Correlation between RPPA expression and clinical features
Stomach and Esophageal carcinoma (Primary solid tumor)
28 January 2016  |  analyses__2016_01_28
Maintainer Information
Citation Information
doi:10.7908/C17D2TM4
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/C17D2TM4
Overview
Introduction

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

Summary

Testing the association between 196 genes and 12 clinical features across 483 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 11 clinical features related to at least one genes.

  • 13 genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP'.

    • MYH9|MYOSIN-IIA_PS1943 ,  SYK|SYK ,  RPS6KA1|P90RSK ,  RICTOR|RICTOR ,  CLDN7|CLAUDIN-7 ,  ...

  • 30 genes correlated to 'YEARS_TO_BIRTH'.

    • BIRC2 |CIAP ,  SRC|SRC_PY416 ,  CLDN7|CLAUDIN-7 ,  RPS6|S6_PS235_S236 ,  PEA15|PEA15 ,  ...

  • 30 genes correlated to 'PATHOLOGIC_STAGE'.

    • MAP2K1|MEK1_PS217_S221 ,  SRC|SRC_PY527 ,  CTNNB1|ALPHA-CATENIN ,  BIRC2 |CIAP ,  RICTOR|RICTOR ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • RB1|RB_PS807_S811 ,  PEA15|PEA15 ,  CTNNB1|ALPHA-CATENIN ,  SRC|SRC_PY416 ,  SRC|SRC_PY527 ,  ...

  • 5 genes correlated to 'PATHOLOGY_N_STAGE'.

    • EIF4EBP1|4E-BP1 ,  MS4A1|CD20 ,  MYH11|MYH11 ,  TGM2|TRANSGLUTAMINASE ,  SMAD3|SMAD3

  • 27 genes correlated to 'PATHOLOGY_M_STAGE'.

    • FOXO3|FOXO3A_PS318_S321 ,  STAT3|STAT3_PY705 ,  ERBB2|HER2_PY1248 ,  CHEK1|CHK1 ,  SRC|SRC_PY527 ,  ...

  • 3 genes correlated to 'GENDER'.

    • CDKN1A|P21 ,  ERBB3|HER3_PY1289 ,  ERBB2|HER2

  • 1 gene correlated to 'RADIATION_THERAPY'.

    • CDKN1A|P21

  • 4 genes correlated to 'KARNOFSKY_PERFORMANCE_SCORE'.

    • CDKN1A|P21 ,  PIK3CA |PI3K-P110-ALPHA ,  RAF1|C-RAF ,  EIF4EBP1|4E-BP1_PT37_T46

  • 6 genes correlated to 'NUMBER_PACK_YEARS_SMOKED'.

    • CCNB1|CYCLIN_B1 ,  FASN|FASN ,  ACACA|ACC1 ,  KIT|C-KIT ,  BCL2L1|BCL-XL ,  ...

  • 30 genes correlated to 'RACE'.

    • SMAD3|SMAD3 ,  PIK3CA |PI3K-P110-ALPHA ,  FASN|FASN ,  EGFR|EGFR ,  FOXM1|FOXM1 ,  ...

  • No genes correlated to '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=13   N=NA   N=NA
YEARS_TO_BIRTH Spearman correlation test N=30 older N=15 younger N=15
PATHOLOGIC_STAGE Kruskal-Wallis test N=30        
PATHOLOGY_T_STAGE Spearman correlation test N=30 higher stage N=16 lower stage N=14
PATHOLOGY_N_STAGE Spearman correlation test N=5 higher stage N=4 lower stage N=1
PATHOLOGY_M_STAGE Wilcoxon test N=27 class1 N=27 class0 N=0
GENDER Wilcoxon test N=3 male N=3 female N=0
RADIATION_THERAPY Wilcoxon test N=1 yes N=1 no N=0
KARNOFSKY_PERFORMANCE_SCORE Spearman correlation test N=4 higher score N=2 lower score N=2
NUMBER_PACK_YEARS_SMOKED Spearman correlation test N=6 higher number_pack_years_smoked N=3 lower number_pack_years_smoked N=3
RACE Kruskal-Wallis test N=30        
ETHNICITY Wilcoxon test   N=0        
Clinical variable #1: 'DAYS_TO_DEATH_OR_LAST_FUP'

13 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) 0.1-122.3 (median=13.5)
  censored N = 294
  death N = 188
     
  Significant markers N = 13
  associated with shorter survival NA
  associated with longer survival NA
List of top 10 genes differentially expressed by 'DAYS_TO_DEATH_OR_LAST_FUP'

Table S2.  Get Full Table List of top 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
MYH9|MYOSIN-IIA_PS1943 5.09e-05 0.01 0.432
SYK|SYK 0.00202 0.14 0.432
RPS6KA1|P90RSK 0.00216 0.14 0.437
RICTOR|RICTOR 0.00306 0.15 0.553
CLDN7|CLAUDIN-7 0.00491 0.19 0.44
ACACA|ACC1 0.00637 0.19 0.443
CDKN1B|P27 0.00674 0.19 0.535
MS4A1|CD20 0.0118 0.27 0.581
ESR1|ER-ALPHA_PS118 0.0124 0.27 0.579
PRDX1|PRDX1 0.0154 0.29 0.459
Clinical variable #2: 'YEARS_TO_BIRTH'

30 genes related to 'YEARS_TO_BIRTH'.

