Correlation between gene methylation status and clinical features
Stomach Adenocarcinoma (Primary solid tumor)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
doi:10.7908/C14T6HHS
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/C14T6HHS
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 19733 genes and 13 clinical features across 390 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 9 clinical features related to at least one genes.

  • 30 genes correlated to 'YEARS_TO_BIRTH'.

    • KIAA1217 ,  ELOVL2 ,  SLC12A7 ,  EARS2 ,  UBFD1 ,  ...

  • 30 genes correlated to 'NEOPLASM_DISEASESTAGE'.

    • DYNC2LI1 ,  EED ,  SNORA25 ,  SNORA32 ,  SNORD6 ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • FEM1B ,  ANKFY1 ,  CDV3 ,  FBXO33 ,  SLC16A5 ,  ...

  • 30 genes correlated to 'PATHOLOGY_M_STAGE'.

    • FKBP14 ,  IFI6 ,  TWF1 ,  OPN5 ,  USP1 ,  ...

  • 30 genes correlated to 'GENDER'.

    • ALG11__1 ,  UTP14C ,  KIF4B ,  RELB ,  RIMBP3 ,  ...

  • 30 genes correlated to 'HISTOLOGICAL_TYPE'.

    • CXCL16__1 ,  ZMYND15__1 ,  C3ORF26 ,  FILIP1L ,  FLOT1 ,  ...

  • 30 genes correlated to 'RADIATIONS_RADIATION_REGIMENINDICATION'.

    • CBWD1 ,  RPL17__1 ,  SNORD58A ,  SNORD58B ,  TRMT11 ,  ...

  • 30 genes correlated to 'COMPLETENESS_OF_RESECTION'.

    • CCDC144A ,  ST13 ,  XPNPEP3 ,  SCP2 ,  MAS1L ,  ...

  • 30 genes correlated to 'RACE'.

    • LOC100271836 ,  PIGY ,  C11ORF58 ,  GRAPL ,  GTF2IRD2B ,  ...

  • No genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP', 'PATHOLOGY_N_STAGE', 'NUMBER_OF_LYMPH_NODES', 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=3 younger N=27
NEOPLASM_DISEASESTAGE Kruskal-Wallis test N=30        
PATHOLOGY_T_STAGE Spearman correlation test N=30 higher stage N=3 lower stage N=27
PATHOLOGY_N_STAGE Spearman correlation test   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
HISTOLOGICAL_TYPE Kruskal-Wallis test N=30        
RADIATIONS_RADIATION_REGIMENINDICATION Wilcoxon test N=30 yes N=30 no N=0
COMPLETENESS_OF_RESECTION Kruskal-Wallis test N=30        
NUMBER_OF_LYMPH_NODES Spearman correlation test   N=0        
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) 0.1-122.3 (median=12.8)
  censored N = 253
  death N = 136
     
  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) 65.16 (11)
  Significant markers N = 30
  pos. correlated 3
  neg. correlated 27
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
KIAA1217 -0.2611 2.168e-07 0.00105
ELOVL2 0.2599 2.485e-07 0.00105
SLC12A7 -0.2574 3.266e-07 0.00105
EARS2 -0.257 3.416e-07 0.00105
UBFD1 -0.257 3.416e-07 0.00105
NRARP -0.2549 4.261e-07 0.00105
CHST9 -0.2535 5.345e-07 0.00105
TOP1MT -0.2527 5.398e-07 0.00105
SIGIRR -0.2519 5.887e-07 0.00105
STARD10 -0.2518 5.97e-07 0.00105
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 3
  STAGE IA 13
  STAGE IB 35
  STAGE II 28
  STAGE IIA 39
  STAGE IIB 54
  STAGE III 3
  STAGE IIIA 79
  STAGE IIIB 61
  STAGE IIIC 40
  STAGE IV 35
     
  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
DYNC2LI1 3.515e-09 6.32e-05
EED 6.407e-09 6.32e-05
SNORA25 4.109e-08 0.000155
SNORA32 4.109e-08 0.000155
SNORD6 4.109e-08 0.000155
MIR197 4.723e-08 0.000155
SMAD1 8.793e-08 0.000234
HIST1H1A 1.026e-07 0.000234
CCDC93 1.067e-07 0.000234
ZFP42 1.268e-07 0.000245
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) 2.99 (0.83)
  N
  T1 20
  T2 75
  T3 185
  T4 110
     
