Correlation between gene methylation status and clinical features
Rectum Adenocarcinoma (Primary solid tumor)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
doi:10.7908/C1HQ3Z0P
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/C1HQ3Z0P
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 20074 genes and 12 clinical features across 98 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 3 clinical features related to at least one genes.

  • 30 genes correlated to 'YEARS_TO_BIRTH'.

    • CHGA ,  PCDHA1__10 ,  PCDHA10__7 ,  PCDHA11__7 ,  PCDHA12__4 ,  ...

  • 15 genes correlated to 'GENDER'.

    • ALG11__2 ,  UTP14C ,  DDX43 ,  KIF4B ,  MIR220B ,  ...

  • 30 genes correlated to 'HISTOLOGICAL_TYPE'.

    • WSCD1 ,  CDK8 ,  LOC100190939 ,  TPT1__1 ,  SLC5A6 ,  ...

  • No genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP', 'NEOPLASM_DISEASESTAGE', 'PATHOLOGY_T_STAGE', 'PATHOLOGY_N_STAGE', 'PATHOLOGY_M_STAGE', 'RADIATIONS_RADIATION_REGIMENINDICATION', 'COMPLETENESS_OF_RESECTION', 'NUMBER_OF_LYMPH_NODES', and 'RACE'.

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=22 younger N=8
NEOPLASM_DISEASESTAGE Kruskal-Wallis test   N=0        
PATHOLOGY_T_STAGE Spearman correlation test   N=0        
PATHOLOGY_N_STAGE Spearman correlation test   N=0        
PATHOLOGY_M_STAGE Wilcoxon test   N=0        
GENDER Wilcoxon test N=15 male N=15 female N=0
HISTOLOGICAL_TYPE Wilcoxon test N=30 rectal mucinous adenocarcinoma N=30 rectal adenocarcinoma N=0
RADIATIONS_RADIATION_REGIMENINDICATION Wilcoxon test   N=0        
COMPLETENESS_OF_RESECTION Kruskal-Wallis test   N=0        
NUMBER_OF_LYMPH_NODES Spearman correlation test   N=0        
RACE Kruskal-Wallis 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) 0.4-129.3 (median=14.2)
  censored N = 85
  death N = 12
     
  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) 62.94 (12)
  Significant markers N = 30
  pos. correlated 22
  neg. correlated 8
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
CHGA 0.3959 5.462e-05 0.072
PCDHA1__10 0.3949 5.735e-05 0.072
PCDHA10__7 0.3949 5.735e-05 0.072
PCDHA11__7 0.3949 5.735e-05 0.072
PCDHA12__4 0.3949 5.735e-05 0.072
PCDHA13__3 0.3949 5.735e-05 0.072
PCDHA2__10 0.3949 5.735e-05 0.072
PCDHA3__10 0.3949 5.735e-05 0.072
PCDHA4__9 0.3949 5.735e-05 0.072
PCDHA5__8 0.3949 5.735e-05 0.072
Clinical variable #3: 'NEOPLASM_DISEASESTAGE'

No gene related to 'NEOPLASM_DISEASESTAGE'.

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

NEOPLASM_DISEASESTAGE Labels N
  STAGE I 11
  STAGE II 6
  STAGE IIA 20
  STAGE IIB 2
  STAGE IIC 2
  STAGE III 4
  STAGE IIIA 9
  STAGE IIIB 13
  STAGE IIIC 11
  STAGE IV 6
  STAGE IVA 9
     
  Significant markers N = 0
Clinical variable #4: 'PATHOLOGY_T_STAGE'

No gene related to 'PATHOLOGY_T_STAGE'.

Table S5.  Basic characteristics of clinical feature: 'PATHOLOGY_T_STAGE'

PATHOLOGY_T_STAGE Mean (SD) 2.9 (0.64)
  N
  T1 4
  T2 13
  T3 69
  T4 11
     
  Significant markers N = 0
Clinical variable #5: 'PATHOLOGY_N_STAGE'

No gene related to 'PATHOLOGY_N_STAGE'.

