Correlation between RPPA expression and clinical features
Glioma (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/C1NV9HNQ
Overview
Introduction

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

Summary

Testing the association between 217 genes and 9 clinical features across 660 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 8 clinical features related to at least one genes.

  • 30 genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP'.

    • CCND1|CYCLIN_D1 ,  EGFR|EGFR ,  EGFR|EGFR_PY1068 ,  ERBB2|HER2_PY1248 ,  IGFBP2|IGFBP2 ,  ...

  • 30 genes correlated to 'YEARS_TO_BIRTH'.

    • ASNS|ASNS ,  IGFBP2|IGFBP2 ,  ANXA1|ANNEXIN-1 ,  PEA15|PEA15 ,  PARK7|DJ-1 ,  ...

  • 30 genes correlated to 'TUMOR_TISSUE_SITE'.

    • PGR|PR ,  BAD|BAD_PS112 ,  RPS6KA1|P90RSK ,  ACVRL1|ACVRL1 ,  TIGAR|TIGAR ,  ...

  • 29 genes correlated to 'GENDER'.

    • SHC1|SHC_PY317 ,  GSK3A GSK3B|GSK3-ALPHA-BETA ,  TSC2|TUBERIN ,  TSC1|TSC1 ,  BRAF|B-RAF ,  ...

  • 30 genes correlated to 'RADIATION_THERAPY'.

    • RPS6KA1|P90RSK ,  ERBB3|HER3_PY1289 ,  EIF4E|EIF4E ,  PRKCD|PKC-DELTA_PS664 ,  PRKCB|PKC-PAN_BETAII_PS660 ,  ...

  • 6 genes correlated to 'KARNOFSKY_PERFORMANCE_SCORE'.

    • ASNS|ASNS ,  IGFBP2|IGFBP2 ,  CTNNA1|ALPHA-CATENIN ,  COPS5|JAB1 ,  SCD1|SCD1 ,  ...

  • 30 genes correlated to 'HISTOLOGICAL_TYPE'.

    • SYK|SYK ,  BAD|BAD_PS112 ,  TIGAR|TIGAR ,  AR|AR ,  PGR|PR ,  ...

  • 7 genes correlated to 'ETHNICITY'.

    • SRC|SRC_PY527 ,  GSK3A GSK3B|GSK3_PS9 ,  EIF4EBP1|4E-BP1_PT37_T46 ,  GSK3A GSK3B|GSK3-ALPHA-BETA_PS21_S9 ,  MYH9|MYOSIN-IIA_PS1943__1 ,  ...

  • No genes correlated to 'RACE'

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=30   N=NA   N=NA
YEARS_TO_BIRTH Spearman correlation test N=30 older N=18 younger N=12
TUMOR_TISSUE_SITE Wilcoxon test N=30 central nervous system N=30 brain N=0
GENDER Wilcoxon test N=29 male N=29 female N=0
RADIATION_THERAPY Wilcoxon test N=30 yes N=30 no N=0
KARNOFSKY_PERFORMANCE_SCORE Spearman correlation test N=6 higher score N=4 lower score N=2
HISTOLOGICAL_TYPE Kruskal-Wallis test N=30        
RACE Kruskal-Wallis test   N=0        
ETHNICITY Wilcoxon test N=7 not hispanic or latino N=7 hispanic or latino N=0
Clinical variable #1: 'DAYS_TO_DEATH_OR_LAST_FUP'

30 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) 0-211.2 (median=16.9)
  censored N = 389
  death N = 270
     
