Correlation between gene methylation status and clinical features
Breast Invasive Carcinoma (Primary solid tumor)
15 July 2014  |  analyses__2014_07_15
Maintainer Information
Citation Information
doi:10.7908/C1BR8QW4
Maintained by Juok Cho (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2014): Correlation between gene methylation status and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C1BR8QW4
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 19971 genes and 12 clinical features across 690 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 10 clinical features related to at least one genes.

  • 803 genes correlated to 'AGE'.

    • KIAA1143 ,  KIF15 ,  LGALS8 ,  C1ORF103 ,  C20ORF199 ,  ...

  • 29 genes correlated to 'NEOPLASM.DISEASESTAGE'.

    • C1QTNF4 ,  TXN ,  PSPN ,  RFFL ,  PLVAP ,  ...

  • 24 genes correlated to 'PATHOLOGY.T.STAGE'.

    • PCDHGA1__8 ,  PCDHGA10__2 ,  PCDHGA11__2 ,  PCDHGA12__2 ,  PCDHGA2__8 ,  ...

  • 13 genes correlated to 'PATHOLOGY.N.STAGE'.

    • TCP11L1 ,  ADA ,  CEBPG ,  KIAA0182 ,  ATP2A2 ,  ...

  • 541 genes correlated to 'PATHOLOGY.M.STAGE'.

    • DNAH1 ,  TSTD1 ,  USF1 ,  C1ORF212 ,  XAB2 ,  ...

  • 1910 genes correlated to 'HISTOLOGICAL.TYPE'.

    • FADS1 ,  MCAM ,  SCD ,  GJA4 ,  SOD1 ,  ...

  • 378 genes correlated to 'RADIATIONS.RADIATION.REGIMENINDICATION'.

    • METAP2 ,  C16ORF58 ,  ZNF639 ,  UHRF1BP1L ,  HMG20B ,  ...

  • 7 genes correlated to 'NUMBER.OF.LYMPH.NODES'.

    • TCP11L1 ,  ATP2A2 ,  LYSMD2__1 ,  SEPT8 ,  ADA ,  ...

  • 1574 genes correlated to 'RACE'.

    • SCAMP5 ,  DHRS7 ,  ISCA1 ,  RHD ,  EIF2AK4 ,  ...

  • 191 genes correlated to 'ETHNICITY'.

    • LRRC66 ,  WDFY3__1 ,  ANAPC5 ,  C3ORF17 ,  NUP98 ,  ...

  • No genes correlated to 'Time to Death', and 'GENDER'.

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
Time to Death Cox regression test   N=0        
AGE Spearman correlation test N=803 older N=627 younger N=176
NEOPLASM DISEASESTAGE Kruskal-Wallis test N=29        
PATHOLOGY T STAGE Spearman correlation test N=24 higher stage N=22 lower stage N=2
PATHOLOGY N STAGE Spearman correlation test N=13 higher stage N=8 lower stage N=5
PATHOLOGY M STAGE Kruskal-Wallis test N=541        
GENDER Wilcoxon test   N=0        
HISTOLOGICAL TYPE Kruskal-Wallis test N=1910        
RADIATIONS RADIATION REGIMENINDICATION Wilcoxon test N=378 yes N=378 no N=0
NUMBER OF LYMPH NODES Spearman correlation test N=7 higher number.of.lymph.nodes N=3 lower number.of.lymph.nodes N=4
RACE Kruskal-Wallis test N=1574        
ETHNICITY Wilcoxon test N=191 not hispanic or latino N=191 hispanic or latino N=0
Clinical variable #1: 'Time to Death'

No gene related to 'Time to Death'.

Table S1.  Basic characteristics of clinical feature: 'Time to Death'

Time to Death Duration (Months) 0-234.3 (median=21.3)
  censored N = 608
  death N = 76
     
  Significant markers N = 0
Clinical variable #2: 'AGE'

803 genes related to 'AGE'.

Table S2.  Basic characteristics of clinical feature: 'AGE'

AGE Mean (SD) 58.11 (13)
  Significant markers N = 803
  pos. correlated 627
  neg. correlated 176
List of top 10 genes differentially expressed by 'AGE'

Table S3.  Get Full Table List of top 10 genes significantly correlated to 'AGE' by Spearman correlation test

SpearmanCorr corrP Q
KIAA1143 0.3234 5.418e-18 1.08e-13
KIF15 0.3234 5.418e-18 1.08e-13
LGALS8 -0.3059 3.56e-16 7.11e-12
C1ORF103 0.3037 5.933e-16 1.18e-11
C20ORF199 0.2902 1.218e-14 2.43e-10
SNORD12 0.2902 1.218e-14 2.43e-10
RPS2__1 0.2887 1.663e-14 3.32e-10
SNORA10 0.2887 1.663e-14 3.32e-10
SNORA64 0.2887 1.663e-14 3.32e-10
MEX3C 0.2867 2.612e-14 5.21e-10
Clinical variable #3: 'NEOPLASM.DISEASESTAGE'

29 genes related to 'NEOPLASM.DISEASESTAGE'.

