Stomach and Esophageal carcinoma (Primary solid tumor)
21 August 2015  |  analyses__2015_08_21
Maintainer Information
Citation Information
doi:10.7908/C14J0DFM
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/C14J0DFM
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 20581 genes and 12 clinical features across 580 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 11 clinical features related to at least one genes.

  • 30 genes correlated to 'YEARS_TO_BIRTH'.

    • PNPLA2 ,  CDC42EP1 ,  ARHGAP27 ,  CLDN7 ,  LYPLA2 ,  ...

  • 30 genes correlated to 'PATHOLOGIC_STAGE'.

    • TOM1L2__1 ,  KRT74 ,  NDE1 ,  STX12 ,  KRT82 ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • MARVELD2 ,  PPM1J ,  C19ORF33__1 ,  YIF1B__1 ,  C1ORF89 ,  ...

  • 30 genes correlated to 'PATHOLOGY_N_STAGE'.

    • PKD1 ,  TRIM35 ,  KRT14 ,  ADA ,  ST3GAL3 ,  ...

  • 30 genes correlated to 'PATHOLOGY_M_STAGE'.

    • RCC2 ,  R3HDM1 ,  ZRANB3 ,  RTN4 ,  CCDC90B ,  ...

  • 30 genes correlated to 'GENDER'.

    • KIF4B ,  FAM35A ,  GLUD1 ,  FRG1B ,  DDX55 ,  ...

  • 30 genes correlated to 'RADIATION_THERAPY'.

    • TIFA ,  VANGL1 ,  YWHAZ ,  DSTYK ,  GTF2IP1 ,  ...

  • 30 genes correlated to 'KARNOFSKY_PERFORMANCE_SCORE'.

    • LOC148189 ,  C1D ,  GFM1__1 ,  NR2C1 ,  FLJ36031 ,  ...

  • 30 genes correlated to 'NUMBER_PACK_YEARS_SMOKED'.

    • KIAA1530 ,  TENC1 ,  D2HGDH ,  MLLT6 ,  C15ORF57 ,  ...

  • 30 genes correlated to 'RACE'.

    • ZYG11B ,  SERHL2 ,  PM20D1 ,  DCUN1D1 ,  NICN1 ,  ...

  • 30 genes correlated to 'ETHNICITY'.

    • C5ORF15 ,  ZNF780B ,  AASDHPPT ,  KBTBD3 ,  C12ORF65 ,  ...

  • No genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP'

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=1 younger N=29
PATHOLOGIC_STAGE Kruskal-Wallis test N=30        
PATHOLOGY_T_STAGE Spearman correlation test N=30 higher stage N=30 lower stage N=0
PATHOLOGY_N_STAGE Spearman correlation test N=30 higher stage N=29 lower stage N=1
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=30 yes N=30 no N=0
KARNOFSKY_PERFORMANCE_SCORE Spearman correlation test N=30 higher score N=30 lower score N=0
NUMBER_PACK_YEARS_SMOKED Spearman correlation test N=30 higher number_pack_years_smoked N=2 lower number_pack_years_smoked N=28
RACE Kruskal-Wallis test N=30        
ETHNICITY Wilcoxon test N=30 not hispanic or latino N=30 hispanic or latino 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) 0.1-122.3 (median=13.5)
  censored N = 354
  death N = 225
     
  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) 64.32 (11)
  Significant markers N = 30
  pos. correlated 1
  neg. correlated 29
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
PNPLA2 -0.294 7.497e-13 1.54e-08
CDC42EP1 -0.2876 2.457e-12 2.53e-08
ARHGAP27 -0.2836 5.013e-12 3.37e-08
CLDN7 -0.2817 7.025e-12 3.37e-08
LYPLA2 -0.2809 8.186e-12 3.37e-08
CLIC1 -0.2791 1.115e-11 3.82e-08
SLC12A7 -0.2783 1.298e-11 3.82e-08
GNA11 -0.2753 2.19e-11 5.63e-08
SLC25A20 -0.2746 2.472e-11 5.65e-08
CTBP2 -0.2725 3.631e-11 6.58e-08
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 11
  STAGE IA 19
  STAGE IB 41
  STAGE II 30
  STAGE IIA 88
  STAGE IIB 87
  STAGE III 29
  STAGE IIIA 91
  STAGE IIIB 72
  STAGE IIIC 45
  STAGE IV 40
  STAGE IVA 4
     