  Significant markers N = 30
  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
CCND1|CYCLIN_D1 0 0 0.517
EGFR|EGFR 0 0 0.485
EGFR|EGFR_PY1068 0 0 0.473
ERBB2|HER2_PY1248 0 0 0.499
IGFBP2|IGFBP2 0 0 0.632
SERPINE1|PAI-1 0 0 0.584
MSH6|MSH6 1.11e-16 3.4e-15 0.46
CCNB1|CYCLIN_B1 1.22e-15 3.3e-14 0.519
ERBB2|HER2 2.08e-14 5e-13 0.527
EGFR|EGFR_PY1173 2.95e-14 6.4e-13 0.48
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) 48.63 (16)
  Significant markers N = 30
  pos. correlated 18
  neg. correlated 12
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
ASNS|ASNS 0.263 6.886e-12 1.49e-09
IGFBP2|IGFBP2 0.2371 7.088e-10 7.69e-08
ANXA1|ANNEXIN-1 0.2028 6.061e-06 0.000361
PEA15|PEA15 -0.1739 7.114e-06 0.000361
PARK7|DJ-1 -0.1726 8.324e-06 0.000361
PDCD4|PDCD4 -0.1659 1.873e-05 0.000677
SRC|SRC_PY527 -0.1609 3.333e-05 0.00103
SERPINE1|PAI-1 0.1524 8.548e-05 0.00232
CAV1|CAVEOLIN-1 0.1434 0.0002209 0.00533
FN1|FIBRONECTIN 0.1384 0.0003676 0.00798
Clinical variable #3: 'TUMOR_TISSUE_SITE'

30 genes related to 'TUMOR_TISSUE_SITE'.

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

TUMOR_TISSUE_SITE Labels N
  BRAIN 232
  CENTRAL NERVOUS SYSTEM 428
     
  Significant markers N = 30
  Higher in CENTRAL NERVOUS SYSTEM 30
  Higher in BRAIN 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 'CENTRAL NERVOUS SYSTEM') wilcoxontestP Q AUC
PGR|PR 36111 7.122e-09 1.55e-06 0.6363
BAD|BAD_PS112 62381 5.202e-08 5.64e-06 0.6282
RPS6KA1|P90RSK 61657 2.826e-07 2.04e-05 0.6209
ACVRL1|ACVRL1 38118.5 8.238e-07 4.47e-05 0.6161
TIGAR|TIGAR 60202 6.406e-06 0.000278 0.6063
CDH1|E-CADHERIN 39367 1.104e-05 0.000399 0.6035
RAB11A RAB11B|RAB11 59083 5.482e-05 0.0017 0.595
ESR1|ER-ALPHA_PS118 40758 0.0001441 0.00383 0.5895
SMAD1|SMAD1 58481 0.0001589 0.00383 0.589
STAT5A|STAT5-ALPHA 57894.5 0.0004221 0.00916 0.583
Clinical variable #4: 'GENDER'

29 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 283
  MALE 377
     
  Significant markers N = 29
  Higher in MALE 29
  Higher in FEMALE 0
List of top 10 genes differentially expressed by 'GENDER'

Table S8.  Get Full Table List of top 10 genes differentially expressed by 'GENDER'. 1 significant gene(s) located in sex chromosomes is(are) filtered out.

W(pos if higher in 'MALE') wilcoxontestP Q AUC
SHC1|SHC_PY317 67012 1.728e-08 3.75e-06 0.6281
GSK3A GSK3B|GSK3-ALPHA-BETA 42762 1.268e-05 0.00138 0.5992
TSC2|TUBERIN 43238 3.057e-05 0.00209 0.5947
TSC1|TSC1 43366 3.849e-05 0.00209 0.5935
BRAF|B-RAF 43502 4.902e-05 0.00213 0.5923
PRKAA1|AMPK_ALPHA 43854 9.038e-05 0.00327 0.589
RAF1|C-RAF 43959.5 0.0001081 0.00335 0.588
STAT5A|STAT5-ALPHA 44263 0.0001794 0.00487 0.5851
AKT1 AKT2 AKT3|AKT 44449 0.0002429 0.00586 0.5834
RBM15|RBM15 45068 0.0006395 0.0139 0.5776
Clinical variable #5: 'RADIATION_THERAPY'

30 genes related to 'RADIATION_THERAPY'.

