Correlation between RPPA expression and clinical features
Thyroid Adenocarcinoma (Primary solid tumor)
28 January 2016  |  analyses__2016_01_28
Maintainer Information
Citation Information
doi:10.7908/C1N58KVZ
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/C1N58KVZ
Overview
Introduction

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

Summary

Testing the association between 175 genes and 17 clinical features across 222 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 11 clinical features related to at least one genes.

  • 30 genes correlated to 'YEARS_TO_BIRTH'.

    • EGFR|EGFR_PY1068 ,  SNAI2|SNAIL ,  EEF2|EEF2 ,  ATM|ATM ,  MAPK8|JNK_PT183_PT185 ,  ...

  • 30 genes correlated to 'PATHOLOGIC_STAGE'.

    • CDK1|CDK1 ,  MAPK8|JNK_PT183_PT185 ,  CASP3|CASPASE-3_ACTIVE ,  RAF1|C-RAF ,  PECAM1|CD31 ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • AKT1S1|PRAS40_PT246 ,  DIABLO|SMAC ,  CLDN7|CLAUDIN-7 ,  PIK3CA |PI3K-P110-ALPHA ,  AR|AR ,  ...

  • 30 genes correlated to 'PATHOLOGY_N_STAGE'.

    • ANXA1|ANNEXIN_I ,  PTCH1|PTCH ,  SRC|SRC_PY527 ,  DVL3|DVL3 ,  RAF1|C-RAF_PS338 ,  ...

  • 21 genes correlated to 'RADIATION_THERAPY'.

    • CCNE1|CYCLIN_E1 ,  SRC|SRC_PY416 ,  ITGA2|CD49B ,  EEF2|EEF2 ,  ERBB2|HER2_PY1248 ,  ...

  • 30 genes correlated to 'HISTOLOGICAL_TYPE'.

    • ANXA1|ANNEXIN_I ,  FN1|FIBRONECTIN ,  PIK3R1/2|PI3K-P85 ,  CHEK2|CHK2 ,  XIAP|XIAP ,  ...

  • 30 genes correlated to 'EXTRATHYROIDAL_EXTENSION'.

    • PIK3CA |PI3K-P110-ALPHA ,  EIF4EBP1|4E-BP1 ,  BCL2|BCL-2 ,  EGFR|EGFR_PY1173 ,  PAI-1|PAL-1 ,  ...

  • 30 genes correlated to 'NUMBER_OF_LYMPH_NODES'.

    • PTCH1|PTCH ,  MAPK14|P38_MAPK ,  ANXA1|ANNEXIN_I ,  DVL3|DVL3 ,  PTGS2|COX-2 ,  ...

  • 10 genes correlated to 'MULTIFOCALITY'.

    • CDKN1B|P27_PT157 ,  EIF4EBP1|4E-BP1 ,  ACACA|ACC1 ,  RAF1|C-RAF_PS338 ,  STK11|LKB1 ,  ...

  • 2 genes correlated to 'TUMOR_SIZE'.

    • STAT5A|STAT5-ALPHA ,  NFKB1|NF-KB-P65_PS536

  • 3 genes correlated to 'RACE'.

    • FOXO3|FOXO3A_PS318_S321 ,  |P-REX1 ,  EIF4EBP1|4E-BP1_PT70

  • No genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP', 'PATHOLOGY_M_STAGE', 'GENDER', 'RADIATION_EXPOSURE', 'RESIDUAL_TUMOR', 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=16 younger N=14
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 Wilcoxon test N=30 n1 N=30 n0 N=0
PATHOLOGY_M_STAGE Wilcoxon test   N=0        
GENDER Wilcoxon test   N=0        
RADIATION_THERAPY Wilcoxon test N=21 yes N=21 no N=0
HISTOLOGICAL_TYPE Kruskal-Wallis test N=30        
RADIATION_EXPOSURE Wilcoxon test   N=0        
EXTRATHYROIDAL_EXTENSION Kruskal-Wallis test N=30        
RESIDUAL_TUMOR Kruskal-Wallis test   N=0        
NUMBER_OF_LYMPH_NODES Spearman correlation test N=30 higher number_of_lymph_nodes N=19 lower number_of_lymph_nodes N=11
MULTIFOCALITY Wilcoxon test N=10 unifocal N=10 multifocal N=0
TUMOR_SIZE Spearman correlation test N=2 higher tumor_size N=0 lower tumor_size N=2
RACE Kruskal-Wallis test N=3        
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) 1.2-178.3 (median=37.2)
  censored N = 207
  death N = 14
     
