Correlation between gene methylation status and clinical features
Breast Invasive Carcinoma (Primary solid tumor)
17 October 2014  |  analyses__2014_10_17
Maintainer Information
Citation Information
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/C1PN94FQ
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 19976 genes and 12 clinical features across 701 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 10 clinical features related to at least one genes.

  • 941 genes correlated to 'AGE'.

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

  • 5 genes correlated to 'NEOPLASM.DISEASESTAGE'.

    • PSPN ,  FAM98C ,  CLP1 ,  RFFL ,  C1QTNF4

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

    • OR2L13 ,  OR2L8 ,  MYOC ,  PCDHGA1__8 ,  PCDHGA10__2 ,  ...

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

    • TCP11L1 ,  ADA ,  CEBPG ,  RFFL ,  KIAA0182 ,  ...

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

    • TSTD1 ,  USF1 ,  KIAA0467 ,  DNAH1 ,  NCRNA00219 ,  ...

  • 1891 genes correlated to 'HISTOLOGICAL.TYPE'.

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

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

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

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

    • TCP11L1 ,  LYSMD2__1 ,  ATP2A2 ,  SEPT8 ,  CCDC80 ,  ...

  • 1956 genes correlated to 'RACE'.

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

  • 202 genes correlated to 'ETHNICITY'.

    • LRRC66 ,  WDFY3__1 ,  ANAPC5 ,  C3ORF17 ,  DPY19L1 ,  ...

  • 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=941 older N=721 younger N=220
NEOPLASM DISEASESTAGE Kruskal-Wallis test N=5        
PATHOLOGY T STAGE Spearman correlation test N=22 higher stage N=19 lower stage N=3
PATHOLOGY N STAGE Spearman correlation test N=11 higher stage N=7 lower stage N=4
PATHOLOGY M STAGE Kruskal-Wallis test N=668        
GENDER Wilcoxon test   N=0        
HISTOLOGICAL TYPE Kruskal-Wallis test N=1891        
RADIATIONS RADIATION REGIMENINDICATION Wilcoxon test N=467 yes N=467 no N=0
NUMBER OF LYMPH NODES Spearman correlation test N=6 higher number.of.lymph.nodes N=3 lower number.of.lymph.nodes N=3
RACE Kruskal-Wallis test N=1956        
ETHNICITY Wilcoxon test N=202 not hispanic or latino N=202 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=22.3)
  censored N = 616
  death N = 80
     
  Significant markers N = 0
Clinical variable #2: 'AGE'

941 genes related to 'AGE'.

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

AGE Mean (SD) 58.02 (13)
  Significant markers N = 941
  pos. correlated 721
  neg. correlated 220
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 0.3203 6.391e-18 1.28e-13
KIF15 0.3203 6.391e-18 1.28e-13
LGALS8 -0.3066 1.738e-16 3.47e-12
C1ORF103 0.2928 4.16e-15 8.31e-11
C20ORF199 0.2925 4.439e-15 8.86e-11
SNORD12 0.2925 4.439e-15 8.86e-11
C9ORF69 0.2888 1.012e-14 2.02e-10
CACNA2D1 0.2884 1.103e-14 2.2e-10
EGR2 0.288 1.199e-14 2.39e-10
DNMT3A 0.2855 2.092e-14 4.18e-10
Clinical variable #3: 'NEOPLASM.DISEASESTAGE'

5 genes related to 'NEOPLASM.DISEASESTAGE'.

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

NEOPLASM.DISEASESTAGE Labels N
  STAGE I 53
  STAGE IA 59
  STAGE IB 4
  STAGE II 4
  STAGE IIA 224
  STAGE IIB 163
  STAGE III 2
  STAGE IIIA 112
  STAGE IIIB 18
  STAGE IIIC 48
  STAGE IV 8
  STAGE X 5
     
  Significant markers N = 5
List of 5 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

Table S5.  Get Full Table List of 5 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

ANOVA_P Q
PSPN 4.095e-06 0.0818
FAM98C 5.567e-06 0.111
CLP1 6.427e-06 0.128
RFFL 7.692e-06 0.154
C1QTNF4 1.053e-05 0.21
Clinical variable #4: 'PATHOLOGY.T.STAGE'

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

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

PATHOLOGY.T.STAGE Mean (SD) 1.92 (0.72)
  N
  1 186
  2 401
  3 91
  4 21
     
  Significant markers N = 22
  pos. correlated 19
  neg. correlated 3
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
OR2L13 -0.1698 6.35e-06 0.127
OR2L8 -0.1698 6.35e-06 0.127
MYOC -0.1653 1.124e-05 0.225
PCDHGA1__8 0.1652 1.13e-05 0.226
PCDHGA10__2 0.1652 1.13e-05 0.226
PCDHGA11__2 0.1652 1.13e-05 0.226
PCDHGA12__2 0.1652 1.13e-05 0.226
PCDHGA2__8 0.1652 1.13e-05 0.226
PCDHGA3__7 0.1652 1.13e-05 0.226
PCDHGA4__6 0.1652 1.13e-05 0.226
Clinical variable #5: 'PATHOLOGY.N.STAGE'

