Correlation between RPPA expression and clinical features
Liver Hepatocellular Carcinoma
14 July 2016  |  awg_lihc__2016_07_14
Maintainer Information
Citation Information
doi:10.7908/C18S4PF3
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/C18S4PF3
Overview
Introduction

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

Summary

Testing the association between 219 genes and 12 clinical features across 184 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 8 clinical features related to at least one genes.

  • 2 genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP'.

    • SERPINE1|PAI-1 ,  TUBA1B|ACETYL-A-TUBULIN-LYS40

  • 30 genes correlated to 'YEARS_TO_BIRTH'.

    • SETD2|SETD2 ,  CHEK2|CHK2 ,  MYC|C-MYC ,  NRAS|N-RAS ,  MAPK1|ERK2 ,  ...

  • 30 genes correlated to 'PATHOLOGIC_STAGE'.

    • YWHAB|14-3-3_BETA ,  MSH6|MSH6 ,  ACACA|ACC1 ,  PTPN11|SHP-2_PY542 ,  BAK1|BAK ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • YWHAB|14-3-3_BETA ,  MSH6|MSH6 ,  ABL1|C-ABL ,  PGR|PR ,  RAF1|C-RAF ,  ...

  • 30 genes correlated to 'PATHOLOGY_N_STAGE'.

    • EIF4G1|EIF4G ,  CDKN1B|P27 ,  XRCC5|KU80 ,  MAPK14|P38_PT180_Y182 ,  BCL2|BCL-2 ,  ...

  • 27 genes correlated to 'GENDER'.

    • BRCA2|BRCA2 ,  AKT1 AKT2 AKT3|AKT ,  PDCD4|PDCD4 ,  PXN|PAXILLIN ,  GAB2|GAB2 ,  ...

  • 30 genes correlated to 'HISTOLOGICAL_TYPE'.

    • FASN|FASN ,  RPS6|S6_PS235_S236 ,  PARP1|PARP1 ,  CHEK1|CHK1_PS345 ,  RPS6KA1|P90RSK ,  ...

  • 30 genes correlated to 'RACE'.

    • ACVRL1|ACVRL1 ,  HSPA1A|HSP70 ,  BAK1|BAK ,  YWHAB|14-3-3_BETA ,  MSH6|MSH6 ,  ...

  • No genes correlated to 'PATHOLOGY_M_STAGE', 'RADIATION_THERAPY', '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=2   N=NA   N=NA
YEARS_TO_BIRTH Spearman correlation test N=30 older N=21 younger N=9
PATHOLOGIC_STAGE Kruskal-Wallis test N=30        
PATHOLOGY_T_STAGE Spearman correlation test N=30 higher stage N=12 lower stage N=18
PATHOLOGY_N_STAGE Wilcoxon test N=30 n1 N=30 n0 N=0
PATHOLOGY_M_STAGE Wilcoxon test   N=0        
GENDER Wilcoxon test N=27 male N=27 female N=0
RADIATION_THERAPY Wilcoxon test   N=0        
HISTOLOGICAL_TYPE Kruskal-Wallis test N=30        
RESIDUAL_TUMOR Kruskal-Wallis test   N=0        
RACE Kruskal-Wallis test N=30        
ETHNICITY Wilcoxon test   N=0        
Clinical variable #1: 'DAYS_TO_DEATH_OR_LAST_FUP'

2 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) 0.2-114.3 (median=17.7)
  censored N = 90
  death N = 93
     
  Significant markers N = 2
  associated with shorter survival NA
  associated with longer survival NA
List of 2 genes differentially expressed by 'DAYS_TO_DEATH_OR_LAST_FUP'

Table S2.  Get Full Table List of 2 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
SERPINE1|PAI-1 1.38e-05 0.003 0.578
TUBA1B|ACETYL-A-TUBULIN-LYS40 0.00185 0.2 0.609
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) 60.42 (15)
  Significant markers N = 30
  pos. correlated 21
  neg. correlated 9
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
SETD2|SETD2 0.2887 7.752e-05 0.00832
CHEK2|CHK2 -0.2865 8.814e-05 0.00832
MYC|C-MYC 0.2821 0.000114 0.00832
NRAS|N-RAS 0.2688 0.000244 0.0107
MAPK1|ERK2 -0.2687 0.0002453 0.0107
MET|C-MET_PY1235 0.2646 0.0003061 0.0112
RAB25|RAB25 0.2581 0.0004363 0.0127
MSH6|MSH6 -0.257 0.0004624 0.0127
YWHAE|14-3-3_EPSILON 0.2502 0.0006577 0.0145
XRCC5|KU80 -0.2501 0.0006621 0.0145
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 71
  STAGE II 38
  STAGE III 3
  STAGE IIIA 45
  STAGE IIIB 6
  STAGE IIIC 6
  STAGE IV 2
  STAGE IVB 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
YWHAB|14-3-3_BETA 3.345e-05 0.00507
MSH6|MSH6 4.627e-05 0.00507
ACACA|ACC1 7.61e-05 0.0054
PTPN11|SHP-2_PY542 9.861e-05 0.0054
BAK1|BAK 0.0002379 0.00721
INPP4B|INPP4B 0.0002561 0.00721
EIF4EBP1|4E-BP1_PS65 0.0003248 0.00721
GSK3A GSK3B|GSK3-ALPHA-BETA 0.0003326 0.00721
PGR|PR 0.0004103 0.00721
MAPK1|ERK2 0.0004196 0.00721
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) 2.01 (0.96)
  N
  T1 74
  T2 43
  T3 57
  T4 9
     