Table S4.  Basic characteristics of clinical feature: 'NEOPLASM.DISEASESTAGE'

NEOPLASM.DISEASESTAGE Labels N
  STAGE I 52
  STAGE IA 58
  STAGE IB 5
  STAGE II 8
  STAGE IIA 220
  STAGE IIB 158
  STAGE III 2
  STAGE IIIA 110
  STAGE IIIB 17
  STAGE IIIC 46
  STAGE IV 8
  STAGE X 5
     
  Significant markers N = 29
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'

ANOVA_P Q
C1QTNF4 4.289e-07 0.00857
TXN 5.284e-07 0.0106
PSPN 7.176e-07 0.0143
RFFL 8.148e-07 0.0163
PLVAP 2.581e-06 0.0515
ZFP36 3.743e-06 0.0747
ZFP91__1 3.754e-06 0.0749
ZFP91-CNTF__1 3.754e-06 0.0749
AP1S3 4.51e-06 0.09
MOSPD3 4.667e-06 0.0932
Clinical variable #4: 'PATHOLOGY.T.STAGE'

24 genes related to 'PATHOLOGY.T.STAGE'.

Table S6.  Basic characteristics of clinical feature: 'PATHOLOGY.T.STAGE'

PATHOLOGY.T.STAGE Mean (SD) 1.92 (0.71)
  N
  1 183
  2 397
  3 88
  4 20
     
  Significant markers N = 24
  pos. correlated 22
  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
PCDHGA1__8 0.1711 6.378e-06 0.127
PCDHGA10__2 0.1711 6.378e-06 0.127
PCDHGA11__2 0.1711 6.378e-06 0.127
PCDHGA12__2 0.1711 6.378e-06 0.127
PCDHGA2__8 0.1711 6.378e-06 0.127
PCDHGA3__7 0.1711 6.378e-06 0.127
PCDHGA4__6 0.1711 6.378e-06 0.127
PCDHGA5__6 0.1711 6.378e-06 0.127
PCDHGA6__6 0.1711 6.378e-06 0.127
PCDHGA7__6 0.1711 6.378e-06 0.127
Clinical variable #5: 'PATHOLOGY.N.STAGE'

13 genes related to 'PATHOLOGY.N.STAGE'.

Table S8.  Basic characteristics of clinical feature: 'PATHOLOGY.N.STAGE'

PATHOLOGY.N.STAGE Mean (SD) 0.82 (0.91)
  N
  0 305
  1 240
  2 87
  3 49
     
  Significant markers N = 13
  pos. correlated 8
  neg. correlated 5
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 0.1974 2.073e-07 0.00414
ADA 0.1965 2.357e-07 0.00471
CEBPG 0.1816 1.845e-06 0.0368
KIAA0182 -0.1759 3.901e-06 0.0779
ATP2A2 -0.1725 6.084e-06 0.121
ARHGEF3__1 0.1709 7.567e-06 0.151
SPATA12 0.1709 7.567e-06 0.151
SEPT8 -0.1698 8.351e-06 0.167
LOC100286844 -0.169 9.206e-06 0.184
TRIM31 0.1688 9.44e-06 0.188
Clinical variable #6: 'PATHOLOGY.M.STAGE'

541 genes related to 'PATHOLOGY.M.STAGE'.

Table S10.  Basic characteristics of clinical feature: 'PATHOLOGY.M.STAGE'

PATHOLOGY.M.STAGE Labels N
  CM0 (I+) 1
  M0 562
  M1 8
  MX 119
     
  Significant markers N = 541
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'

ANOVA_P Q
DNAH1 7.181e-12 1.43e-07
TSTD1 7.207e-12 1.44e-07
USF1 7.207e-12 1.44e-07
C1ORF212 2.998e-11 5.99e-07
XAB2 6.529e-11 1.3e-06
ARHGAP1__1 7.695e-11 1.54e-06
ZNF408__1 7.695e-11 1.54e-06
KIAA0467 8.083e-11 1.61e-06
ZNF862 8.23e-11 1.64e-06
FDX1L__1 1.397e-10 2.79e-06
Clinical variable #7: 'GENDER'

No gene related to 'GENDER'.

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

GENDER Labels N
  FEMALE 682
  MALE 8
     
  Significant markers N = 0
Clinical variable #8: 'HISTOLOGICAL.TYPE'

1910 genes related to 'HISTOLOGICAL.TYPE'.