  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) 48.08 (17)
  Significant markers N = 30
  pos. correlated 16
  neg. correlated 14
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
EGFR|EGFR_PY1068 0.3019 4.631e-06 0.000618
SNAI2|SNAIL 0.2963 7.068e-06 0.000618
EEF2|EEF2 -0.2861 1.495e-05 0.000872
ATM|ATM -0.2808 2.177e-05 0.000952
MAPK8|JNK_PT183_PT185 0.2756 3.125e-05 0.00109
AKT1 AKT2 AKT3|AKT_PT308 0.2621 7.753e-05 0.00226
AKT1 AKT2 AKT3|AKT_PS473 0.2567 0.00011 0.00275
DVL3|DVL3 -0.2507 0.0001599 0.00338
RAD50|RAD50 -0.2494 0.0001739 0.00338
PRKCA |PKC-ALPHA 0.2423 0.0002683 0.0043
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 117
  STAGE II 33
  STAGE III 46
  STAGE IVA 20
  STAGE IVC 4
     
  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
CDK1|CDK1 1.908e-05 0.00334
MAPK8|JNK_PT183_PT185 5.513e-05 0.00482
CASP3|CASPASE-3_ACTIVE 0.0001268 0.0074
RAF1|C-RAF 0.0003806 0.0141
PECAM1|CD31 0.0004303 0.0141
BECN1|BECLIN 0.0004848 0.0141
MSH6|MSH6 0.0006012 0.015
EGFR|EGFR_PY1068 0.001059 0.0167
AKT1 AKT2 AKT3|AKT_PS473 0.001102 0.0167
EIF4EBP1|4E-BP1_PS65 0.001123 0.0167
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) 2.21 (0.86)
  N
  T1 51
  T2 83
  T3 76
  T4 11
     
  Significant markers N = 30
  pos. correlated 14
  neg. correlated 16
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
AKT1S1|PRAS40_PT246 -0.3264 7.002e-07 0.000123
DIABLO|SMAC 0.2822 2.061e-05 0.0018
CLDN7|CLAUDIN-7 -0.2694 4.972e-05 0.0029
PIK3CA |PI3K-P110-ALPHA 0.2534 0.0001399 0.00612
AR|AR -0.2455 0.0002288 0.00801
C12ORF5|TIGAR -0.2381 0.0003564 0.0104
WWTR1|TAZ -0.2313 0.0005292 0.0119
CCNE1|CYCLIN_E1 0.2308 0.0005437 0.0119
COL6A1|COLLAGEN_VI -0.2262 0.000706 0.0135
RAF1|C-RAF -0.2246 0.0007716 0.0135
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 Labels N
  N0 98
  N1 95
     
  Significant markers N = 30
  Higher in N1 30
  Higher in N0 0
List of top 10 genes differentially expressed by 'PATHOLOGY_N_STAGE'

Table S9.  Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGY_N_STAGE'

W(pos if higher in 'N1') wilcoxontestP Q AUC
ANXA1|ANNEXIN_I 6777 4.542e-08 7.95e-06 0.7279
PTCH1|PTCH 6672 2.017e-07 1.77e-05 0.7166
SRC|SRC_PY527 2729 6.935e-07 4.05e-05 0.7069
DVL3|DVL3 6555.5 9.71e-07 4.25e-05 0.7041
RAF1|C-RAF_PS338 2928 8.578e-06 0.00025 0.6855
ERBB2|HER2_PY1248 2928 8.578e-06 0.00025 0.6855
EEF2|EEF2 6346.5 1.308e-05 0.000313 0.6817
VASP|VASP 6339 1.429e-05 0.000313 0.6809
FN1|FIBRONECTIN 6299 2.273e-05 0.000442 0.6766
PXN|PAXILLIN 6267 3.27e-05 0.000572 0.6731
Clinical variable #6: 'PATHOLOGY_M_STAGE'

No gene related to 'PATHOLOGY_M_STAGE'.

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

PATHOLOGY_M_STAGE Labels N
  class0 118
  class1 5
     
  Significant markers N = 0
Clinical variable #7: 'GENDER'

No gene related to 'GENDER'.

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

GENDER Labels N
  FEMALE 154
  MALE 68
     
  Significant markers N = 0
Clinical variable #8: 'RADIATION_THERAPY'

21 genes related to 'RADIATION_THERAPY'.