  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
TOM1L2__1 4.418e-11 9.09e-07
KRT74 1.531e-10 1.58e-06
NDE1 2.539e-10 1.74e-06
STX12 3.824e-10 1.97e-06
KRT82 1.202e-09 3.52e-06
FBXO31 1.407e-09 3.52e-06
MAP1LC3B 1.407e-09 3.52e-06
C9ORF70 1.538e-09 3.52e-06
GLIS3__1 1.538e-09 3.52e-06
CES2__1 2.767e-09 5e-06
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) 2.8 (0.88)
  N
  T0 1
  T1 52
  T2 121
  T3 274
  T4 115
     
  Significant markers N = 30
  pos. correlated 30
  neg. correlated 0
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
MARVELD2 0.3079 7.854e-14 1.62e-09
PPM1J 0.2929 1.387e-12 8.23e-09
C19ORF33__1 0.2919 1.6e-12 8.23e-09
YIF1B__1 0.2919 1.6e-12 8.23e-09
C1ORF89 0.2839 6.796e-12 2.8e-08
SERTAD2 0.2812 1.077e-11 3.7e-08
SRCRB4D 0.278 1.88e-11 5.53e-08
TOM1L1__1 0.2756 2.849e-11 6.23e-08
PRR7 0.2749 3.217e-11 6.23e-08
C15ORF62__1 0.2743 3.575e-11 6.23e-08
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) 1.13 (1.1)
  N
  N0 201
  N1 171
  N2 92
  N3 91
     
  Significant markers N = 30
  pos. correlated 29
  neg. correlated 1
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
PKD1 0.2476 3.376e-09 6.95e-05
TRIM35 0.2222 1.229e-07 0.00127
KRT14 0.217 2.448e-07 0.00135
ADA 0.2148 3.261e-07 0.00135
ST3GAL3 0.2139 3.629e-07 0.00135
PODNL1 0.213 4.093e-07 0.00135
MICAL3 0.2118 4.733e-07 0.00135
LOC342346 0.211 5.252e-07 0.00135
NDE1 0.2085 7.184e-07 0.00147
GARNL3 0.2074 8.314e-07 0.00147
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 489
  class1 32
     
  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
RCC2 4306 2.013e-05 0.188 0.7248
R3HDM1 11254 3.228e-05 0.188 0.7192
ZRANB3 11254 3.228e-05 0.188 0.7192
RTN4 11231 3.645e-05 0.188 0.7177
CCDC90B 11176 4.86e-05 0.2 0.7142
CHURC1 11063 8.663e-05 0.2 0.707
OSBPL11 11061 8.751e-05 0.2 0.7069
C2ORF7 11045 9.483e-05 0.2 0.7058
CCT7 11045 9.483e-05 0.2 0.7058
MPL 4608 9.723e-05 0.2 0.7055
Clinical variable #7: 'GENDER'

30 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 163
  MALE 417
     
  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
KIF4B 12816 1.831e-31 3.77e-27 0.8114
FAM35A 17167 1.848e-20 1.27e-16 0.7474
GLUD1 17167 1.848e-20 1.27e-16 0.7474
FRG1B 17383 5.605e-20 2.88e-16 0.7443
DDX55 49114 7.482e-17 3.08e-13 0.7226
C6ORF174 21107 1.258e-12 4.31e-09 0.6895
RIMBP3 45145 7.686e-10 2.26e-06 0.6642
FAM24B 22967 1.251e-09 2.86e-06 0.6621
LOC399815 22967 1.251e-09 2.86e-06 0.6621
NCRNA00116 23090 1.904e-09 3.8e-06 0.6603
Clinical variable #8: 'RADIATION_THERAPY'

30 genes related to 'RADIATION_THERAPY'.

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

RADIATION_THERAPY Labels N
  NO 425
  YES 115
     
  Significant markers N = 30
  Higher in YES 30
  Higher in NO 0
List of top 10 genes differentially expressed by 'RADIATION_THERAPY'

Table S15.  Get Full Table List of top 10 genes differentially expressed by 'RADIATION_THERAPY'

W(pos if higher in 'YES') wilcoxontestP Q AUC
TIFA 17281 1.43e-06 0.0126 0.6464
VANGL1 17380 1.993e-06 0.0126 0.6444
YWHAZ 16568 2.015e-06 0.0126 0.6461
DSTYK 17443 2.457e-06 0.0126 0.6431
GTF2IP1 17677 5.263e-06 0.015 0.6383
LOC100093631 17677 5.263e-06 0.015 0.6383
C10ORF105 17708 5.811e-06 0.015 0.6377
CDH23__2 17708 5.811e-06 0.015 0.6377
FAM40A 17788 7.491e-06 0.0171 0.6361
NINJ1 17913 1.108e-05 0.0207 0.6335
Clinical variable #9: 'KARNOFSKY_PERFORMANCE_SCORE'

30 genes related to 'KARNOFSKY_PERFORMANCE_SCORE'.