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

RADIATION_THERAPY Labels N
  NO 181
  YES 431
     
  Significant markers N = 30
  Higher in YES 30
  Higher in NO 0
List of top 10 genes differentially expressed by 'RADIATION_THERAPY'

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

W(pos if higher in 'YES') wilcoxontestP Q AUC
RPS6KA1|P90RSK 30994 5.995e-05 0.013 0.6027
ERBB3|HER3_PY1289 32152.5 0.0005977 0.0648 0.5878
EIF4E|EIF4E 45192.5 0.001941 0.111 0.5793
PRKCD|PKC-DELTA_PS664 32999 0.002624 0.111 0.577
PRKCB|PKC-PAN_BETAII_PS660 33081 0.003002 0.111 0.5759
BAX|BAX 44756 0.003972 0.111 0.5737
XRCC1|XRCC1 44711 0.004265 0.111 0.5731
CCNE1|CYCLIN_E1 44707 0.004292 0.111 0.5731
SCD1|SCD1 15406 0.004619 0.111 0.5846
CAV1|CAVEOLIN-1 44416 0.006727 0.131 0.5694
Clinical variable #6: 'KARNOFSKY_PERFORMANCE_SCORE'

6 genes related to 'KARNOFSKY_PERFORMANCE_SCORE'.

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

KARNOFSKY_PERFORMANCE_SCORE Mean (SD) 80.98 (16)
  Significant markers N = 6
  pos. correlated 4
  neg. correlated 2
List of 6 genes differentially expressed by 'KARNOFSKY_PERFORMANCE_SCORE'

Table S12.  Get Full Table List of 6 genes significantly correlated to 'KARNOFSKY_PERFORMANCE_SCORE' by Spearman correlation test

SpearmanCorr corrP Q
ASNS|ASNS -0.2222 4.64e-06 0.00101
IGFBP2|IGFBP2 -0.1573 0.001269 0.131
CTNNA1|ALPHA-CATENIN 0.1938 0.002362 0.131
COPS5|JAB1 0.271 0.002994 0.131
SCD1|SCD1 0.1911 0.00301 0.131
G6PD|G6PD 0.1308 0.007472 0.27
Clinical variable #7: 'HISTOLOGICAL_TYPE'

30 genes related to 'HISTOLOGICAL_TYPE'.

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

HISTOLOGICAL_TYPE Labels N
  ASTROCYTOMA 147
  GLIOBLASTOMA MULTIFORME (GBM) 19
  OLIGOASTROCYTOMA 114
  OLIGODENDROGLIOMA 167
  TREATED PRIMARY GBM 3
  UNTREATED PRIMARY (DE NOVO) GBM 210
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'HISTOLOGICAL_TYPE'

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

kruskal_wallis_P Q
SYK|SYK 4.629e-17 1e-14
BAD|BAD_PS112 4.245e-10 4.61e-08
TIGAR|TIGAR 1.041e-08 7.53e-07
AR|AR 1.419e-08 7.7e-07
PGR|PR 2.352e-08 1.02e-06
ANXA1|ANNEXIN-1 1.308e-07 4.73e-06
BAX|BAX 1.711e-07 5.31e-06
MAPK14|P38_MAPK 4.873e-07 1.32e-05
PRDX1|PRDX1 5.637e-07 1.36e-05
RPS6KA1|P90RSK 6.74e-07 1.46e-05
Clinical variable #8: 'RACE'

No gene related to 'RACE'.

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

RACE Labels N
  AMERICAN INDIAN OR ALASKA NATIVE 1
  ASIAN 12
  BLACK OR AFRICAN AMERICAN 45
  WHITE 578
     
  Significant markers N = 0
Clinical variable #9: 'ETHNICITY'

7 genes related to 'ETHNICITY'.

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

ETHNICITY Labels N
  HISPANIC OR LATINO 29
  NOT HISPANIC OR LATINO 573
     
  Significant markers N = 7
  Higher in NOT HISPANIC OR LATINO 7
  Higher in HISPANIC OR LATINO 0
Methods & Data
Input
  • Expresson data file = GBMLGG-TP.rppa.txt

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

  • Number of patients = 660

  • Number of genes = 217

  • Number of clinical features = 9

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)