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

RADIATION_THERAPY Labels N
  NO 90
  YES 128
     
  Significant markers N = 21
  Higher in YES 21
  Higher in NO 0
List of top 10 genes differentially expressed by 'RADIATION_THERAPY'

Table S13.  Get Full Table List of top 10 genes differentially expressed by 'RADIATION_THERAPY'

W(pos if higher in 'YES') wilcoxontestP Q AUC
CCNE1|CYCLIN_E1 7181 0.001948 0.131 0.6234
SRC|SRC_PY416 4371.5 0.002469 0.131 0.6205
ITGA2|CD49B 7120 0.003027 0.131 0.6181
EEF2|EEF2 7107 0.003318 0.131 0.6169
ERBB2|HER2_PY1248 4430 0.003737 0.131 0.6155
STAT3|STAT3_PY705 4506 0.006261 0.161 0.6089
XRCC1|XRCC1 7009.5 0.00645 0.161 0.6085
ESR1|ER-ALPHA_PS118 6979.5 0.007848 0.172 0.6059
BCL2L1|BCL-XL 6945.5 0.009755 0.19 0.6029
GAB2|GAB2 4611 0.01225 0.198 0.5997
Clinical variable #9: 'HISTOLOGICAL_TYPE'

30 genes related to 'HISTOLOGICAL_TYPE'.

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

HISTOLOGICAL_TYPE Labels N
  OTHER, SPECIFY 2
  THYROID PAPILLARY CARCINOMA - CLASSICAL/USUAL 158
  THYROID PAPILLARY CARCINOMA - FOLLICULAR (>= 99% FOLLICULAR PATTERNED) 52
  THYROID PAPILLARY CARCINOMA - TALL CELL (>= 50% TALL CELL FEATURES) 10
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'HISTOLOGICAL_TYPE'

Table S15.  Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL_TYPE'

kruskal_wallis_P Q
ANXA1|ANNEXIN_I 2.162e-10 3.78e-08
FN1|FIBRONECTIN 1.139e-09 9.94e-08
PIK3R1/2|PI3K-P85 1.703e-09 9.94e-08
CHEK2|CHK2 1.443e-07 6.31e-06
XIAP|XIAP 2.429e-07 8.44e-06
NEK7|NEK7 2.894e-07 8.44e-06
ERCC1|ERCC1 7.334e-07 1.83e-05
PXN|PAXILLIN 8.551e-07 1.87e-05
RAF1|C-RAF_PS338 1.306e-06 2.54e-05
COL6A1|COLLAGEN_VI 3.725e-06 6.52e-05
Clinical variable #10: 'RADIATION_EXPOSURE'

No gene related to 'RADIATION_EXPOSURE'.

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

RADIATION_EXPOSURE Labels N
  NO 184
  YES 11
     
  Significant markers N = 0
Clinical variable #11: 'EXTRATHYROIDAL_EXTENSION'

30 genes related to 'EXTRATHYROIDAL_EXTENSION'.

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

EXTRATHYROIDAL_EXTENSION Labels N
  MINIMAL (T3) 55
  MODERATE/ADVANCED (T4A) 10
  NONE 149
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'EXTRATHYROIDAL_EXTENSION'

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

kruskal_wallis_P Q
PIK3CA |PI3K-P110-ALPHA 2.353e-05 0.00232
EIF4EBP1|4E-BP1 2.748e-05 0.00232
BCL2|BCL-2 5.105e-05 0.00232
EGFR|EGFR_PY1173 5.295e-05 0.00232
PAI-1|PAL-1 9.793e-05 0.00343
BECN1|BECLIN 0.0001491 0.00435
DIABLO|SMAC 0.0001829 0.00445
MAPT|TAU 0.0002035 0.00445
RAF1|C-RAF 0.001013 0.0187
INPP4B|INPP4B 0.001154 0.0187
Clinical variable #12: 'RESIDUAL_TUMOR'

No gene related to 'RESIDUAL_TUMOR'.

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

RESIDUAL_TUMOR Labels N
  R0 168
  R1 23
  R2 2
  RX 14
     
  Significant markers N = 0
Clinical variable #13: 'NUMBER_OF_LYMPH_NODES'

30 genes related to 'NUMBER_OF_LYMPH_NODES'.

