Correlation between gene methylation status and clinical features
Esophageal Carcinoma (Primary solid tumor)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
doi:10.7908/C1JH3K5M
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/C1JH3K5M
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 19730 genes and 10 clinical features across 174 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 7 clinical features related to at least one genes.

  • 30 genes correlated to 'YEARS_TO_BIRTH'.

    • KRBA2 ,  GPRC5A ,  MAP3K14 ,  SLC46A1 ,  FRMD6 ,  ...

  • 30 genes correlated to 'NEOPLASM_DISEASESTAGE'.

    • TIAM1 ,  ELOVL5 ,  FAM135A ,  METTL7B ,  MYH9 ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • CLDN15 ,  SSH1 ,  FAM135A ,  ZZEF1__1 ,  NEU4 ,  ...

  • 30 genes correlated to 'PATHOLOGY_N_STAGE'.

    • ASAP1 ,  ZNF611 ,  HMCN1 ,  GBP1 ,  GPR124 ,  ...

  • 1 gene correlated to 'GENDER'.

    • KIF4B

  • 4 genes correlated to 'NUMBER_PACK_YEARS_SMOKED'.

    • TENC1 ,  MLLT6 ,  NDUFA12 ,  MAPK3

  • 30 genes correlated to 'RACE'.

    • YEATS2 ,  HABP4 ,  RIMS2 ,  GATM ,  DCUN1D1 ,  ...

  • No genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP', 'PATHOLOGY_M_STAGE', 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=28 lower stage N=2
PATHOLOGY_N_STAGE Spearman correlation test N=30 higher stage N=29 lower stage N=1
PATHOLOGY_M_STAGE Wilcoxon test   N=0        
GENDER Wilcoxon test N=1 male N=1 female N=0
NUMBER_PACK_YEARS_SMOKED Spearman correlation test N=4 higher number_pack_years_smoked N=1 lower number_pack_years_smoked N=3
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) 0.1-122.1 (median=12.6)
  censored N = 102
  death N = 71
     
  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) 62.62 (12)
  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
KRBA2 0.4073 2.428e-08 0.000288
GPRC5A -0.3985 5.172e-08 0.000288
MAP3K14 -0.3971 5.797e-08 0.000288
SLC46A1 -0.3903 1.013e-07 0.000288
FRMD6 0.3884 1.188e-07 0.000288
ANKRD34C 0.3882 1.205e-07 0.000288
KCNJ15 0.3882 1.209e-07 0.000288
LGALS9 -0.3878 1.246e-07 0.000288
ARL4C 0.387 1.33e-07 0.000288
C12ORF56 0.3858 1.461e-07 0.000288
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 8
  STAGE IA 5
  STAGE IB 7
  STAGE II 1
  STAGE IIA 39
  STAGE IIB 29
  STAGE III 26
  STAGE IIIA 12
  STAGE IIIB 10
  STAGE IIIC 7
  STAGE IV 5
  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
TIAM1 4.197e-06 0.0408
ELOVL5 9.239e-06 0.0408
FAM135A 1.475e-05 0.0408
METTL7B 1.791e-05 0.0408
MYH9 1.854e-05 0.0408
CLDN18 2.642e-05 0.0408
C3ORF43 2.701e-05 0.0408
SNORA1 3.009e-05 0.0408
SNORA32 3.009e-05 0.0408
SNORA8__1 3.009e-05 0.0408
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) 2.41 (0.85)
  N
  T0 1
  T1 30
  T2 36
  T3 86
  T4 5
     
  Significant markers N = 30
  pos. correlated 28
  neg. correlated 2
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
CLDN15 0.3483 7.292e-06 0.0638
SSH1 -0.3382 1.387e-05 0.0638
FAM135A 0.332 2.032e-05 0.0638
ZZEF1__1 0.3296 2.355e-05 0.0638
NEU4 0.3287 2.477e-05 0.0638
SELV 0.3286 2.493e-05 0.0638
MGST1 0.3275 2.662e-05 0.0638
CES2__1 0.3272 2.721e-05 0.0638
CST4 0.3246 3.167e-05 0.0638
ITGA6 0.3253 3.233e-05 0.0638
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) 0.72 (0.82)
  N
  N0 71
  N1 65
  N2 12
  N3 8
     
  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
ASAP1 0.3322 2.267e-05 0.0575
ZNF611 -0.3242 3.644e-05 0.0575
HMCN1 0.321 4.39e-05 0.0575
GBP1 0.3165 5.678e-05 0.0575
GPR124 0.3117 7.473e-05 0.0575
PCDHGA1 0.3107 7.874e-05 0.0575
PCDHGA10 0.3107 7.874e-05 0.0575
PCDHGA11 0.3107 7.874e-05 0.0575
PCDHGA12 0.3107 7.874e-05 0.0575
PCDHGA2 0.3107 7.874e-05 0.0575
Clinical variable #6: 'PATHOLOGY_M_STAGE'

No gene related to 'PATHOLOGY_M_STAGE'.

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

PATHOLOGY_M_STAGE Labels N
  class0 127
  class1 9
     
  Significant markers N = 0
Clinical variable #7: 'GENDER'

One gene related to 'GENDER'.

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

GENDER Labels N
  FEMALE 24
  MALE 150
     
  Significant markers N = 1
  Higher in MALE 1
  Higher in FEMALE 0
List of one gene differentially expressed by 'GENDER'

Table S12.  Get Full Table List of one gene 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 486 9.891e-09 0.000195 0.865
Clinical variable #8: 'NUMBER_PACK_YEARS_SMOKED'

4 genes related to 'NUMBER_PACK_YEARS_SMOKED'.

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

NUMBER_PACK_YEARS_SMOKED Mean (SD) 35.15 (22)
  Significant markers N = 4
  pos. correlated 1
  neg. correlated 3
List of 4 genes differentially expressed by 'NUMBER_PACK_YEARS_SMOKED'

Table S14.  Get Full Table List of 4 genes significantly correlated to 'NUMBER_PACK_YEARS_SMOKED' by Spearman correlation test

SpearmanCorr corrP Q
TENC1 -0.4683 2.513e-06 0.0496
MLLT6 -0.42 3.08e-05 0.238
NDUFA12 0.4117 4.568e-05 0.238
MAPK3 -0.4104 4.834e-05 0.238
Clinical variable #9: 'RACE'

30 genes related to 'RACE'.

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

RACE Labels N
  ASIAN 41
  BLACK OR AFRICAN AMERICAN 2
  WHITE 111
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'RACE'

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

kruskal_wallis_P Q
YEATS2 4.149e-12 3.62e-08
HABP4 5.005e-12 3.62e-08
RIMS2 6.487e-12 3.62e-08
GATM 7.341e-12 3.62e-08
DCUN1D1 1.521e-11 6e-08
AP2A2 2.074e-11 6.82e-08
LASP1 3.135e-11 8.84e-08
TMEM108 4.092e-11 9.15e-08
CTBP2 4.665e-11 9.15e-08
PRKCD 5.501e-11 9.15e-08
Clinical variable #10: 'ETHNICITY'

No gene related to 'ETHNICITY'.

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

ETHNICITY Labels N
  HISPANIC OR LATINO 3
  NOT HISPANIC OR LATINO 81
     
  Significant markers N = 0
Methods & Data
Input

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

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

  • Number of patients = 174

  • Number of genes = 19730

  • Number of clinical features = 10

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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