Correlation between RPPA expression and clinical features
Colon Adenocarcinoma (Primary solid tumor)
28 January 2016  |  analyses__2016_01_28
Maintainer Information
Citation Information
Maintained by Juok Cho (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2016): Correlation between RPPA expression and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C1TM79GC
Overview
Introduction

This pipeline uses various statistical tests to identify RPPAs whose expression levels correlated to selected clinical features. The input file "COAD-TP.rppa.txt" is generated in the pipeline RPPA_AnnotateWithGene in the stddata run.

Summary

Testing the association between 208 genes and 12 clinical features across 358 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 10 clinical features related to at least one genes.

  • 6 genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP'.

    • EGFR|EGFR ,  CCNB1|CYCLIN_B1 ,  CDH3|P-CADHERIN ,  SRC|SRC ,  MAP2K1|MEK1 ,  ...

  • 5 genes correlated to 'YEARS_TO_BIRTH'.

    • SRC|SRC ,  MYH11|MYH11 ,  EGFR|EGFR ,  MAP2K1|MEK1_PS217_S221 ,  RB1|RB_PS807_S811

  • 30 genes correlated to 'PATHOLOGIC_STAGE'.

    • CASP7|CASPASE-7_CLEAVEDD198 ,  YAP1|YAP ,  IRS1|IRS1 ,  NOTCH1|NOTCH1 ,  PXN|PAXILLIN ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • ERRFI1|MIG-6 ,  SERPINE1|PAI-1 ,  NOTCH1|NOTCH1 ,  CDKN1A|P21 ,  EIF4EBP1|4E-BP1_PT37_T46 ,  ...

  • 30 genes correlated to 'PATHOLOGY_N_STAGE'.

    • IRS1|IRS1 ,  PREX1|PREX1 ,  BCL2|BCL-2 ,  INPP4B|INPP4B ,  ARID1A|ARID1A ,  ...

  • 3 genes correlated to 'PATHOLOGY_M_STAGE'.

    • CASP7|CASPASE-7_CLEAVEDD198 ,  PREX1|PREX1 ,  CCNE1|CYCLIN_E1

  • 30 genes correlated to 'HISTOLOGICAL_TYPE'.

    • BAK1|BAK ,  MRE11A|MRE11 ,  TFRC|TFRC ,  RAD50|RAD50 ,  MET|C-MET_PY1235 ,  ...

  • 30 genes correlated to 'RESIDUAL_TUMOR'.

    • EIF4G1|EIF4G ,  RBM15|RBM15 ,  G6PD|G6PD ,  ANXA7|ANNEXIN_VII ,  PEA15|PEA15 ,  ...

  • 30 genes correlated to 'NUMBER_OF_LYMPH_NODES'.

    • IRS1|IRS1 ,  PREX1|PREX1 ,  GAB2|GAB2 ,  PXN|PAXILLIN ,  CASP7|CASPASE-7_CLEAVEDD198 ,  ...

  • 30 genes correlated to 'RACE'.

    • PRKCB|PKC-PAN_BETAII_PS660 ,  CDKN1B|P27_PT157 ,  NRAS|N-RAS ,  MRE11A|MRE11 ,  ERBB2|HER2 ,  ...

  • No genes correlated to 'GENDER', and 'RADIATION_THERAPY'.

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=6   N=NA   N=NA
YEARS_TO_BIRTH Spearman correlation test N=5 older N=3 younger N=2
PATHOLOGIC_STAGE Kruskal-Wallis test N=30        
PATHOLOGY_T_STAGE Spearman correlation test N=30 higher stage N=14 lower stage N=16
PATHOLOGY_N_STAGE Spearman correlation test N=30 higher stage N=18 lower stage N=12
PATHOLOGY_M_STAGE Wilcoxon test N=3 class1 N=3 class0 N=0
GENDER Wilcoxon test   N=0        
RADIATION_THERAPY Wilcoxon test   N=0        
HISTOLOGICAL_TYPE Wilcoxon test N=30 colon mucinous adenocarcinoma N=30 colon adenocarcinoma N=0
RESIDUAL_TUMOR Kruskal-Wallis test N=30        
NUMBER_OF_LYMPH_NODES Spearman correlation test N=30 higher number_of_lymph_nodes N=18 lower number_of_lymph_nodes N=12
RACE Kruskal-Wallis test N=30        
Clinical variable #1: 'DAYS_TO_DEATH_OR_LAST_FUP'