Table S20.  Basic characteristics of clinical feature: 'NUMBER_OF_LYMPH_NODES'

NUMBER_OF_LYMPH_NODES Mean (SD) 3.51 (5.8)
  Significant markers N = 30
  pos. correlated 19
  neg. correlated 11
List of top 10 genes differentially expressed by 'NUMBER_OF_LYMPH_NODES'

Table S21.  Get Full Table List of top 10 genes significantly correlated to 'NUMBER_OF_LYMPH_NODES' by Spearman correlation test

SpearmanCorr corrP Q
PTCH1|PTCH 0.3271 1.51e-05 0.00246
MAPK14|P38_MAPK 0.3171 2.806e-05 0.00246
ANXA1|ANNEXIN_I 0.2967 9.39e-05 0.00432
DVL3|DVL3 0.2959 9.873e-05 0.00432
PTGS2|COX-2 0.2817 0.0002157 0.00755
PAI-1|PAL-1 0.2754 0.0003031 0.00809
PXN|PAXILLIN 0.2738 0.0003298 0.00809
SRC|SRC_PY527 -0.2716 0.00037 0.00809
CASP9|CASPASE-9_CLEAVEDD330 0.2634 0.0005612 0.0109
KIT|C-KIT -0.2559 0.0008121 0.0142
Clinical variable #14: 'MULTIFOCALITY'

10 genes related to 'MULTIFOCALITY'.

Table S22.  Basic characteristics of clinical feature: 'MULTIFOCALITY'

MULTIFOCALITY Labels N
  MULTIFOCAL 100
  UNIFOCAL 115
     
  Significant markers N = 10
  Higher in UNIFOCAL 10
  Higher in MULTIFOCAL 0
List of 10 genes differentially expressed by 'MULTIFOCALITY'

Table S23.  Get Full Table List of 10 genes differentially expressed by 'MULTIFOCALITY'

W(pos if higher in 'UNIFOCAL') wilcoxontestP Q AUC
CDKN1B|P27_PT157 4219 0.0007684 0.134 0.6331
EIF4EBP1|4E-BP1 7069 0.003756 0.199 0.6147
ACACA|ACC1 7009 0.005673 0.199 0.6095
RAF1|C-RAF_PS338 4530 0.007354 0.199 0.6061
STK11|LKB1 4535 0.007599 0.199 0.6057
CDKN1A|P21 6958.5 0.007928 0.199 0.6051
DIABLO|SMAC 6954 0.008164 0.199 0.6047
BAX|BAX 6922 0.01003 0.199 0.6019
ERBB3|HER3_PY1298 4581 0.01022 0.199 0.6017
YAP1|YAP 4628 0.0137 0.24 0.5976
Clinical variable #15: 'TUMOR_SIZE'

2 genes related to 'TUMOR_SIZE'.

Table S24.  Basic characteristics of clinical feature: 'TUMOR_SIZE'

TUMOR_SIZE Mean (SD) 3.29 (1.6)
  Significant markers N = 2
  pos. correlated 0
  neg. correlated 2
List of 2 genes differentially expressed by 'TUMOR_SIZE'

Table S25.  Get Full Table List of 2 genes significantly correlated to 'TUMOR_SIZE' by Spearman correlation test

SpearmanCorr corrP Q
STAT5A|STAT5-ALPHA -0.215 0.002817 0.25
NFKB1|NF-KB-P65_PS536 -0.2147 0.002853 0.25
Clinical variable #16: 'RACE'

3 genes related to 'RACE'.

Table S26.  Basic characteristics of clinical feature: 'RACE'

RACE Labels N
  ASIAN 16
  BLACK OR AFRICAN AMERICAN 13
  WHITE 149
     
  Significant markers N = 3
List of 3 genes differentially expressed by 'RACE'

Table S27.  Get Full Table List of 3 genes differentially expressed by 'RACE'

kruskal_wallis_P Q
FOXO3|FOXO3A_PS318_S321 0.0002176 0.0381
|P-REX1 0.0005804 0.0508
EIF4EBP1|4E-BP1_PT70 0.001095 0.0639
Clinical variable #17: 'ETHNICITY'

No gene related to 'ETHNICITY'.

Table S28.  Basic characteristics of clinical feature: 'ETHNICITY'

ETHNICITY Labels N
  HISPANIC OR LATINO 16
  NOT HISPANIC OR LATINO 168
     
  Significant markers N = 0
Methods & Data
Input

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

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

  • Number of patients = 222

  • Number of genes = 175

  • Number of clinical features = 17

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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