Correlation between mRNA expression and clinical features
Breast Invasive Carcinoma (Primary solid tumor)
21 August 2015  |  analyses__2015_08_21
Maintainer Information
Citation Information
Maintained by TCGA GDAC Team (Broad Institute/MD Anderson Cancer Center/Harvard Medical School)
Cite as Broad Institute TCGA Genome Data Analysis Center (2015): Correlation between mRNA expression and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C1S75FG5
Overview
Introduction

This pipeline uses various statistical tests to identify mRNAs whose log2 expression levels correlated to selected clinical features.

Summary

Testing the association between 17814 genes and 12 clinical features across 526 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 9 clinical features related to at least one genes.

  • 30 genes correlated to 'YEARS_TO_BIRTH'.

    • ESR1 ,  CNTNAP3 ,  KRT17 ,  C20ORF42 ,  MAGED4B ,  ...

  • 30 genes correlated to 'PATHOLOGIC_STAGE'.

    • RANBP2 ,  RWDD3 ,  CHST5 ,  OR4D1 ,  LOC51252 ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • RBBP5 ,  PPP2R5D ,  TMEM81 ,  CCNF ,  TMEM63B ,  ...

  • 30 genes correlated to 'PATHOLOGY_N_STAGE'.

    • RWDD3 ,  RPL5 ,  HIST1H2AG ,  PBX1 ,  LRP6 ,  ...

  • 1 gene correlated to 'PATHOLOGY_M_STAGE'.

    • OR4C13

  • 30 genes correlated to 'RADIATION_THERAPY'.

    • SRGN ,  MPP1 ,  CTSS ,  CD300A ,  LAPTM5 ,  ...

  • 30 genes correlated to 'HISTOLOGICAL_TYPE'.

    • CDH1 ,  ADRM1 ,  GLTSCR2 ,  C10ORF56 ,  PPIL1 ,  ...

  • 30 genes correlated to 'NUMBER_OF_LYMPH_NODES'.

    • CSDE1 ,  RWDD3 ,  BCAR1 ,  STS ,  DDX20 ,  ...

  • 30 genes correlated to 'RACE'.

    • PSPH ,  CRYBB2 ,  IL27 ,  PRSS36 ,  RAI16 ,  ...

  • No genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP', 'GENDER', 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=6 younger N=24
PATHOLOGIC_STAGE Kruskal-Wallis test N=30        
PATHOLOGY_T_STAGE Spearman correlation test N=30 higher stage N=21 lower stage N=9
PATHOLOGY_N_STAGE Spearman correlation test N=30 higher stage N=15 lower stage N=15
PATHOLOGY_M_STAGE Wilcoxon test N=1 class1 N=1 class0 N=0
GENDER Wilcoxon test   N=0        
RADIATION_THERAPY Wilcoxon test N=30 yes N=30 no N=0
HISTOLOGICAL_TYPE Kruskal-Wallis test N=30        
NUMBER_OF_LYMPH_NODES Spearman correlation test N=30 higher number_of_lymph_nodes N=16 lower number_of_lymph_nodes N=14
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) 0.2-282.9 (median=33.1)
  censored N = 443
  death N = 82
     
  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) 58.07 (13)
  Significant markers N = 30
  pos. correlated 6
  neg. correlated 24
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
ESR1 0.4219 7.358e-24 1.31e-19
CNTNAP3 -0.3026 1.779e-12 1.58e-08
KRT17 -0.2961 5.531e-12 2.65e-08
C20ORF42 -0.2957 5.952e-12 2.65e-08
MAGED4B -0.2924 1.032e-11 3.61e-08
FOXD2 0.2914 1.228e-11 3.61e-08
KLK6 -0.2903 1.487e-11 3.61e-08
SOSTDC1 -0.2891 1.81e-11 3.61e-08
SYT8 -0.289 1.83e-11 3.61e-08
PPP1R14C -0.288 2.17e-11 3.61e-08
Clinical variable #3: 'PATHOLOGIC_STAGE'

30 genes related to 'PATHOLOGIC_STAGE'.