6 genes 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) 0-140.4 (median=22)
  censored N = 280
  death N = 77
     
  Significant markers N = 6
  associated with shorter survival NA
  associated with longer survival NA
List of 6 genes differentially expressed by 'DAYS_TO_DEATH_OR_LAST_FUP'

Table S2.  Get Full Table List of 6 genes significantly associated with 'Time to Death' by Cox regression test. For the survival curves, it compared quantile intervals at c(0, 0.25, 0.50, 0.75, 1) and did not try survival analysis if there is only one interval.

logrank_P Q C_index
EGFR|EGFR 0.00138 0.25 0.608
CCNB1|CYCLIN_B1 0.00356 0.25 0.465
CDH3|P-CADHERIN 0.00452 0.25 0.517
SRC|SRC 0.00633 0.25 0.379
MAP2K1|MEK1 0.00674 0.25 0.54
CTNNA1|ALPHA-CATENIN 0.00721 0.25 0.154
Clinical variable #2: 'YEARS_TO_BIRTH'

5 genes related to 'YEARS_TO_BIRTH'.

Table S3.  Basic characteristics of clinical feature: 'YEARS_TO_BIRTH'

YEARS_TO_BIRTH Mean (SD) 66.91 (13)
  Significant markers N = 5
  pos. correlated 3
  neg. correlated 2
List of 5 genes differentially expressed by 'YEARS_TO_BIRTH'

Table S4.  Get Full Table List of 5 genes significantly correlated to 'YEARS_TO_BIRTH' by Spearman correlation test

SpearmanCorr corrP Q
SRC|SRC -0.1722 0.00109 0.193
MYH11|MYH11 -0.1634 0.001949 0.193
EGFR|EGFR 0.1528 0.003795 0.193
MAP2K1|MEK1_PS217_S221 0.1521 0.00398 0.193
RB1|RB_PS807_S811 0.1495 0.004639 0.193
Clinical variable #3: 'PATHOLOGIC_STAGE'

30 genes related to 'PATHOLOGIC_STAGE'.

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

PATHOLOGIC_STAGE Labels N
  STAGE I 54
  STAGE IA 1
  STAGE II 21
  STAGE IIA 115
  STAGE IIB 9
  STAGE IIC 1
  STAGE III 17
  STAGE IIIA 6
  STAGE IIIB 48
  STAGE IIIC 34
  STAGE IV 30
  STAGE IVA 15
  STAGE IVB 2
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'PATHOLOGIC_STAGE'

Table S6.  Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGIC_STAGE'

kruskal_wallis_P Q
CASP7|CASPASE-7_CLEAVEDD198 2.636e-05 0.00548
YAP1|YAP 0.0006016 0.0626
IRS1|IRS1 0.001495 0.0896
NOTCH1|NOTCH1 0.001723 0.0896
PXN|PAXILLIN 0.002927 0.122
NRG1|HEREGULIN 0.004562 0.136
ERRFI1|MIG-6 0.005189 0.136
PRKAA1|AMPK_ALPHA 0.005231 0.136
EGFR|EGFR 0.006259 0.143
RICTOR|RICTOR 0.007551 0.143
Clinical variable #4: 'PATHOLOGY_T_STAGE'

30 genes related to 'PATHOLOGY_T_STAGE'.