  Significant markers N = 30
  pos. correlated 3
  neg. correlated 27
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
FEM1B -0.2875 7.355e-09 9.66e-05
ANKFY1 -0.2805 1.759e-08 9.66e-05
CDV3 -0.2798 1.911e-08 9.66e-05
FBXO33 -0.2786 2.214e-08 9.66e-05
SLC16A5 0.2751 3.329e-08 9.66e-05
LRRC40 -0.2749 3.427e-08 9.66e-05
SFRS11 -0.2749 3.427e-08 9.66e-05
CYB5RL__1 -0.2676 8.012e-08 0.000176
MRPL37__1 -0.2676 8.012e-08 0.000176
LTA4H -0.2637 1.264e-07 0.000216
Clinical variable #5: 'PATHOLOGY_N_STAGE'

No gene related to 'PATHOLOGY_N_STAGE'.

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

PATHOLOGY_N_STAGE Mean (SD) 1.32 (1.1)
  N
  N0 123
  N1 100
  N2 78
  N3 84
     
  Significant markers N = 0
Clinical variable #6: 'PATHOLOGY_M_STAGE'

30 genes related to 'PATHOLOGY_M_STAGE'.

Table S9.  Basic characteristics of clinical feature: 'PATHOLOGY_M_STAGE'

PATHOLOGY_M_STAGE Labels N
  class0 351
  class1 23
     
  Significant markers N = 30
  Higher in class1 30
  Higher in class0 0
List of top 10 genes differentially expressed by 'PATHOLOGY_M_STAGE'

Table S10.  Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGY_M_STAGE'

W(pos if higher in 'class1') wilcoxontestP Q AUC
FKBP14 6278 8.132e-06 0.111 0.7777
IFI6 1877 1.72e-05 0.111 0.7675
TWF1 6113 3.578e-05 0.111 0.7572
OPN5 1971 3.935e-05 0.111 0.7559
USP1 6078 4.834e-05 0.111 0.7529
JPH2 2001 5.088e-05 0.111 0.7521
HNRNPR 6045 5.535e-05 0.111 0.7509
LATS1 6052 6.027e-05 0.111 0.7497
MAPRE1 6045 6.393e-05 0.111 0.7488
SPG11 6008 8.704e-05 0.111 0.7442
Clinical variable #7: 'GENDER'

30 genes related to 'GENDER'.

Table S11.  Basic characteristics of clinical feature: 'GENDER'

GENDER Labels N
  FEMALE 136
  MALE 254
     
  Significant markers N = 30
  Higher in MALE 30
  Higher in FEMALE 0
List of top 10 genes differentially expressed by 'GENDER'

Table S12.  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__1 32581 3.38e-47 3.33e-43 0.9432
UTP14C 32581 3.38e-47 3.33e-43 0.9432
KIF4B 5694 1.003e-27 6.6e-24 0.8352
RELB 23319 1.203e-08 5.94e-05 0.6751
RIMBP3 23104 3.871e-08 0.000153 0.6688
HAX1 12063 9.135e-07 0.003 0.6508
DDX43 12369 3.819e-06 0.00981 0.6419
FRG1B 12378 3.979e-06 0.00981 0.6417
CDH15 22130 4.682e-06 0.0103 0.6406
NLRP2 21939 1.09e-05 0.0215 0.6351
Clinical variable #8: 'HISTOLOGICAL_TYPE'

30 genes related to 'HISTOLOGICAL_TYPE'.

Table S13.  Basic characteristics of clinical feature: 'HISTOLOGICAL_TYPE'

HISTOLOGICAL_TYPE Labels N
  STOMACH ADENOCARCINOMA DIFFUSE TYPE 66
  STOMACH ADENOCARCINOMA NOT OTHERWISE SPECIFIED (NOS) 134
  STOMACH INTESTINAL ADENOCARCINOMA NOT OTHERWISE SPECIFIED (NOS) 72
  STOMACH INTESTINAL ADENOCARCINOMA TUBULAR TYPE 77
  STOMACH INTESTINAL ADENOCARCINOMA  MUCINOUS TYPE 20
  STOMACH INTESTINAL ADENOCARCINOMA  PAPILLARY TYPE 8
  STOMACH ADENOCARCINOMA SIGNET RING TYPE 13
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'HISTOLOGICAL_TYPE'

