Correlation between gene methylation status and clinical features
Stomach and Esophageal carcinoma (Primary solid tumor)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
doi:10.7908/C1V69HQX
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/C1V69HQX
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 19752 genes and 14 clinical features across 564 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'.

    • SLC12A7 ,  ARHGEF16 ,  CDK2AP2 ,  PNPLA2 ,  CLDN7 ,  ...

  • 30 genes correlated to 'NEOPLASM_DISEASESTAGE'.

    • KRT74 ,  PADI6 ,  TOM1L2__1 ,  WDR47 ,  ABHD5 ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • RCAN3 ,  ARHGAP8 ,  PRR5-ARHGAP8 ,  PPM1J ,  B3GNT9 ,  ...

  • 30 genes correlated to 'PATHOLOGY_N_STAGE'.

    • ADAM15__1 ,  DCST1__1 ,  KRT14 ,  TRIM35 ,  ADA ,  ...

  • 30 genes correlated to 'PATHOLOGY_M_STAGE'.

    • RPL11 ,  CCDC90B ,  JAGN1 ,  UBR4 ,  TMED2 ,  ...

  • 30 genes correlated to 'GENDER'.

    • KIF4B ,  FRG1B ,  RIMBP3 ,  GPX1 ,  ISOC2 ,  ...

  • 30 genes correlated to 'HISTOLOGICAL_TYPE'.

    • FLOT1 ,  IER3 ,  SLC23A1 ,  KRT23 ,  C20ORF151 ,  ...

  • 30 genes correlated to 'NUMBER_PACK_YEARS_SMOKED'.

    • TENC1 ,  C15ORF57 ,  MAPK3 ,  TAOK2 ,  ACD__1 ,  ...

  • 30 genes correlated to 'COMPLETENESS_OF_RESECTION'.

    • CCDC144A ,  C17ORF70 ,  ALKBH6 ,  HIST1H1B ,  SCP2 ,  ...

  • 30 genes correlated to 'RACE'.

    • MRPL36 ,  SERHL2 ,  GRAPL ,  RSPH10B ,  RSPH10B2 ,  ...

  • No genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP', 'RADIATIONS_RADIATION_REGIMENINDICATION', '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=1 younger N=29
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=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
HISTOLOGICAL_TYPE Kruskal-Wallis test N=30        
RADIATIONS_RADIATION_REGIMENINDICATION Wilcoxon test   N=0        
NUMBER_PACK_YEARS_SMOKED Spearman correlation test N=30 higher number_pack_years_smoked N=7 lower number_pack_years_smoked N=23
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 = 356
  death N = 207
     
  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) 64.36 (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
SLC12A7 -0.2878 4.403e-12 8.7e-08
ARHGEF16 -0.2804 1.598e-11 1.08e-07
CDK2AP2 -0.279 2.021e-11 1.08e-07
PNPLA2 -0.2786 2.18e-11 1.08e-07
CLDN7 -0.2706 8.36e-11 3.3e-07
ARHGAP27 -0.2684 1.214e-10 3.65e-07
MRPL43__1 -0.2672 1.478e-10 3.65e-07
SEMA4G__2 -0.2672 1.478e-10 3.65e-07
SLC25A20 -0.2588 5.644e-10 1.1e-06
RPH3AL -0.2583 6.148e-10 1.1e-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 11
  STAGE IA 18
  STAGE IB 42
  STAGE II 29
  STAGE IIA 78
  STAGE IIB 83
  STAGE III 29
  STAGE IIIA 91
  STAGE IIIB 71
  STAGE IIIC 47
  STAGE IV 40
  STAGE IVA 4
     
  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
KRT74 2.665e-09 3.09e-05
PADI6 3.179e-09 3.09e-05
TOM1L2__1 5.215e-09 3.09e-05
WDR47 9.613e-09 3.09e-05
ABHD5 1.254e-08 3.09e-05
OLA1 1.343e-08 3.09e-05
LSG1 1.352e-08 3.09e-05
CPT1A 1.555e-08 3.09e-05
SIN3A 1.819e-08 3.09e-05
TSPAN13 1.957e-08 3.09e-05
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) 2.82 (0.87)
  N
  T0 1
  T1 50
  T2 111
  T3 271
  T4 115
     
  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
RCAN3 0.3001 7.179e-13 1.38e-08
ARHGAP8 0.2942 2.098e-12 1.38e-08
PRR5-ARHGAP8 0.2942 2.098e-12 1.38e-08
PPM1J 0.286 9.268e-12 4.03e-08
B3GNT9 0.2852 1.02e-11 4.03e-08
LDLRAP1 0.2823 1.675e-11 5.52e-08
TGFA 0.2805 2.312e-11 5.99e-08
PRR7 0.2802 2.427e-11 5.99e-08
SPTLC2 0.2794 2.74e-11 6.01e-08
LOC284837 0.2783 3.338e-11 6.59e-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) 1.15 (1.1)
  N
  N0 194
  N1 165
  N2 90
  N3 92
     