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

PATHOLOGY_T_STAGE Mean (SD) 2.93 (0.6)
  N
  T1 6
  T2 58
  T3 247
  T4 46
     
  Significant markers N = 30
  pos. correlated 14
  neg. correlated 16
List of top 10 genes differentially expressed by 'PATHOLOGY_T_STAGE'

Table S8.  Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY_T_STAGE' by Spearman correlation test

SpearmanCorr corrP Q
ERRFI1|MIG-6 0.2144 4.404e-05 0.00743
SERPINE1|PAI-1 0.2086 7.14e-05 0.00743
NOTCH1|NOTCH1 0.1641 0.001867 0.104
CDKN1A|P21 0.1546 0.003402 0.104
EIF4EBP1|4E-BP1_PT37_T46 -0.1544 0.003453 0.104
SRC|SRC_PY527 -0.1543 0.003466 0.104
SETD2|SETD2 0.1538 0.003584 0.104
RB1|RB_PS807_S811 -0.152 0.00399 0.104
CHEK2|CHK2 -0.1423 0.007086 0.164
RAF1|C-RAF 0.1363 0.009902 0.185
Clinical variable #5: 'PATHOLOGY_N_STAGE'

30 genes related to 'PATHOLOGY_N_STAGE'.

Table S9.  Basic characteristics of clinical feature: 'PATHOLOGY_N_STAGE'

PATHOLOGY_N_STAGE Mean (SD) 0.59 (0.77)
  N
  N0 210
  N1 85
  N2 63
     
  Significant markers N = 30
  pos. correlated 18
  neg. correlated 12
List of top 10 genes differentially expressed by 'PATHOLOGY_N_STAGE'

Table S10.  Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY_N_STAGE' by Spearman correlation test

SpearmanCorr corrP Q
IRS1|IRS1 0.23 1.1e-05 0.00229
PREX1|PREX1 -0.2054 9.054e-05 0.00942
BCL2|BCL-2 -0.1657 0.001653 0.111
INPP4B|INPP4B 0.1594 0.00248 0.111
ARID1A|ARID1A 0.1644 0.002699 0.111
CASP7|CASPASE-7_CLEAVEDD198 -0.1542 0.003453 0.111
EIF4E|EIF4E -0.1528 0.003752 0.111
PXN|PAXILLIN 0.147 0.005325 0.138
MYC|C-MYC 0.141 0.007562 0.158
BAX|BAX -0.1403 0.007847 0.158
Clinical variable #6: 'PATHOLOGY_M_STAGE'

3 genes related to 'PATHOLOGY_M_STAGE'.

Table S11.  Basic characteristics of clinical feature: 'PATHOLOGY_M_STAGE'

PATHOLOGY_M_STAGE Labels N
  class0 270
  class1 47
     
  Significant markers N = 3
  Higher in class1 3
  Higher in class0 0
List of 3 genes differentially expressed by 'PATHOLOGY_M_STAGE'

Table S12.  Get Full Table List of 3 genes differentially expressed by 'PATHOLOGY_M_STAGE'

W(pos if higher in 'class1') wilcoxontestP Q AUC
CASP7|CASPASE-7_CLEAVEDD198 4091 0.0001019 0.0212 0.6776
PREX1|PREX1 4294 0.0004063 0.0423 0.6616
CCNE1|CYCLIN_E1 4482 0.001319 0.0915 0.6468
Clinical variable #7: 'GENDER'

No gene related to 'GENDER'.

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

GENDER Labels N
  FEMALE 173
  MALE 185
     
  Significant markers N = 0
Clinical variable #8: 'RADIATION_THERAPY'

No gene related to 'RADIATION_THERAPY'.

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

RADIATION_THERAPY Labels N
  NO 298
  YES 7
     
  Significant markers N = 0
Clinical variable #9: 'HISTOLOGICAL_TYPE'

30 genes related to 'HISTOLOGICAL_TYPE'.

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

HISTOLOGICAL_TYPE Labels N
  COLON ADENOCARCINOMA 313
  COLON MUCINOUS ADENOCARCINOMA 42
     
  Significant markers N = 30
  Higher in COLON MUCINOUS ADENOCARCINOMA 30
  Higher in COLON ADENOCARCINOMA 0
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'

W(pos if higher in 'COLON MUCINOUS ADENOCARCINOMA') wilcoxontestP Q AUC
BAK1|BAK 9626 1.019e-06 0.000212 0.7322
MRE11A|MRE11 9518 2.417e-06 0.000251 0.724
TFRC|TFRC 3782 7.881e-06 0.000546 0.7123
RAD50|RAD50 3878 1.598e-05 0.000665 0.705
MET|C-MET_PY1235 9268 1.598e-05 0.000665 0.705
PDK1|PDK1_PS241 3993 3.619e-05 0.00125 0.6963
AR|AR 9086 5.741e-05 0.00149 0.6912
HSPA1A|HSP70 9086 5.741e-05 0.00149 0.6912
XRCC5|KU80 4150 0.0001048 0.00209 0.6843
SERPINE1|PAI-1 8994 0.0001062 0.00209 0.6842
Clinical variable #10: 'RESIDUAL_TUMOR'

30 genes related to 'RESIDUAL_TUMOR'.

