Correlation between gene methylation status and clinical features
Breast Invasive Carcinoma (Primary solid tumor)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
doi:10.7908/C1GX49J4
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/C1GX49J4
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 19990 genes and 12 clinical features across 750 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'.

    • KIAA1143 ,  KIF15 ,  LGALS8 ,  CACNA2D1 ,  EGR2 ,  ...

  • 30 genes correlated to 'NEOPLASM_DISEASESTAGE'.

    • RFFL ,  FAM98C ,  C1QTNF4 ,  PSPN ,  C11ORF10 ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • MYOC ,  OR2L13 ,  OR2L8 ,  SOX2OT__1 ,  FOXI2 ,  ...

  • 30 genes correlated to 'PATHOLOGY_N_STAGE'.

    • TCP11L1 ,  ADA ,  KIAA0182 ,  LOC100286844 ,  ZNF521 ,  ...

  • 30 genes correlated to 'PATHOLOGY_M_STAGE'.

    • PRELID1 ,  RAB24 ,  RFX1 ,  KDM3B ,  FAM13B ,  ...

  • 30 genes correlated to 'GENDER'.

    • WNT7B ,  SLC16A12 ,  ARSG ,  LGALS1 ,  PRRT3 ,  ...

  • 30 genes correlated to 'HISTOLOGICAL_TYPE'.

    • SCD ,  MCAM ,  PRCD ,  GJA4 ,  FADS1 ,  ...

  • 30 genes correlated to 'RADIATIONS_RADIATION_REGIMENINDICATION'.

    • METAP2 ,  RAD50 ,  ZNF639 ,  UHRF1BP1L ,  DCLRE1C ,  ...

  • 30 genes correlated to 'NUMBER_OF_LYMPH_NODES'.

    • TCP11L1 ,  CCDC80 ,  ATP2A2 ,  ZNF521 ,  SEPT8 ,  ...

  • 30 genes correlated to 'RACE'.

    • DHRS7 ,  PPP1R15B ,  ISCA1 ,  ZNF639 ,  SCAMP5 ,  ...

  • 30 genes correlated to 'ETHNICITY'.

    • LRRC66 ,  ANAPC5 ,  WDFY3__1 ,  SCFD2 ,  C3ORF17 ,  ...

  • 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=28 younger N=2
NEOPLASM_DISEASESTAGE Kruskal-Wallis test N=30        
PATHOLOGY_T_STAGE Spearman correlation test N=30 higher stage N=23 lower stage N=7
PATHOLOGY_N_STAGE Spearman correlation test N=30 higher stage N=21 lower stage N=9
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
NUMBER_OF_LYMPH_NODES Spearman correlation test N=30 higher number_of_lymph_nodes N=17 lower number_of_lymph_nodes N=13
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) 0-234.3 (median=23.5)
  censored N = 662
  death N = 87
     
  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) 58.11 (13)
  Significant markers N = 30
  pos. correlated 28
  neg. correlated 2
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
KIAA1143 0.323 2.357e-19 2.36e-15
KIF15 0.323 2.357e-19 2.36e-15
LGALS8 -0.3067 1.602e-17 1.07e-13
CACNA2D1 0.288 1.528e-15 7.64e-12
EGR2 0.286 2.451e-15 9.8e-12
C1ORF103 0.2826 5.308e-15 1.77e-11
MEX3C 0.2773 1.764e-14 4.15e-11
C20ORF199 0.2771 1.87e-14 4.15e-11
SNORD12 0.2771 1.87e-14 4.15e-11
RPS2__1 0.2718 6.058e-14 9.42e-11
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 61
  STAGE IA 60
  STAGE IB 4
  STAGE II 2
  STAGE IIA 237
  STAGE IIB 176
  STAGE III 2
  STAGE IIIA 121
  STAGE IIIB 19
  STAGE IIIC 50
  STAGE IV 11
  STAGE X 5
     
