Correlation between RPPA expression and clinical features
Colorectal Adenocarcinoma (Primary solid tumor)
28 January 2016  |  analyses__2016_01_28
Maintainer Information
Citation Information
doi:10.7908/C1125S1X
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/C1125S1X
Overview
Introduction

This pipeline uses various statistical tests to identify RPPAs whose expression levels correlated to selected clinical features. The input file "COADREAD-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 489 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 10 clinical features related to at least one genes.

  • 10 genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP'.

    • CCNB1|CYCLIN_B1 ,  PTEN|PTEN ,  BCL2L1|BCL-XL ,  CTNNA1|ALPHA-CATENIN ,  DIABLO|SMAC ,  ...

  • 8 genes correlated to 'YEARS_TO_BIRTH'.

    • SRC|SRC ,  MET|C-MET_PY1235 ,  BID|BID ,  EGFR|EGFR ,  YAP1|YAP ,  ...

  • 16 genes correlated to 'TUMOR_TISSUE_SITE'.

    • BID|BID ,  IRS1|IRS1 ,  RAF1|C-RAF ,  ERBB3|HER3_PY1289 ,  SRC|SRC ,  ...

  • 30 genes correlated to 'PATHOLOGIC_STAGE'.

    • CASP7|CASPASE-7_CLEAVEDD198 ,  PIK3CA |PI3K-P110-ALPHA ,  YAP1|YAP ,  IRS1|IRS1 ,  PXN|PAXILLIN ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • SERPINE1|PAI-1 ,  ERRFI1|MIG-6 ,  SRC|SRC_PY527 ,  RB1|RB_PS807_S811 ,  EIF4EBP1|4E-BP1_PT37_T46 ,  ...

  • 30 genes correlated to 'PATHOLOGY_N_STAGE'.

    • IRS1|IRS1 ,  MYC|C-MYC ,  EIF4E|EIF4E ,  GAB2|GAB2 ,  PXN|PAXILLIN ,  ...

  • 30 genes correlated to 'PATHOLOGY_M_STAGE'.

    • CASP7|CASPASE-7_CLEAVEDD198 ,  MAPK14|P38_MAPK ,  RBM15|RBM15 ,  CCNE1|CYCLIN_E1 ,  PREX1|PREX1 ,  ...

  • 30 genes correlated to 'HISTOLOGICAL_TYPE'.

    • BID|BID ,  RAD50|RAD50 ,  RAF1|C-RAF ,  MRE11A|MRE11 ,  ERBB3|HER3_PY1289 ,  ...

  • 30 genes correlated to 'RESIDUAL_TUMOR'.

    • RBM15|RBM15 ,  EIF4G1|EIF4G ,  PEA15|PEA15 ,  EGFR|EGFR_PY1068 ,  MAPK14|P38_MAPK ,  ...

  • 30 genes correlated to 'NUMBER_OF_LYMPH_NODES'.

    • IRS1|IRS1 ,  GAB2|GAB2 ,  PXN|PAXILLIN ,  EIF4E|EIF4E ,  MYC|C-MYC ,  ...

  • 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=10   N=NA   N=NA
YEARS_TO_BIRTH Spearman correlation test N=8 older N=3 younger N=5
TUMOR_TISSUE_SITE Wilcoxon test N=16 rectum N=16 colon N=0
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=15 lower stage N=15
PATHOLOGY_M_STAGE Wilcoxon test N=30 class1 N=30 class0 N=0
GENDER Wilcoxon test   N=0        
RADIATION_THERAPY Wilcoxon test   N=0        
HISTOLOGICAL_TYPE Kruskal-Wallis test N=30        
RESIDUAL_TUMOR Kruskal-Wallis test N=30        
NUMBER_OF_LYMPH_NODES Spearman correlation test N=30 higher number_of_lymph_nodes N=14 lower number_of_lymph_nodes N=16
Clinical variable #1: 'DAYS_TO_DEATH_OR_LAST_FUP'

10 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=21.4)
  censored N = 384
  death N = 104
     