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

YEARS_TO_BIRTH Mean (SD) 64.88 (11)
  Significant markers N = 30
  pos. correlated 15
  neg. correlated 15
List of top 10 genes differentially expressed by 'YEARS_TO_BIRTH'

Table S4.  Get Full Table List of top 10 genes significantly correlated to 'YEARS_TO_BIRTH' by Spearman correlation test

SpearmanCorr corrP Q
BIRC2 |CIAP 0.1886 3.516e-05 0.00689
SRC|SRC_PY416 0.1746 0.0001311 0.0128
CLDN7|CLAUDIN-7 0.1581 0.0005432 0.0355
RPS6|S6_PS235_S236 0.1499 0.001052 0.0515
PEA15|PEA15 -0.1392 0.002361 0.0925
KIT|C-KIT -0.133 0.003682 0.12
SRC|SRC_PY527 0.1281 0.00517 0.13
IGFBP2|IGFBP2 -0.1277 0.005312 0.13
ASNS|ASNS 0.1199 0.008905 0.194
RPS6KA1|P90RSK 0.1175 0.01036 0.203
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 8
  STAGE IA 14
  STAGE IB 36
  STAGE II 30
  STAGE IIA 74
  STAGE IIB 67
  STAGE III 19
  STAGE IIIA 79
  STAGE IIIB 58
  STAGE IIIC 34
  STAGE IV 36
  STAGE IVA 1
     
  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
MAP2K1|MEK1_PS217_S221 2.512e-05 0.00291
SRC|SRC_PY527 2.971e-05 0.00291
CTNNB1|ALPHA-CATENIN 7.597e-05 0.00496
BIRC2 |CIAP 0.0001769 0.00867
RICTOR|RICTOR 0.0008551 0.0283
BCL2L1|BCL-XL 0.0008648 0.0283
RB1|RB_PS807_S811 0.001243 0.0348
PEA15|PEA15 0.00161 0.0385
MAPK1 MAPK3|MAPK_PT202_Y204 0.001841 0.0385
TGM2|TRANSGLUTAMINASE 0.002234 0.0385
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) 2.85 (0.84)
  N
  T1 32
  T2 111
  T3 225
  T4 103
     
  Significant markers N = 30
  pos. correlated 16
  neg. correlated 14
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
RB1|RB_PS807_S811 -0.2417 1.092e-07 1.29e-05
PEA15|PEA15 0.2402 1.318e-07 1.29e-05
CTNNB1|ALPHA-CATENIN -0.2219 1.155e-06 7.54e-05
SRC|SRC_PY416 -0.2053 7.033e-06 0.000345
SRC|SRC_PY527 -0.183 6.482e-05 0.00216
MYH11|MYH11 0.1828 6.61e-05 0.00216
TGM2|TRANSGLUTAMINASE 0.1801 8.485e-05 0.00238
ACVRL1|ACVRL1 0.1763 0.00012 0.00294
BIRC2 |CIAP -0.1633 0.0003737 0.00754
CLDN7|CLAUDIN-7 -0.1625 0.0003995 0.00754
Clinical variable #5: 'PATHOLOGY_N_STAGE'

5 genes related to 'PATHOLOGY_N_STAGE'.

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

PATHOLOGY_N_STAGE Mean (SD) 1.11 (1.1)
  N
  N0 171
  N1 145
  N2 74
  N3 74
     
  Significant markers N = 5
  pos. correlated 4
  neg. correlated 1
List of 5 genes differentially expressed by 'PATHOLOGY_N_STAGE'

Table S10.  Get Full Table List of 5 genes significantly correlated to 'PATHOLOGY_N_STAGE' by Spearman correlation test

SpearmanCorr corrP Q
EIF4EBP1|4E-BP1 -0.1549 0.0008154 0.16
MS4A1|CD20 0.1399 0.002528 0.248
MYH11|MYH11 0.1339 0.003867 0.253
TGM2|TRANSGLUTAMINASE 0.1274 0.005981 0.277
SMAD3|SMAD3 0.1249 0.007072 0.277
Clinical variable #6: 'PATHOLOGY_M_STAGE'

27 genes related to 'PATHOLOGY_M_STAGE'.