  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
RFFL 5.346e-06 0.0555
FAM98C 5.555e-06 0.0555
C1QTNF4 1.906e-05 0.0802
PSPN 2.094e-05 0.0802
C11ORF10 4.312e-05 0.0802
FEN1 4.312e-05 0.0802
MIR611 4.312e-05 0.0802
CYFIP1 5.057e-05 0.0802
DLL4 5.21e-05 0.0802
CCNT2 5.438e-05 0.0802
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) 1.94 (0.72)
  N
  T1 195
  T2 427
  T3 101
  T4 24
     
  Significant markers N = 30
  pos. correlated 23
  neg. correlated 7
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
MYOC -0.1652 5.635e-06 0.0392
OR2L13 -0.1626 8.451e-06 0.0392
OR2L8 -0.1626 8.451e-06 0.0392
SOX2OT__1 0.1507 3.55e-05 0.0392
FOXI2 0.1492 4.217e-05 0.0392
SFRS14__1 -0.1485 4.593e-05 0.0392
PAPPA2 -0.1483 4.716e-05 0.0392
C3ORF20 -0.1472 5.398e-05 0.0392
PCDHGA1__12 0.1467 5.693e-05 0.0392
PCDHGA10__5 0.1467 5.693e-05 0.0392
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) 0.82 (0.92)
  N
  N0 334
  N1 258
  N2 92
  N3 54
     
  Significant markers N = 30
  pos. correlated 21
  neg. correlated 9
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
TCP11L1 0.1797 8.929e-07 0.00991
ADA 0.179 9.915e-07 0.00991
KIAA0182 -0.1758 1.55e-06 0.0103
LOC100286844 -0.1719 2.646e-06 0.0132
ZNF521 0.1657 6.063e-06 0.0242
PDE9A 0.161 1.114e-05 0.027
KIAA1462 -0.1608 1.13e-05 0.027
ATP2A2 -0.1609 1.306e-05 0.027
DLX5 0.1593 1.365e-05 0.027
BTG1 0.1589 1.45e-05 0.027
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 590
  class1 12
     
  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
PRELID1 965 1.587e-05 0.159 0.8637
RAB24 965 1.587e-05 0.159 0.8637
RFX1 1239 0.0001148 0.249 0.825
KDM3B 5780 0.0001626 0.249 0.8178
FAM13B 5785 0.0001679 0.249 0.8171
THAP4 1306 0.0001807 0.249 0.8155
C14ORF135 5768 0.0001881 0.249 0.8147
FER 5753 0.0002078 0.249 0.8126
COBLL1 5748 0.0002148 0.249 0.8119
EHMT1__1 1335 0.0002191 0.249 0.8114
Clinical variable #7: 'GENDER'

30 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 742
  MALE 8
     
  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
WNT7B 352 1.777e-05 0.279 0.9407
SLC16A12 608 0.0001089 0.279 0.8974
ARSG 643 0.0001369 0.279 0.8917
LGALS1 650 0.0001434 0.279 0.8905
PRRT3 675 0.0001691 0.279 0.8863
ALDOC 729 0.00024 0.279 0.8772
C15ORF62 5203 0.0002463 0.279 0.8765
DNAJC17 5203 0.0002463 0.279 0.8765
TANC2 739 0.0002559 0.279 0.8755
BCAS1 741 0.0002592 0.279 0.8752
Clinical variable #8: 'HISTOLOGICAL_TYPE'

30 genes related to 'HISTOLOGICAL_TYPE'.

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

HISTOLOGICAL_TYPE Labels N
  INFILTRATING CARCINOMA NOS 1
  INFILTRATING DUCTAL CARCINOMA 498
  INFILTRATING LOBULAR CARCINOMA 164
  MEDULLARY CARCINOMA 6
  METAPLASTIC CARCINOMA 3
  MIXED HISTOLOGY (PLEASE SPECIFY) 25
  MUCINOUS CARCINOMA 15
  OTHER SPECIFY 37
     
  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
SCD 5.087e-20 6.17e-16
MCAM 6.176e-20 6.17e-16
PRCD 1.348e-19 8.98e-16
GJA4 1.987e-19 9.93e-16
FADS1 3.986e-19 1.59e-15
SOD1 2.052e-18 6.84e-15
ITGA1__1 3.898e-18 9.74e-15
PELO__1 3.898e-18 9.74e-15
LCAT 8.11e-18 1.62e-14
SLC12A4 8.11e-18 1.62e-14
Clinical variable #9: 'RADIATIONS_RADIATION_REGIMENINDICATION'

30 genes related to 'RADIATIONS_RADIATION_REGIMENINDICATION'.