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

KARNOFSKY_PERFORMANCE_SCORE Mean (SD) 73.82 (16)
  Significant markers N = 30
  pos. correlated 30
  neg. correlated 0
List of top 10 genes differentially expressed by 'KARNOFSKY_PERFORMANCE_SCORE'

Table S17.  Get Full Table List of top 10 genes significantly correlated to 'KARNOFSKY_PERFORMANCE_SCORE' by Spearman correlation test

SpearmanCorr corrP Q
LOC148189 0.671 3.81e-10 7.84e-06
C1D 0.6579 1.085e-09 1.12e-05
GFM1__1 0.6518 1.737e-09 1.19e-05
NR2C1 0.6438 3.167e-09 1.63e-05
FLJ36031 0.6306 1.391e-08 5.73e-05
GORAB 0.6148 2.436e-08 5.82e-05
DEPDC4__1 0.6127 2.811e-08 5.82e-05
SCYL2__1 0.6127 2.811e-08 5.82e-05
COPS2 0.6115 3.036e-08 5.82e-05
GALK2__1 0.6115 3.036e-08 5.82e-05
Clinical variable #10: 'NUMBER_PACK_YEARS_SMOKED'

30 genes related to 'NUMBER_PACK_YEARS_SMOKED'.

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

NUMBER_PACK_YEARS_SMOKED Mean (SD) 34.48 (22)
  Significant markers N = 30
  pos. correlated 2
  neg. correlated 28
List of top 10 genes differentially expressed by 'NUMBER_PACK_YEARS_SMOKED'

Table S19.  Get Full Table List of top 10 genes significantly correlated to 'NUMBER_PACK_YEARS_SMOKED' by Spearman correlation test

SpearmanCorr corrP Q
KIAA1530 -0.51 8.115e-08 0.00167
TENC1 -0.4841 4.416e-07 0.00454
D2HGDH -0.4618 1.696e-06 0.0116
MLLT6 -0.4527 2.874e-06 0.0148
C15ORF57 -0.4432 5.464e-06 0.0225
MAPK3 -0.4346 7.757e-06 0.0266
C19ORF23 -0.4252 1.274e-05 0.0328
CIRBP -0.4252 1.274e-05 0.0328
MAP2K3 -0.4143 2.229e-05 0.0476
ABCC10 -0.4135 2.311e-05 0.0476
Clinical variable #11: 'RACE'

30 genes related to 'RACE'.

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

RACE Labels N
  ASIAN 135
  BLACK OR AFRICAN AMERICAN 18
  NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER 1
  WHITE 367
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'RACE'

Table S21.  Get Full Table List of top 10 genes differentially expressed by 'RACE'

kruskal_wallis_P Q
ZYG11B 1.892e-24 3.89e-20
SERHL2 3.88e-20 3.99e-16
PM20D1 5.872e-19 4.03e-15
DCUN1D1 4.525e-17 2.33e-13
NICN1 1.448e-16 5.96e-13
SPATA22 1.091e-15 3.74e-12
C12ORF47 4.644e-15 1.19e-11
MAPKAPK5 4.644e-15 1.19e-11
ASB16 1.078e-14 2.22e-11
C17ORF65 1.078e-14 2.22e-11
Clinical variable #12: 'ETHNICITY'

30 genes related to 'ETHNICITY'.

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

ETHNICITY Labels N
  HISPANIC OR LATINO 11
  NOT HISPANIC OR LATINO 381
     
  Significant markers N = 30
  Higher in NOT HISPANIC OR LATINO 30
  Higher in HISPANIC OR LATINO 0
List of top 10 genes differentially expressed by 'ETHNICITY'

Methods & Data
Input

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

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

  • Number of patients = 580

  • Number of genes = 20581

  • Number of clinical features = 12

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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