  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
ADAM15__1 0.2128 6.457e-07 0.00425
DCST1__1 0.2128 6.457e-07 0.00425
KRT14 0.2108 7.535e-07 0.00425
TRIM35 0.2095 8.777e-07 0.00425
ADA 0.2079 1.076e-06 0.00425
MICAL3 0.2036 1.805e-06 0.00594
OSBPL10__1 -0.1972 3.801e-06 0.0104
SDC1 0.1964 4.192e-06 0.0104
MRPL14 0.1933 5.974e-06 0.0108
TMEM63B 0.1933 5.974e-06 0.0108
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 478
  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
RPL11 11042 2.614e-05 0.172 0.7219
CCDC90B 11000 3.286e-05 0.172 0.7191
JAGN1 10941 4.511e-05 0.172 0.7153
UBR4 10935 4.658e-05 0.172 0.7149
TMED2 10842 7.592e-05 0.172 0.7088
OSBPL11 10826 8.247e-05 0.172 0.7078
METTL2B 10816 8.683e-05 0.172 0.7071
HNRNPR 10721 0.0001258 0.172 0.7024
PEX13 10725 0.0001379 0.172 0.7012
PUS10 10725 0.0001379 0.172 0.7012
Clinical variable #7: 'GENDER'

30 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 160
  MALE 404
     
  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 9814 4.476e-38 8.84e-34 0.8482
FRG1B 16466 1.014e-19 1e-15 0.7453
RIMBP3 42564 4.313e-09 2.83e-05 0.6585
GPX1 22178 6.128e-09 2.83e-05 0.6569
ISOC2 42416 7.171e-09 2.83e-05 0.6562
CAPZA1__1 22328 1.021e-08 2.88e-05 0.6546
ST7L__1 22328 1.021e-08 2.88e-05 0.6546
DDX43 23019 9.759e-08 0.000241 0.6439
EIF4A1 23546 4.928e-07 0.000973 0.6357
SNORA48 23546 4.928e-07 0.000973 0.6357
Clinical variable #8: 'HISTOLOGICAL_TYPE'

30 genes related to 'HISTOLOGICAL_TYPE'.

Table S14.  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 S15.  Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL_TYPE'

kruskal_wallis_P Q
FLOT1 1.11e-12 1.01e-08
IER3 1.11e-12 1.01e-08
SLC23A1 1.639e-12 1.01e-08
KRT23 2.04e-12 1.01e-08
C20ORF151 3.318e-12 1.31e-08
GRAMD1B 1.154e-11 3.8e-08
DTX4 1.746e-11 4.68e-08
SLC40A1 1.897e-11 4.68e-08
LCT 2.187e-11 4.8e-08
LIF 3.098e-11 5.93e-08
Clinical variable #9: 'RADIATIONS_RADIATION_REGIMENINDICATION'

No gene related to 'RADIATIONS_RADIATION_REGIMENINDICATION'.

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

RADIATIONS_RADIATION_REGIMENINDICATION Labels N
  NO 6
  YES 558
     
  Significant markers N = 0
Clinical variable #10: 'NUMBER_PACK_YEARS_SMOKED'

30 genes related to 'NUMBER_PACK_YEARS_SMOKED'.

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

NUMBER_PACK_YEARS_SMOKED Mean (SD) 35.15 (22)
  Significant markers N = 30
  pos. correlated 7
  neg. correlated 23
List of top 10 genes differentially expressed by 'NUMBER_PACK_YEARS_SMOKED'

Table S18.  Get Full Table List of top 10 genes significantly correlated to 'NUMBER_PACK_YEARS_SMOKED' by Spearman correlation test

SpearmanCorr corrP Q
TENC1 -0.4683 2.513e-06 0.0496
C15ORF57 -0.4242 2.79e-05 0.276
MAPK3 -0.4104 4.834e-05 0.299
TAOK2 -0.3953 9.607e-05 0.299
ACD__1 -0.3927 0.0001079 0.299
PARD6A__1 -0.3927 0.0001079 0.299
AXIN2 -0.3897 0.0001231 0.299
EAF2 0.3842 0.0001562 0.299
IQCB1 0.3842 0.0001562 0.299
SEPW1 -0.3802 0.0001849 0.299
Clinical variable #11: 'COMPLETENESS_OF_RESECTION'

30 genes related to 'COMPLETENESS_OF_RESECTION'.

Table S19.  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 S20.  Get Full Table List of top 10 genes differentially expressed by 'COMPLETENESS_OF_RESECTION'

kruskal_wallis_P Q
CCDC144A 8.15e-05 0.255
C17ORF70 8.171e-05 0.255
ALKBH6 9.699e-05 0.255
HIST1H1B 0.0001816 0.255
SCP2 0.0001922 0.255
CPNE4 0.000202 0.255
HRASLS 0.0002035 0.255
MGC2889 0.0002035 0.255
CCDC144NL 0.000227 0.255
LOC151658 0.0002666 0.255
Clinical variable #12: 'NUMBER_OF_LYMPH_NODES'

No gene related to 'NUMBER_OF_LYMPH_NODES'.

Table S21.  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 #13: 'RACE'

30 genes related to 'RACE'.

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

RACE Labels N
  ASIAN 130
  BLACK OR AFRICAN AMERICAN 14
  NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER 1
  WHITE 360
     
  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
MRPL36 1.418e-20 2.8e-16
SERHL2 1.094e-19 1.08e-15
GRAPL 1.607e-18 6.68e-15
RSPH10B 1.691e-18 6.68e-15
RSPH10B2 1.691e-18 6.68e-15
DCUN1D1 2.541e-16 8.37e-13
CRYZ 8.781e-16 2.17e-12
TYW3 8.781e-16 2.17e-12
PM20D1 7.582e-15 1.66e-11
CRYZ__1 1.394e-14 2.5e-11
Clinical variable #14: 'ETHNICITY'

No gene related to 'ETHNICITY'.

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

ETHNICITY Labels N
  HISPANIC OR LATINO 7
  NOT HISPANIC OR LATINO 371
     
  Significant markers N = 0
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 = 564

  • Number of genes = 19752

  • Number of clinical features = 14

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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