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

RADIATIONS_RADIATION_REGIMENINDICATION Labels N
  NO 220
  YES 530
     
  Significant markers N = 30
  Higher in YES 30
  Higher in NO 0
List of top 10 genes differentially expressed by 'RADIATIONS_RADIATION_REGIMENINDICATION'

Table S17.  Get Full Table List of top 10 genes differentially expressed by 'RADIATIONS_RADIATION_REGIMENINDICATION'

W(pos if higher in 'YES') wilcoxontestP Q AUC
METAP2 82280 6.875e-19 8.4e-15 0.7057
RAD50 82157 1.034e-18 8.4e-15 0.7046
ZNF639 82097 1.261e-18 8.4e-15 0.7041
UHRF1BP1L 81509 8.585e-18 4.29e-14 0.699
DCLRE1C 81165 2.58e-17 1.03e-13 0.6961
USP34 80925 5.508e-17 1.84e-13 0.694
NECAP1 80867 6.608e-17 1.89e-13 0.6935
HMG20B 36030 1.667e-16 4.17e-13 0.691
KLHL9 79934 1.162e-15 2.58e-12 0.6855
FYTTD1 79790 1.789e-15 3.25e-12 0.6843
Clinical variable #10: 'NUMBER_OF_LYMPH_NODES'

30 genes related to 'NUMBER_OF_LYMPH_NODES'.

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

NUMBER_OF_LYMPH_NODES Mean (SD) 2.61 (4.9)
  Significant markers N = 30
  pos. correlated 17
  neg. correlated 13
List of top 10 genes differentially expressed by 'NUMBER_OF_LYMPH_NODES'

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

SpearmanCorr corrP Q
TCP11L1 0.2063 4.563e-08 0.000912
CCDC80 -0.181 1.707e-06 0.0141
ATP2A2 -0.1808 2.119e-06 0.0141
ZNF521 0.1737 4.467e-06 0.0197
SEPT8 -0.1726 5.135e-06 0.0197
ADA 0.1706 6.601e-06 0.0197
KIAA0182 -0.1703 6.894e-06 0.0197
BTG1 0.1672 1.006e-05 0.0226
ABCC8 0.1665 1.102e-05 0.0226
ARAP2 0.1667 1.133e-05 0.0226
Clinical variable #11: 'RACE'

30 genes related to 'RACE'.

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

RACE Labels N
  AMERICAN INDIAN OR ALASKA NATIVE 1
  ASIAN 37
  BLACK OR AFRICAN AMERICAN 143
  WHITE 554
     
  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
DHRS7 5.345e-33 1.07e-28
PPP1R15B 4.39e-32 4.39e-28
ISCA1 3.663e-30 2.44e-26
ZNF639 3.554e-28 1.78e-24
SCAMP5 5.591e-26 2.24e-22
RHD 2.169e-25 7.23e-22
TOMM34 4.46e-25 1.27e-21
DZIP3 2.447e-24 5.44e-21
KIAA1524 2.447e-24 5.44e-21
FYTTD1 6.8e-24 1.24e-20
Clinical variable #12: 'ETHNICITY'

30 genes related to 'ETHNICITY'.

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

ETHNICITY Labels N
  HISPANIC OR LATINO 37
  NOT HISPANIC OR LATINO 647
     
  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 = BRCA-TP.meth.by_min_clin_corr.data.txt

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

  • Number of patients = 750

  • Number of genes = 19990

  • 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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