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

PATHOLOGIC_STAGE Labels N
  STAGE I 50
  STAGE IA 36
  STAGE IB 3
  STAGE II 1
  STAGE IIA 183
  STAGE IIB 112
  STAGE IIIA 77
  STAGE IIIB 15
  STAGE IIIC 19
  STAGE IV 13
  STAGE TIS 1
  STAGE X 13
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'PATHOLOGIC_STAGE'

Table S5.  Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGIC_STAGE'

kruskal_wallis_P Q
RANBP2 1.581e-06 0.0167
RWDD3 1.871e-06 0.0167
CHST5 5.177e-06 0.0307
OR4D1 8.521e-06 0.0379
LOC51252 1.464e-05 0.038
RPL11 1.562e-05 0.038
FRMD1 1.688e-05 0.038
OR51L1 1.707e-05 0.038
DHPS 2.139e-05 0.0423
SATB2 4.241e-05 0.0622
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 132
  T2 312
  T3 59
  T4 20
     
  Significant markers N = 30
  pos. correlated 21
  neg. correlated 9
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
RBBP5 0.2756 1.423e-10 2.53e-06
PPP2R5D 0.234 6.174e-08 0.000375
TMEM81 0.2338 6.319e-08 0.000375
CCNF 0.2253 1.927e-07 0.000819
TMEM63B 0.2231 2.537e-07 0.000819
TBRG4 0.2224 2.76e-07 0.000819
ZBED5 -0.2177 4.958e-07 0.00113
SEPT10 -0.2171 5.351e-07 0.00113
RWDD3 -0.2166 5.699e-07 0.00113
RRM2 0.2081 1.587e-06 0.00283
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) 0.73 (0.88)
  N
  N0 255
  N1 171
  N2 60
  N3 29
     
  Significant markers N = 30
  pos. correlated 15
  neg. correlated 15
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
RWDD3 -0.2534 5.457e-09 9.72e-05
RPL5 -0.2305 1.233e-07 0.0011
HIST1H2AG 0.2258 2.226e-07 0.00132
PBX1 0.2213 3.932e-07 0.00175
LRP6 -0.217 6.626e-07 0.00236
SRD5A2L 0.2132 1.042e-06 0.003
CALM1 0.212 1.212e-06 0.003
C11ORF80 0.211 1.362e-06 0.003
RBBP8 -0.2092 1.684e-06 0.003
USP33 -0.2092 1.685e-06 0.003
Clinical variable #6: 'PATHOLOGY_M_STAGE'

One gene related to 'PATHOLOGY_M_STAGE'.

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

PATHOLOGY_M_STAGE Labels N
  class0 495
  class1 15
     
  Significant markers N = 1
  Higher in class1 1
  Higher in class0 0
List of one gene differentially expressed by 'PATHOLOGY_M_STAGE'

Table S11.  Get Full Table List of one gene differentially expressed by 'PATHOLOGY_M_STAGE'

W(pos if higher in 'class1') wilcoxontestP Q AUC
OR4C13 1239.5 1.12e-05 0.2 0.8327
Clinical variable #7: 'GENDER'

No gene related to 'GENDER'.

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

GENDER Labels N
  FEMALE 520
  MALE 6
     
  Significant markers N = 0
Clinical variable #8: 'RADIATION_THERAPY'

30 genes related to 'RADIATION_THERAPY'.

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

RADIATION_THERAPY Labels N
  NO 203
  YES 236
     
  Significant markers N = 30
  Higher in YES 30
  Higher in NO 0
List of top 10 genes differentially expressed by 'RADIATION_THERAPY'

Table S14.  Get Full Table List of top 10 genes differentially expressed by 'RADIATION_THERAPY'

W(pos if higher in 'YES') wilcoxontestP Q AUC
SRGN 29925 6.645e-06 0.0679 0.6246
MPP1 29749 1.231e-05 0.0679 0.621
CTSS 29698.5 1.465e-05 0.0679 0.6199
CD300A 29687 1.524e-05 0.0679 0.6197
LAPTM5 29451.5 3.361e-05 0.102 0.6148
AQP9 29402.5 3.948e-05 0.102 0.6137
NMI 29396.5 4.026e-05 0.102 0.6136
CRELD1 18553.5 4.615e-05 0.103 0.6127
C1ORF162 29317.5 5.201e-05 0.103 0.612
HOXA6 18658 6.457e-05 0.113 0.6105
Clinical variable #9: 'HISTOLOGICAL_TYPE'

30 genes related to 'HISTOLOGICAL_TYPE'.