Table S14.  Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL_TYPE'

kruskal_wallis_P Q
CXCL16__1 1.221e-14 1.2e-10
ZMYND15__1 1.221e-14 1.2e-10
C3ORF26 2.745e-13 1.35e-09
FILIP1L 2.745e-13 1.35e-09
FLOT1 1.11e-12 3.65e-09
IER3 1.11e-12 3.65e-09
SLC23A1 1.639e-12 4.47e-09
SHBG__1 1.983e-12 4.47e-09
KRT23 2.04e-12 4.47e-09
LRIG3 7.527e-12 1.49e-08
Clinical variable #9: 'RADIATIONS_RADIATION_REGIMENINDICATION'

30 genes related to 'RADIATIONS_RADIATION_REGIMENINDICATION'.

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

RADIATIONS_RADIATION_REGIMENINDICATION Labels N
  NO 6
  YES 384
     
  Significant markers N = 30
  Higher in YES 30
  Higher in NO 0
List of top 10 genes differentially expressed by 'RADIATIONS_RADIATION_REGIMENINDICATION'

Table S16.  Get Full Table List of top 10 genes differentially expressed by 'RADIATIONS_RADIATION_REGIMENINDICATION'

W(pos if higher in 'YES') wilcoxontestP Q AUC
CBWD1 2197 0.0001378 0.291 0.9536
RPL17__1 121 0.0001692 0.291 0.9475
SNORD58A 121 0.0001692 0.291 0.9475
SNORD58B 121 0.0001692 0.291 0.9475
TRMT11 121 0.0001692 0.291 0.9475
ZNF837 147 0.0002462 0.291 0.9362
LARP1 168 0.0003313 0.291 0.9271
PTGES3 171 0.0003455 0.291 0.9258
CCDC28A 174 0.0003602 0.291 0.9245
NCK1 181 0.000397 0.291 0.9214
Clinical variable #10: 'COMPLETENESS_OF_RESECTION'

30 genes related to 'COMPLETENESS_OF_RESECTION'.

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

COMPLETENESS_OF_RESECTION Labels N
  R0 333
  R1 17
  R2 12
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'COMPLETENESS_OF_RESECTION'

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

kruskal_wallis_P Q
CCDC144A 8.15e-05 0.269
ST13 9.498e-05 0.269
XPNPEP3 9.498e-05 0.269
SCP2 0.0001922 0.269
MAS1L 0.0001941 0.269
CCDC144NL 0.000227 0.269
PPP3R1 0.0002474 0.269
CDC27 0.0002502 0.269
LOC151658 0.0002666 0.269
CR1L 0.0002855 0.269
Clinical variable #11: 'NUMBER_OF_LYMPH_NODES'

No gene related to 'NUMBER_OF_LYMPH_NODES'.

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

NUMBER_OF_LYMPH_NODES Mean (SD) 5.62 (8.4)
  Significant markers N = 0
Clinical variable #12: 'RACE'

30 genes related to 'RACE'.

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

RACE Labels N
  ASIAN 89
  BLACK OR AFRICAN AMERICAN 12
  NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER 1
  WHITE 249
     
  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
LOC100271836 1.895e-14 3.74e-10
PIGY 9.199e-14 9.08e-10
C11ORF58 1.748e-13 1.15e-09
GRAPL 3.315e-13 1.64e-09
GTF2IRD2B 7.441e-13 2.94e-09
HIST1H4K 2.621e-12 8.62e-09
CRYZ__1 4.72e-12 1.16e-08
TYW3__1 4.72e-12 1.16e-08
PYCRL 6.821e-12 1.5e-08
CHCHD1 1.5e-11 2.96e-08
Clinical variable #13: 'ETHNICITY'

No gene related to 'ETHNICITY'.

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

ETHNICITY Labels N
  HISPANIC OR LATINO 4
  NOT HISPANIC OR LATINO 290
     
  Significant markers N = 0
Methods & Data
Input

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

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

  • Number of patients = 390

  • Number of genes = 19733

  • 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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