Table S6.  Basic characteristics of clinical feature: 'PATHOLOGY_N_STAGE'

PATHOLOGY_N_STAGE Mean (SD) 0.78 (0.8)
  N
  N0 43
  N1 30
  N2 22
     
  Significant markers N = 0
Clinical variable #6: 'PATHOLOGY_M_STAGE'

No gene related to 'PATHOLOGY_M_STAGE'.

Table S7.  Basic characteristics of clinical feature: 'PATHOLOGY_M_STAGE'

PATHOLOGY_M_STAGE Labels N
  class0 70
  class1 12
     
  Significant markers N = 0
Clinical variable #7: 'GENDER'

15 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 44
  MALE 54
     
  Significant markers N = 15
  Higher in MALE 15
  Higher in FEMALE 0
List of top 10 genes differentially expressed by 'GENDER'

Table S9.  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 2249 3.602e-14 3.62e-10 0.9465
UTP14C 2249 3.602e-14 3.62e-10 0.9465
DDX43 450 1.382e-07 0.000925 0.8106
KIF4B 461 2.114e-07 0.00106 0.806
MIR220B 1846 2.651e-06 0.00887 0.7769
TUBB4 1846 2.651e-06 0.00887 0.7769
PXDNL 616 4.466e-05 0.128 0.7407
TSC2__1 1747 6.633e-05 0.166 0.7353
ANGPTL1 1733 0.0001006 0.202 0.7294
RALGPS2 1733 0.0001006 0.202 0.7294
Clinical variable #8: 'HISTOLOGICAL_TYPE'

30 genes related to 'HISTOLOGICAL_TYPE'.

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

HISTOLOGICAL_TYPE Labels N
  RECTAL ADENOCARCINOMA 90
  RECTAL MUCINOUS ADENOCARCINOMA 6
     
  Significant markers N = 30
  Higher in RECTAL MUCINOUS ADENOCARCINOMA 30
  Higher in RECTAL ADENOCARCINOMA 0
List of top 10 genes differentially expressed by 'HISTOLOGICAL_TYPE'

Table S11.  Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL_TYPE'

W(pos if higher in 'RECTAL MUCINOUS ADENOCARCINOMA') wilcoxontestP Q AUC
WSCD1 523 0.0001325 0.224 0.9685
CDK8 522 0.0001408 0.224 0.9667
LOC100190939 514 0.0002282 0.224 0.9519
TPT1__1 514 0.0002282 0.224 0.9519
SLC5A6 510 0.0002889 0.224 0.9444
UGT2B10 509 0.0003063 0.224 0.9426
TMEM150B 508 0.0003247 0.224 0.9407
KIAA0355 506 0.0003645 0.224 0.937
LRRC49 505 0.0003862 0.224 0.9352
POLG 35 0.0004089 0.224 0.9337
Clinical variable #9: 'RADIATIONS_RADIATION_REGIMENINDICATION'

No gene related to 'RADIATIONS_RADIATION_REGIMENINDICATION'.

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

RADIATIONS_RADIATION_REGIMENINDICATION Labels N
  NO 5
  YES 93
     
  Significant markers N = 0
Clinical variable #10: 'COMPLETENESS_OF_RESECTION'

No gene related to 'COMPLETENESS_OF_RESECTION'.

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

COMPLETENESS_OF_RESECTION Labels N
  R0 66
  R1 2
  R2 2
  RX 5
     
  Significant markers N = 0
Clinical variable #11: 'NUMBER_OF_LYMPH_NODES'

No gene related to 'NUMBER_OF_LYMPH_NODES'.

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

NUMBER_OF_LYMPH_NODES Mean (SD) 3.13 (5.7)
  Significant markers N = 0
Clinical variable #12: 'RACE'

No gene related to 'RACE'.

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

RACE Labels N
  ASIAN 1
  BLACK OR AFRICAN AMERICAN 5
  WHITE 77
     
  Significant markers N = 0
Methods & Data
Input

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

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

  • Number of patients = 98

  • Number of genes = 20074

  • Number of clinical features = 12

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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