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

RESIDUAL_TUMOR Labels N
  R0 267
  R1 1
  R2 17
  RX 16
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'RESIDUAL_TUMOR'

Table S18.  Get Full Table List of top 10 genes differentially expressed by 'RESIDUAL_TUMOR'

kruskal_wallis_P Q
EIF4G1|EIF4G 6.826e-06 0.00142
RBM15|RBM15 7.18e-05 0.00747
G6PD|G6PD 0.0001205 0.00835
ANXA7|ANNEXIN_VII 0.0003971 0.0206
PEA15|PEA15 0.0006983 0.0211
EGFR|EGFR_PY1068 0.0008141 0.0211
ACVRL1|ACVRL1 0.0008692 0.0211
CDKN1B|P27 0.0008883 0.0211
RPS6KB1|P70S6K_PT389 0.001001 0.0211
ERBB2|HER2_PY1248 0.001015 0.0211
Clinical variable #11: 'NUMBER_OF_LYMPH_NODES'

30 genes related to 'NUMBER_OF_LYMPH_NODES'.

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

NUMBER_OF_LYMPH_NODES Mean (SD) 2.02 (4.4)
  Significant markers N = 30
  pos. correlated 18
  neg. correlated 12
List of top 10 genes differentially expressed by 'NUMBER_OF_LYMPH_NODES'

Table S20.  Get Full Table List of top 10 genes significantly correlated to 'NUMBER_OF_LYMPH_NODES' by Spearman correlation test

SpearmanCorr corrP Q
IRS1|IRS1 0.2634 9.358e-07 0.000195
PREX1|PREX1 -0.2046 0.0001555 0.0162
GAB2|GAB2 0.1708 0.001652 0.115
PXN|PAXILLIN 0.1641 0.002509 0.116
CASP7|CASPASE-7_CLEAVEDD198 -0.1598 0.003269 0.116
ARID1A|ARID1A 0.1654 0.003383 0.116
INPP4B|INPP4B 0.1567 0.003921 0.116
XRCC1|XRCC1 -0.1545 0.004476 0.116
EIF4E|EIF4E -0.1504 0.005653 0.131
BCL2|BCL-2 -0.1462 0.007178 0.143
Clinical variable #12: 'RACE'

30 genes related to 'RACE'.

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

RACE Labels N
  AMERICAN INDIAN OR ALASKA NATIVE 1
  ASIAN 11
  BLACK OR AFRICAN AMERICAN 48
  WHITE 181
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'RACE'

Table S22.  Get Full Table List of top 10 genes differentially expressed by 'RACE'

kruskal_wallis_P Q
PRKCB|PKC-PAN_BETAII_PS660 0.0005162 0.107
CDKN1B|P27_PT157 0.001718 0.128
NRAS|N-RAS 0.001988 0.128
MRE11A|MRE11 0.003198 0.128
ERBB2|HER2 0.003646 0.128
PREX1|PREX1 0.003699 0.128
AKT1S1|PRAS40_PT246 0.005151 0.153
BID|BID 0.007487 0.174
DIABLO|SMAC 0.007528 0.174
TP53|P53 0.008442 0.176
Methods & Data
Input
  • Expresson data file = COAD-TP.rppa.txt

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

  • Number of patients = 358

  • Number of genes = 208

  • 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, logrank test in univariate Cox regression analysis with proportional hazards model (Andersen and Gill 1982) was used to estimate the P values comparing quantile intervals using the 'coxph' function in R. Kaplan-Meier survival curves were plotted using quantile intervals at c(0, 0.25, 0.50, 0.75, 1). If there is only one interval group, it will not try survival analysis.

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)