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

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

PATHOLOGY.N.STAGE Mean (SD) 0.83 (0.92)
  N
  0 309
  1 242
  2 89
  3 51
     
  Significant markers N = 11
  pos. correlated 7
  neg. correlated 4
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 0.1948 2.473e-07 0.00494
ADA 0.1889 5.671e-07 0.0113
CEBPG 0.1771 2.813e-06 0.0562
RFFL 0.1712 6.049e-06 0.121
KIAA0182 -0.1696 7.326e-06 0.146
ABCD2 0.1695 7.49e-06 0.15
ARHGEF3__1 0.1673 1.013e-05 0.202
SPATA12 0.1673 1.013e-05 0.202
SEPT8 -0.165 1.3e-05 0.26
ATP2A2 -0.1646 1.385e-05 0.277
Clinical variable #6: 'PATHOLOGY.M.STAGE'

668 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 564
  M1 9
  MX 127
     
  Significant markers N = 668
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
TSTD1 2.639e-13 5.27e-09
USF1 2.639e-13 5.27e-09
KIAA0467 6.009e-12 1.2e-07
DNAH1 8.474e-12 1.69e-07
NCRNA00219 8.642e-12 1.73e-07
SNORA13 8.642e-12 1.73e-07
ZNF862 1.154e-11 2.31e-07
ARHGAP1__1 1.185e-11 2.37e-07
ZNF408__1 1.185e-11 2.37e-07
FDX1L__1 1.322e-11 2.64e-07
Clinical variable #7: 'GENDER'

No gene related to 'GENDER'.

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

GENDER Labels N
  FEMALE 693
  MALE 8
     
  Significant markers N = 0
Clinical variable #8: 'HISTOLOGICAL.TYPE'

1891 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 479
  INFILTRATING LOBULAR CARCINOMA 147
  MEDULLARY CARCINOMA 5
  MIXED HISTOLOGY (PLEASE SPECIFY) 24
  MUCINOUS CARCINOMA 12
  OTHER SPECIFY 32
     
  Significant markers N = 1891
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 3.956e-19 7.9e-15
SCD 4.17e-19 8.33e-15
MCAM 3.17e-18 6.33e-14
PRCD 3.831e-18 7.65e-14
GJA4 5.097e-18 1.02e-13
SOD1 1.2e-17 2.4e-13
ITGA1__1 3.009e-17 6.01e-13
PELO__1 3.009e-17 6.01e-13
FIS1 5.478e-17 1.09e-12
PRPF40A 1.022e-16 2.04e-12
Clinical variable #9: 'RADIATIONS.RADIATION.REGIMENINDICATION'

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

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

RADIATIONS.RADIATION.REGIMENINDICATION Labels N
  NO 215
  YES 486
     
  Significant markers N = 467
  Higher in YES 467
  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 70489 1.596e-13 3.19e-09 0.6746
ZNF639 70088 5.325e-13 1.06e-08 0.6708
HMG20B 34634 1.057e-12 2.11e-08 0.6685
C16ORF58 34686 1.231e-12 2.46e-08 0.668
UHRF1BP1L 69758 1.408e-12 2.81e-08 0.6676
RAD50 69614 2.14e-12 4.27e-08 0.6662
USP34 69477 3.178e-12 6.35e-08 0.6649
NECAP1 69292 5.395e-12 1.08e-07 0.6631
MAEA 35540 1.414e-11 2.82e-07 0.6599
ATG4B 35552 1.462e-11 2.92e-07 0.6598
Clinical variable #10: 'NUMBER.OF.LYMPH.NODES'

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

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

NUMBER.OF.LYMPH.NODES Mean (SD) 2.63 (4.9)
  Significant markers N = 6
  pos. correlated 3
  neg. correlated 3
List of 6 genes differentially expressed by 'NUMBER.OF.LYMPH.NODES'

Table S18.  Get Full Table List of 6 genes significantly correlated to 'NUMBER.OF.LYMPH.NODES' by Spearman correlation test

SpearmanCorr corrP Q
TCP11L1 0.2215 1.169e-08 0.000234
LYSMD2__1 0.1798 4.047e-06 0.0808
ATP2A2 -0.179 4.518e-06 0.0902
SEPT8 -0.1764 6.177e-06 0.123
CCDC80 -0.1748 7.475e-06 0.149
ADA 0.1734 8.874e-06 0.177
Clinical variable #11: 'RACE'

1956 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 119
  WHITE 533
     
  Significant markers N = 1956
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
DHRS7 3.133e-28 6.26e-24
SCAMP5 5.788e-28 1.16e-23
ISCA1 1.936e-25 3.87e-21
EIF2AK4 2.819e-23 5.63e-19
RHD 4.744e-23 9.47e-19
ZNF639 1.035e-22 2.07e-18
TOMM34 8.331e-21 1.66e-16
C14ORF167 2.116e-20 4.23e-16
DHRS4 2.116e-20 4.23e-16
TRIM73 7.248e-20 1.45e-15
Clinical variable #12: 'ETHNICITY'

202 genes related to 'ETHNICITY'.

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

ETHNICITY Labels N
  HISPANIC OR LATINO 35
  NOT HISPANIC OR LATINO 601
     
  Significant markers N = 202
  Higher in NOT HISPANIC OR LATINO 202
  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 = 701

  • Number of genes = 19976

  • 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)