Table S13.  Basic characteristics of clinical feature: 'HISTOLOGICAL.TYPE'

HISTOLOGICAL.TYPE Labels N
  INFILTRATING CARCINOMA NOS 1
  INFILTRATING DUCTAL CARCINOMA 473
  INFILTRATING LOBULAR CARCINOMA 142
  MEDULLARY CARCINOMA 5
  MIXED HISTOLOGY (PLEASE SPECIFY) 24
  MUCINOUS CARCINOMA 12
  OTHER SPECIFY 32
     
  Significant markers N = 1910
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'

ANOVA_P Q
FADS1 8.204e-19 1.64e-14
MCAM 1.065e-18 2.13e-14
SCD 1.893e-18 3.78e-14
GJA4 3.722e-18 7.43e-14
SOD1 6.914e-18 1.38e-13
PRCD 8.113e-18 1.62e-13
ITGA1__1 6.383e-17 1.27e-12
PELO__1 6.383e-17 1.27e-12
FIS1 1.512e-16 3.02e-12
ACOT7 2.473e-16 4.94e-12
Clinical variable #9: 'RADIATIONS.RADIATION.REGIMENINDICATION'

378 genes related to 'RADIATIONS.RADIATION.REGIMENINDICATION'.

Table S15.  Basic characteristics of clinical feature: 'RADIATIONS.RADIATION.REGIMENINDICATION'

RADIATIONS.RADIATION.REGIMENINDICATION Labels N
  NO 215
  YES 475
     
  Significant markers N = 378
  Higher in YES 378
  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
METAP2 68440 7.737e-13 1.55e-08 0.6702
C16ORF58 34127 2.88e-12 5.75e-08 0.6658
ZNF639 67831 4.692e-12 9.37e-08 0.6642
UHRF1BP1L 67671 7.457e-12 1.49e-07 0.6626
HMG20B 34484 8.13e-12 1.62e-07 0.6623
RAD50 67367 1.777e-11 3.55e-07 0.6597
NECAP1 67342 1.907e-11 3.81e-07 0.6594
USP34 67328 1.984e-11 3.96e-07 0.6593
MAEA 35204 6.179e-11 1.23e-06 0.6553
ATG4B 35264 7.288e-11 1.45e-06 0.6547
Clinical variable #10: 'NUMBER.OF.LYMPH.NODES'

7 genes related to 'NUMBER.OF.LYMPH.NODES'.

Table S17.  Basic characteristics of clinical feature: 'NUMBER.OF.LYMPH.NODES'

NUMBER.OF.LYMPH.NODES Mean (SD) 2.59 (4.8)
  Significant markers N = 7
  pos. correlated 3
  neg. correlated 4
List of 7 genes differentially expressed by 'NUMBER.OF.LYMPH.NODES'

Table S18.  Get Full Table List of 7 genes significantly correlated to 'NUMBER.OF.LYMPH.NODES' by Spearman correlation test

SpearmanCorr corrP Q
TCP11L1 0.2223 1.421e-08 0.000284
ATP2A2 -0.1857 2.416e-06 0.0483
LYSMD2__1 0.1833 3.22e-06 0.0643
SEPT8 -0.1772 6.827e-06 0.136
ADA 0.1769 7.067e-06 0.141
CEP170L -0.1729 1.138e-05 0.227
FOXP1 -0.1716 1.331e-05 0.266
Clinical variable #11: 'RACE'

1574 genes related to 'RACE'.

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

RACE Labels N
  AMERICAN INDIAN OR ALASKA NATIVE 1
  ASIAN 34
  BLACK OR AFRICAN AMERICAN 112
  WHITE 529
     
  Significant markers N = 1574
List of top 10 genes differentially expressed by 'RACE'

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

ANOVA_P Q
SCAMP5 1.097e-26 2.19e-22
DHRS7 1.355e-25 2.71e-21
ISCA1 2.916e-24 5.82e-20
RHD 3.335e-22 6.66e-18
EIF2AK4 2.171e-21 4.34e-17
ZNF639 6.333e-21 1.26e-16
C14ORF167 2.841e-19 5.67e-15
DHRS4 2.841e-19 5.67e-15
TOMM34 7.398e-19 1.48e-14
TRIM73 1.442e-17 2.88e-13
Clinical variable #12: 'ETHNICITY'

191 genes related to 'ETHNICITY'.

Table S21.  Basic characteristics of clinical feature: 'ETHNICITY'

ETHNICITY Labels N
  HISPANIC OR LATINO 35
  NOT HISPANIC OR LATINO 590
     
  Significant markers N = 191
  Higher in NOT HISPANIC OR LATINO 191
  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 = 690

  • Number of genes = 19971

  • Number of clinical features = 12

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

ANOVA analysis

For multi-class clinical features (ordinal or nominal), one-way analysis of variance (Howell 2002) was applied to compare the log2-expression levels between different clinical classes using 'anova' function in R

Student's t-test analysis

For two-class clinical features, two-tailed Student's t test with unequal variance (Lehmann and Romano 2005) was applied to compare the log2-expression levels between the two clinical classes using 't.test' function in R

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] Howell, D, Statistical Methods for Psychology. (5th ed.), Duxbury Press:324-5 (2002)
[4] Lehmann and Romano, Testing Statistical Hypotheses (3E ed.), New York: Springer. ISBN 0387988645 (2005)
[5] 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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