  Significant markers N = 30
  pos. correlated 12
  neg. correlated 18
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
YWHAB|14-3-3_BETA -0.3458 1.631e-06 0.000357
MSH6|MSH6 0.3222 8.693e-06 0.000524
ABL1|C-ABL 0.318 1.147e-05 0.000524
PGR|PR -0.3143 1.471e-05 0.000524
RAF1|C-RAF 0.3122 1.685e-05 0.000524
INPP4B|INPP4B -0.3116 1.756e-05 0.000524
ACACA|ACC1 0.3084 2.159e-05 0.000524
BAK1|BAK -0.3081 2.211e-05 0.000524
BECN1|BECLIN -0.3076 2.284e-05 0.000524
NRG1|HEREGULIN -0.3068 2.394e-05 0.000524
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 Labels N
  N0 112
  N1 3
     
  Significant markers N = 30
  Higher in N1 30
  Higher in N0 0
List of top 10 genes differentially expressed by 'PATHOLOGY_N_STAGE'

Table S10.  Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGY_N_STAGE'

W(pos if higher in 'N1') wilcoxontestP Q AUC
EIF4G1|EIF4G 321 0.007454 0.261 0.9554
CDKN1B|P27 21 0.01015 0.261 0.9375
XRCC5|KU80 310 0.01303 0.261 0.9226
MAPK14|P38_PT180_Y182 29 0.01509 0.261 0.9137
BCL2|BCL-2 31 0.01662 0.261 0.9077
RPTOR|RAPTOR 305 0.01662 0.261 0.9077
MTOR|MTOR 303 0.01827 0.261 0.9018
MAPK8|JNK_PT183_PY185 34 0.01916 0.261 0.8988
BRAF|B-RAF 300 0.02103 0.261 0.8929
ANXA1|ANNEXIN-1 37 0.02203 0.261 0.8899
Clinical variable #6: 'PATHOLOGY_M_STAGE'

No gene related to 'PATHOLOGY_M_STAGE'.

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

PATHOLOGY_M_STAGE Labels N
  class0 132
  class1 3
     
  Significant markers N = 0
Clinical variable #7: 'GENDER'

27 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 70
  MALE 114
     
  Significant markers N = 27
  Higher in MALE 27
  Higher in FEMALE 0
List of top 10 genes differentially expressed by 'GENDER'

Table S13.  Get Full Table List of top 10 genes differentially expressed by 'GENDER'. 4 significant gene(s) located in sex chromosomes is(are) filtered out.

W(pos if higher in 'MALE') wilcoxontestP Q AUC
BRCA2|BRCA2 5342 0.0001166 0.0176 0.6694
AKT1 AKT2 AKT3|AKT 2710 0.0002644 0.0193 0.6604
PDCD4|PDCD4 2777 0.0005465 0.0235 0.652
PXN|PAXILLIN 2798 0.0006813 0.0235 0.6494
GAB2|GAB2 2814 0.000804 0.0235 0.6474
YWHAE|14-3-3_EPSILON 5157 0.0008818 0.0235 0.6462
SQSTM1|P62-LCK-LIGAND 5148 0.0009666 0.0235 0.6451
PRDX1|PRDX1 5124 0.001231 0.027 0.6421
FOXM1|FOXM1 5088 0.001754 0.0349 0.6376
RBM15|RBM15 2910 0.002086 0.0361 0.6353
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 165
  YES 3
     
  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
  FIBROLAMELLAR CARCINOMA 2
  HEPATOCELLULAR CARCINOMA 180
  HEPATOCHOLANGIOCARCINOMA (MIXED) 2
     
  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
FASN|FASN 0.007613 0.237
RPS6|S6_PS235_S236 0.0127 0.237
PARP1|PARP1 0.01294 0.237
CHEK1|CHK1_PS345 0.01309 0.237
RPS6KA1|P90RSK 0.01464 0.237
WWTR1|TAZ 0.01506 0.237
ITGA2|CD49B 0.01511 0.237
RPS6|S6_PS240_S244 0.01813 0.237
ERBB2|HER2_PY1248 0.019 0.237
ACACA ACACB|ACC_PS79 0.01983 0.237
Clinical variable #10: 'RESIDUAL_TUMOR'

No gene related to 'RESIDUAL_TUMOR'.

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

RESIDUAL_TUMOR Labels N
  R0 148
  R1 12
  R2 1
  RX 16
     
  Significant markers N = 0
Clinical variable #11: 'RACE'

30 genes related to 'RACE'.

Table S18.  Basic characteristics of clinical feature: 'RACE'

RACE Labels N
  ASIAN 52
  BLACK OR AFRICAN AMERICAN 12
  WHITE 113
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'RACE'

Table S19.  Get Full Table List of top 10 genes differentially expressed by 'RACE'

kruskal_wallis_P Q
ACVRL1|ACVRL1 5.46e-06 0.0012
HSPA1A|HSP70 0.0001854 0.0126
BAK1|BAK 0.0002054 0.0126
YWHAB|14-3-3_BETA 0.000294 0.0126
MSH6|MSH6 0.000406 0.0126
SRSF1|SF2 0.0004171 0.0126
PEA15|PEA15_PS116 0.0005053 0.0126
NRAS|N-RAS 0.0005667 0.0126
DIRAS3|DIRAS3 0.0007009 0.0126
XRCC5|KU80 0.000811 0.0126
Clinical variable #12: 'ETHNICITY'

No gene related to 'ETHNICITY'.

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

ETHNICITY Labels N
  HISPANIC OR LATINO 8
  NOT HISPANIC OR LATINO 162
     
  Significant markers N = 0
Methods & Data
Input

  • Expresson data file = LIHC.rppa.txt

  • Clinical data file = LIHC.merged_data.txt

  • Number of patients = 184

  • Number of genes = 219

  • 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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