  Significant markers N = 10
  associated with shorter survival NA
  associated with longer survival NA
List of 10 genes differentially expressed by 'DAYS_TO_DEATH_OR_LAST_FUP'

Table S2.  Get Full Table List of 10 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
CCNB1|CYCLIN_B1 0.000635 0.13 0.457
PTEN|PTEN 0.00322 0.19 0.504
BCL2L1|BCL-XL 0.0057 0.19 0.533
CTNNA1|ALPHA-CATENIN 0.00593 0.19 0.181
DIABLO|SMAC 0.00652 0.19 0.553
MAP2K1|MEK1 0.00667 0.19 0.556
ACACA|ACC1 0.00672 0.19 0.446
SMAD4|SMAD4 0.00791 0.19 0.45
EGFR|EGFR 0.0082 0.19 0.599
CCNE1|CYCLIN_E1 0.0108 0.23 0.436
Clinical variable #2: 'YEARS_TO_BIRTH'

8 genes related to 'YEARS_TO_BIRTH'.

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

YEARS_TO_BIRTH Mean (SD) 66.51 (13)
  Significant markers N = 8
  pos. correlated 3
  neg. correlated 5
List of 8 genes differentially expressed by 'YEARS_TO_BIRTH'

Table S4.  Get Full Table List of 8 genes significantly correlated to 'YEARS_TO_BIRTH' by Spearman correlation test

SpearmanCorr corrP Q
SRC|SRC -0.1473 0.001103 0.105
MET|C-MET_PY1235 -0.1456 0.001255 0.105
BID|BID -0.1432 0.001512 0.105
EGFR|EGFR 0.1363 0.002545 0.13
YAP1|YAP -0.1335 0.003126 0.13
ESR1|ER-ALPHA_PS118 -0.1263 0.005208 0.175
MAP2K1|MEK1_PS217_S221 0.1245 0.005894 0.175
RB1|RB_PS807_S811 0.1157 0.01054 0.274
Clinical variable #3: 'TUMOR_TISSUE_SITE'

16 genes related to 'TUMOR_TISSUE_SITE'.

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

TUMOR_TISSUE_SITE Labels N
  COLON 358
  RECTUM 131
     
  Significant markers N = 16
  Higher in RECTUM 16
  Higher in COLON 0
List of top 10 genes differentially expressed by 'TUMOR_TISSUE_SITE'

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

W(pos if higher in 'RECTUM') wilcoxontestP Q AUC
BID|BID 29491 1.267e-05 0.00263 0.6288
IRS1|IRS1 28335 0.0004149 0.0301 0.6042
RAF1|C-RAF 28318 0.0004346 0.0301 0.6038
ERBB3|HER3_PY1289 28035 0.000921 0.0479 0.5978
SRC|SRC 27561 0.002967 0.112 0.5877
BAD|BAD_PS112 19372 0.003221 0.112 0.5869
RPS6|S6 19540 0.004737 0.141 0.5834
JUN|C-JUN_PS73 19702 0.006783 0.176 0.5799
MYC|C-MYC 27037 0.00953 0.22 0.5765
KDR|VEGFR2 20111 0.01588 0.266 0.5712
Clinical variable #4: 'PATHOLOGIC_STAGE'

30 genes related to 'PATHOLOGIC_STAGE'.

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

PATHOLOGIC_STAGE Labels N
  STAGE I 75
  STAGE IA 1
  STAGE II 28
  STAGE IIA 147
  STAGE IIB 10
  STAGE IIC 1
  STAGE III 22
  STAGE IIIA 13
  STAGE IIIB 69
  STAGE IIIC 43
  STAGE IV 46
  STAGE IVA 19
  STAGE IVB 2
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'PATHOLOGIC_STAGE'

Table S8.  Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGIC_STAGE'

kruskal_wallis_P Q
CASP7|CASPASE-7_CLEAVEDD198 7.777e-07 0.000162
PIK3CA |PI3K-P110-ALPHA 5.747e-05 0.00463
YAP1|YAP 6.673e-05 0.00463
IRS1|IRS1 0.0003792 0.0197
PXN|PAXILLIN 0.001145 0.0349
ERRFI1|MIG-6 0.001156 0.0349
DIRAS3|ARHI 0.001174 0.0349
NOTCH1|NOTCH1 0.002363 0.0555
GATA3|GATA3 0.002401 0.0555
RB1|RB_PS807_S811 0.002798 0.0582
Clinical variable #5: 'PATHOLOGY_T_STAGE'

30 genes related to 'PATHOLOGY_T_STAGE'.