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

HISTOLOGICAL_TYPE Labels N
  INFILTRATING DUCTAL CARCINOMA 446
  INFILTRATING LOBULAR CARCINOMA 43
  MEDULLARY CARCINOMA 1
  MIXED HISTOLOGY (PLEASE SPECIFY) 11
  MUCINOUS CARCINOMA 2
  OTHER SPECIFY 22
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'HISTOLOGICAL_TYPE'

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

kruskal_wallis_P Q
CDH1 1.301e-18 2.32e-14
ADRM1 7.738e-11 6.89e-07
GLTSCR2 1.195e-10 7.09e-07
C10ORF56 2.344e-10 1.04e-06
PPIL1 5.306e-10 1.89e-06
MFAP4 7.708e-10 2.19e-06
ORC6L 8.618e-10 2.19e-06
ALG3 9.994e-10 2.23e-06
SSTR1 2.155e-09 3.9e-06
CCDC90A 2.188e-09 3.9e-06
Clinical variable #10: 'NUMBER_OF_LYMPH_NODES'

30 genes related to 'NUMBER_OF_LYMPH_NODES'.

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

NUMBER_OF_LYMPH_NODES Mean (SD) 1.82 (3.5)
  Significant markers N = 30
  pos. correlated 16
  neg. correlated 14
List of top 10 genes differentially expressed by 'NUMBER_OF_LYMPH_NODES'

Table S18.  Get Full Table List of top 10 genes significantly correlated to 'NUMBER_OF_LYMPH_NODES' by Spearman correlation test

SpearmanCorr corrP Q
CSDE1 -0.2397 9.632e-07 0.0168
RWDD3 -0.2328 1.998e-06 0.0168
BCAR1 0.2294 2.832e-06 0.0168
STS 0.2229 5.475e-06 0.0244
DDX20 -0.2181 8.777e-06 0.0263
ACY1L2 -0.2165 1.027e-05 0.0263
ARRDC1 0.214 1.296e-05 0.0263
NFATC1 -0.2134 1.375e-05 0.0263
HIST1H2AG 0.2131 1.416e-05 0.0263
SH3GL1 0.2114 1.659e-05 0.0263
Clinical variable #11: 'RACE'

30 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 40
  WHITE 361
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'RACE'

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

kruskal_wallis_P Q
PSPH 2.725e-16 4.85e-12
CRYBB2 1.187e-13 1.06e-09
IL27 8.988e-11 4.51e-07
PRSS36 1.012e-10 4.51e-07
RAI16 1.656e-10 5.9e-07
DPF2 1.832e-09 5.44e-06
UTS2 2.16e-09 5.5e-06
CRCT1 1.266e-08 2.58e-05
MAB21L2 1.302e-08 2.58e-05
TNMD 2.08e-08 3.7e-05
Clinical variable #12: 'ETHNICITY'

No gene related to 'ETHNICITY'.

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

ETHNICITY Labels N
  HISPANIC OR LATINO 7
  NOT HISPANIC OR LATINO 372
     
  Significant markers N = 0
Methods & Data
Input
  • Expresson data file = BRCA-TP.medianexp.txt

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

  • Number of patients = 526

  • Number of genes = 17814

  • Number of clinical features = 12

Selected clinical features
  • Further details on clinical features selected for this analysis, please find a documentation on selected CDEs (Clinical Data Elements). The first column of the file is a formula to convert values and the second column is a clinical parameter name.

  • 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)