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

PATHOLOGY_M_STAGE Labels N
  class0 427
  class1 25
     
  Significant markers N = 27
  Higher in class1 27
  Higher in class0 0
List of top 10 genes differentially expressed by 'PATHOLOGY_M_STAGE'

Table S12.  Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGY_M_STAGE'

W(pos if higher in 'class1') wilcoxontestP Q AUC
FOXO3|FOXO3A_PS318_S321 7452 0.000868 0.132 0.6981
STAT3|STAT3_PY705 7346 0.001561 0.132 0.6881
ERBB2|HER2_PY1248 7259 0.002477 0.132 0.68
CHEK1|CHK1 3472 0.003304 0.132 0.6748
SRC|SRC_PY527 7196 0.003424 0.132 0.6741
MAPK1 MAPK3|MAPK_PT202_Y204 7163 0.004042 0.132 0.671
PRKCA |PKC-ALPHA_PS657 6973 0.01001 0.247 0.6532
ERBB2|HER2 6971 0.0101 0.247 0.653
SHC1|SHC_PY317 6944 0.01141 0.247 0.6505
ASNS|ASNS 3803 0.01567 0.247 0.6437
Clinical variable #7: 'GENDER'

3 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 139
  MALE 344
     
  Significant markers N = 3
  Higher in MALE 3
  Higher in FEMALE 0
List of 3 genes differentially expressed by 'GENDER'

Table S14.  Get Full Table List of 3 genes differentially expressed by 'GENDER'. 0 significant gene(s) located in sex chromosomes is(are) filtered out.

W(pos if higher in 'MALE') wilcoxontestP Q AUC
CDKN1A|P21 18743 0.0002001 0.0392 0.608
ERBB3|HER3_PY1289 19849 0.003473 0.241 0.5849
ERBB2|HER2 27940 0.003696 0.241 0.5843
Clinical variable #8: 'RADIATION_THERAPY'

One gene related to 'RADIATION_THERAPY'.

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

RADIATION_THERAPY Labels N
  NO 349
  YES 89
     
  Significant markers N = 1
  Higher in YES 1
  Higher in NO 0
List of one gene differentially expressed by 'RADIATION_THERAPY'

Table S16.  Get Full Table List of one gene differentially expressed by 'RADIATION_THERAPY'

W(pos if higher in 'YES') wilcoxontestP Q AUC
CDKN1A|P21 11850 0.000556 0.109 0.6185
Clinical variable #9: 'KARNOFSKY_PERFORMANCE_SCORE'

4 genes related to 'KARNOFSKY_PERFORMANCE_SCORE'.

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

KARNOFSKY_PERFORMANCE_SCORE Mean (SD) 69.17 (16)
  Significant markers N = 4
  pos. correlated 2
  neg. correlated 2
List of 4 genes differentially expressed by 'KARNOFSKY_PERFORMANCE_SCORE'

Table S18.  Get Full Table List of 4 genes significantly correlated to 'KARNOFSKY_PERFORMANCE_SCORE' by Spearman correlation test

SpearmanCorr corrP Q
CDKN1A|P21 0.6852 7.755e-08 1.52e-05
PIK3CA |PI3K-P110-ALPHA -0.5046 0.0002549 0.025
RAF1|C-RAF -0.4172 0.003174 0.192
EIF4EBP1|4E-BP1_PT37_T46 0.4087 0.003923 0.192
Clinical variable #10: 'NUMBER_PACK_YEARS_SMOKED'

6 genes related to 'NUMBER_PACK_YEARS_SMOKED'.

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

NUMBER_PACK_YEARS_SMOKED Mean (SD) 36.39 (21)
  Significant markers N = 6
  pos. correlated 3
  neg. correlated 3
List of 6 genes differentially expressed by 'NUMBER_PACK_YEARS_SMOKED'

Table S20.  Get Full Table List of 6 genes significantly correlated to 'NUMBER_PACK_YEARS_SMOKED' by Spearman correlation test

SpearmanCorr corrP Q
CCNB1|CYCLIN_B1 -0.3691 0.002294 0.263
FASN|FASN -0.3443 0.004641 0.263
ACACA|ACC1 -0.3415 0.005015 0.263
KIT|C-KIT 0.3315 0.006548 0.263
BCL2L1|BCL-XL 0.3281 0.007163 0.263
RPTOR|RAPTOR 0.3236 0.008049 0.263
Clinical variable #11: 'RACE'

30 genes related to 'RACE'.

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

RACE Labels N
  ASIAN 109
  BLACK OR AFRICAN AMERICAN 7
  NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER 1
  WHITE 305
     
  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
SMAD3|SMAD3 2.655e-06 0.00052
PIK3CA |PI3K-P110-ALPHA 9.685e-05 0.00949
FASN|FASN 0.000221 0.0144
EGFR|EGFR 0.0007465 0.0366
FOXM1|FOXM1 0.001347 0.0528
SRC|SRC_PY416 0.002176 0.0711
EEF2K|EEF2K 0.003293 0.0888
TUBA1B|ACETYL-A-TUBULIN-LYS40 0.003626 0.0888
CCND1|CYCLIN_D1 0.005269 0.112
NOTCH1|NOTCH1 0.005963 0.112
Clinical variable #12: 'ETHNICITY'

No gene related to 'ETHNICITY'.

Table S23.  Basic characteristics of clinical feature: 'ETHNICITY'

ETHNICITY Labels N
  HISPANIC OR LATINO 4
  NOT HISPANIC OR LATINO 323
     
  Significant markers N = 0
Methods & Data
Input

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

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

  • Number of patients = 483

  • Number of genes = 196

  • 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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