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

PATHOLOGY_T_STAGE Mean (SD) 2.9 (0.6)
  N
  T1 11
  T2 81
  T3 338
  T4 56
     
  Significant markers N = 30
  pos. correlated 14
  neg. correlated 16
List of top 10 genes differentially expressed by 'PATHOLOGY_T_STAGE'

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

SpearmanCorr corrP Q
SERPINE1|PAI-1 0.2052 5.081e-06 0.00106
ERRFI1|MIG-6 0.1875 3.179e-05 0.00331
SRC|SRC_PY527 -0.1521 0.00077 0.0357
RB1|RB_PS807_S811 -0.1514 0.0008117 0.0357
EIF4EBP1|4E-BP1_PT37_T46 -0.15 0.0009073 0.0357
SMAD1|SMAD1 -0.1476 0.001099 0.0357
CDK1|CDK1_PY15 -0.1505 0.00124 0.0357
SRC|SRC_PY416 -0.1448 0.001371 0.0357
EIF4E|EIF4E -0.1418 0.001723 0.0398
GAB2|GAB2 0.1314 0.00372 0.0774
Clinical variable #6: 'PATHOLOGY_N_STAGE'

30 genes related to 'PATHOLOGY_N_STAGE'.

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

PATHOLOGY_N_STAGE Mean (SD) 0.62 (0.78)
  N
  N0 274
  N1 122
  N2 89
     
  Significant markers N = 30
  pos. correlated 15
  neg. correlated 15
List of top 10 genes differentially expressed by 'PATHOLOGY_N_STAGE'

Table S12.  Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY_N_STAGE' by Spearman correlation test

SpearmanCorr corrP Q
IRS1|IRS1 0.2412 7.511e-08 1.56e-05
MYC|C-MYC 0.1925 1.963e-05 0.00204
EIF4E|EIF4E -0.1828 5.141e-05 0.00304
GAB2|GAB2 0.1814 5.852e-05 0.00304
PXN|PAXILLIN 0.169 0.0001841 0.00761
CASP7|CASPASE-7_CLEAVEDD198 -0.167 0.0002196 0.00761
BAX|BAX -0.1628 0.0003186 0.00947
PREX1|PREX1 -0.1555 0.0005902 0.0149
DVL3|DVL3 0.1536 0.0006881 0.0149
CCNE1|CYCLIN_E1 -0.1531 0.0007147 0.0149
Clinical variable #7: 'PATHOLOGY_M_STAGE'

30 genes related to 'PATHOLOGY_M_STAGE'.

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

PATHOLOGY_M_STAGE Labels N
  class0 368
  class1 67
     
  Significant markers N = 30
  Higher in class1 30
  Higher in class0 0
List of top 10 genes differentially expressed by 'PATHOLOGY_M_STAGE'

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

W(pos if higher in 'class1') wilcoxontestP Q AUC
CASP7|CASPASE-7_CLEAVEDD198 8461 4.406e-05 0.00916 0.6568
MAPK14|P38_MAPK 9087 0.0006177 0.0468 0.6314
RBM15|RBM15 15546 0.0006753 0.0468 0.6305
CCNE1|CYCLIN_E1 9209 0.0009848 0.0512 0.6265
PREX1|PREX1 9506 0.002873 0.12 0.6145
YBX1|YB-1 14910 0.006382 0.221 0.6047
IRS1|IRS1 14799 0.009049 0.24 0.6002
PXN|PAXILLIN 14738 0.0109 0.24 0.5977
AKT1S1|PRAS40_PT246 14734 0.01104 0.24 0.5976
MYC|C-MYC 14707 0.01197 0.24 0.5965
Clinical variable #8: 'GENDER'

No gene related to 'GENDER'.

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

GENDER Labels N
  FEMALE 234
  MALE 255
     
  Significant markers N = 0
Clinical variable #9: 'RADIATION_THERAPY'

No gene related to 'RADIATION_THERAPY'.

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

RADIATION_THERAPY Labels N
  NO 386
  YES 23
     
  Significant markers N = 0
Clinical variable #10: 'HISTOLOGICAL_TYPE'

30 genes related to 'HISTOLOGICAL_TYPE'.

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

HISTOLOGICAL_TYPE Labels N
  COLON ADENOCARCINOMA 313
  COLON MUCINOUS ADENOCARCINOMA 42
  RECTAL ADENOCARCINOMA 118
  RECTAL MUCINOUS ADENOCARCINOMA 10
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'HISTOLOGICAL_TYPE'

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

kruskal_wallis_P Q
BID|BID 4.046e-07 8.41e-05
RAD50|RAD50 1.551e-06 0.000148
RAF1|C-RAF 2.136e-06 0.000148
MRE11A|MRE11 4.019e-06 0.000178
ERBB3|HER3_PY1289 4.277e-06 0.000178
TFRC|TFRC 1.972e-05 0.000607
BAK1|BAK 2.042e-05 0.000607
AR|AR 0.000227 0.00538
SRC|SRC 0.000238 0.00538
PDK1|PDK1_PS241 0.0002586 0.00538
Clinical variable #11: 'RESIDUAL_TUMOR'

30 genes related to 'RESIDUAL_TUMOR'.

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

RESIDUAL_TUMOR Labels N
  R0 365
  R1 3
  R2 29
  RX 19
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'RESIDUAL_TUMOR'

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

kruskal_wallis_P Q
RBM15|RBM15 4.464e-05 0.00929
EIF4G1|EIF4G 0.0003037 0.0316
PEA15|PEA15 0.0006605 0.0448
EGFR|EGFR_PY1068 0.001144 0.0448
MAPK14|P38_MAPK 0.001357 0.0448
PIK3CA |PI3K-P110-ALPHA 0.001423 0.0448
ERBB2|HER2_PY1248 0.001611 0.0448
BRD4|BRD4 0.001721 0.0448
G6PD|G6PD 0.002068 0.0478
TSC2|TUBERIN 0.003139 0.0554
Clinical variable #12: 'NUMBER_OF_LYMPH_NODES'

30 genes related to 'NUMBER_OF_LYMPH_NODES'.

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

NUMBER_OF_LYMPH_NODES Mean (SD) 2.13 (4.5)
  Significant markers N = 30
  pos. correlated 14
  neg. correlated 16
List of top 10 genes differentially expressed by 'NUMBER_OF_LYMPH_NODES'

Table S22.  Get Full Table List of top 10 genes significantly correlated to 'NUMBER_OF_LYMPH_NODES' by Spearman correlation test

SpearmanCorr corrP Q
IRS1|IRS1 0.272 2.702e-09 5.62e-07
GAB2|GAB2 0.2182 2.14e-06 0.000223
PXN|PAXILLIN 0.192 3.199e-05 0.00171
EIF4E|EIF4E -0.1917 3.291e-05 0.00171
MYC|C-MYC 0.1729 0.0001851 0.0069
BAX|BAX -0.1721 0.0001989 0.0069
CASP7|CASPASE-7_CLEAVEDD198 -0.17 0.0002384 0.00708
DVL3|DVL3 0.1655 0.0003475 0.00904
PREX1|PREX1 -0.161 0.0005053 0.0111
EEF2K|EEF2K 0.1603 0.0005344 0.0111
Methods & Data
Input

  • Expresson data file = COADREAD-TP.rppa.txt

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

  • Number of patients = 489

  • 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)
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