Correlation between RPPA expression and clinical features
Lung Adenocarcinoma (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/C1XD1145
Overview
Introduction

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

Summary

Testing the association between 223 genes and 15 clinical features across 365 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 9 clinical features related to at least one genes.

  • 30 genes correlated to 'YEARS_TO_BIRTH'.

    • EIF4EBP1|4E-BP1 ,  MSH6|MSH6 ,  RPS6|S6 ,  EIF4EBP1|4E-BP1_PT70 ,  ARID1A|ARID1A ,  ...

  • 16 genes correlated to 'PATHOLOGIC_STAGE'.

    • EIF4EBP1|4E-BP1_PS65 ,  MAPK1 MAPK3|MAPK_PT202_Y204 ,  PDCD4|PDCD4 ,  EIF4G1|EIF4G ,  ITGA2|CD49B ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • AKT1 AKT2 AKT3|AKT_PS473 ,  ITGA2|CD49B ,  STAT3|STAT3_PY705 ,  MAPK1 MAPK3|MAPK_PT202_Y204 ,  RPS6|S6_PS235_S236 ,  ...

  • 22 genes correlated to 'PATHOLOGY_N_STAGE'.

    • CDKN1B|P27 ,  ACACA|ACC1 ,  CDKN1B|P27_PT157 ,  ARAF|A-RAF_PS299 ,  PDCD4|PDCD4 ,  ...

  • 28 genes correlated to 'GENDER'.

    • EGFR|EGFR ,  FASN|FASN ,  MTOR|MTOR_PS2448 ,  BAD|BAD_PS112 ,  RPS6KA1|P90RSK ,  ...

  • 24 genes correlated to 'HISTOLOGICAL_TYPE'.

    • NKX2-1|TTF1 ,  CCNB1|CYCLIN_B1 ,  FN1|FIBRONECTIN ,  YAP1|YAP_PS127 ,  RPS6KB1|P70S6K ,  ...

  • 30 genes correlated to 'YEAR_OF_TOBACCO_SMOKING_ONSET'.

    • CCNB1|CYCLIN_B1 ,  DIRAS3|ARHI ,  EIF4EBP1|4E-BP1_PT70 ,  CASP7|CASPASE-7_CLEAVEDD198 ,  EIF4EBP1|4E-BP1 ,  ...

  • 1 gene correlated to 'RESIDUAL_TUMOR'.

    • INPP4B|INPP4B

  • 30 genes correlated to 'ETHNICITY'.

    • EIF4EBP1|4E-BP1_PS65 ,  MSH6|MSH6 ,  TGM2|TRANSGLUTAMINASE ,  CHEK1|CHK1 ,  SQSTM1|P62-LCK-LIGAND ,  ...

  • No genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP', 'PATHOLOGY_M_STAGE', 'RADIATION_THERAPY', 'KARNOFSKY_PERFORMANCE_SCORE', 'NUMBER_PACK_YEARS_SMOKED', and '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=0        
YEARS_TO_BIRTH Spearman correlation test N=30 older N=12 younger N=18
PATHOLOGIC_STAGE Kruskal-Wallis test N=16        
PATHOLOGY_T_STAGE Spearman correlation test N=30 higher stage N=10 lower stage N=20
PATHOLOGY_N_STAGE Spearman correlation test N=22 higher stage N=12 lower stage N=10
PATHOLOGY_M_STAGE Wilcoxon test   N=0        
GENDER Wilcoxon test N=28 male N=28 female N=0
RADIATION_THERAPY Wilcoxon test   N=0        
KARNOFSKY_PERFORMANCE_SCORE Spearman correlation test   N=0        
HISTOLOGICAL_TYPE Kruskal-Wallis test N=24        
NUMBER_PACK_YEARS_SMOKED Spearman correlation test   N=0        
YEAR_OF_TOBACCO_SMOKING_ONSET Spearman correlation test N=30 higher year_of_tobacco_smoking_onset N=16 lower year_of_tobacco_smoking_onset N=14
RESIDUAL_TUMOR Kruskal-Wallis test N=1        
RACE Kruskal-Wallis test   N=0        
ETHNICITY Wilcoxon test N=30 not hispanic or latino N=30 hispanic or latino 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) 0.1-238.3 (median=23.2)
  censored N = 219
  death N = 145
     
  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) 64.37 (9.8)
  Significant markers N = 30
  pos. correlated 12
  neg. correlated 18
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
EIF4EBP1|4E-BP1 -0.2708 3.387e-07 7.55e-05
MSH6|MSH6 -0.2417 5.785e-06 0.000645
RPS6|S6 -0.2149 5.841e-05 0.00434
EIF4EBP1|4E-BP1_PT70 -0.2023 0.0001578 0.00712
ARID1A|ARID1A -0.2541 0.0001597 0.00712
CCNB1|CYCLIN_B1 -0.1989 0.0002055 0.00764
BIRC2 |CIAP -0.1963 0.0002496 0.00795
DVL3|DVL3 -0.1941 0.0002919 0.00814
AKT1 AKT2 AKT3|AKT_PS473 0.1864 0.00051 0.0126
YWHAZ|14-3-3_ZETA -0.1755 0.001081 0.0241
Clinical variable #3: 'PATHOLOGIC_STAGE'

16 genes related to 'PATHOLOGIC_STAGE'.

Table S4.  Basic characteristics of clinical feature: 'PATHOLOGIC_STAGE'

PATHOLOGIC_STAGE Labels N
  STAGE I 2
  STAGE IA 94
  STAGE IB 95
  STAGE II 1
  STAGE IIA 35
  STAGE IIB 51
  STAGE IIIA 57
  STAGE IIIB 8
  STAGE IV 17
     
  Significant markers N = 16
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
EIF4EBP1|4E-BP1_PS65 0.001154 0.202
MAPK1 MAPK3|MAPK_PT202_Y204 0.00181 0.202
PDCD4|PDCD4 0.002969 0.221
EIF4G1|EIF4G 0.004536 0.237
ITGA2|CD49B 0.005904 0.237
ERRFI1|MIG-6 0.007643 0.237
TSC2|TUBERIN_PT1462 0.008055 0.237
AKT1 AKT2 AKT3|AKT_PS473 0.008994 0.237
AKT1S1|PRAS40_PT246 0.01099 0.237
PIK3R1 PIK3R2|PI3K-P85 0.01101 0.237
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) 1.84 (0.74)
  N
  T1 117
  T2 203
  T3 28
  T4 16
     
  Significant markers N = 30
  pos. correlated 10
  neg. correlated 20
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
AKT1 AKT2 AKT3|AKT_PS473 -0.228 1.12e-05 0.0025
ITGA2|CD49B 0.2173 2.894e-05 0.00323
STAT3|STAT3_PY705 -0.2117 4.688e-05 0.00348
MAPK1 MAPK3|MAPK_PT202_Y204 -0.202 0.0001037 0.00578
RPS6|S6_PS235_S236 -0.1921 0.0002272 0.0101
ERRFI1|MIG-6 0.1868 0.0003404 0.0122
SRC|SRC_PY527 -0.1852 0.0003832 0.0122
MTOR|MTOR_PS2448 -0.1818 0.0004919 0.0135
SMAD1|SMAD1 0.1791 0.000597 0.0135
KDR|VEGFR2 0.1789 0.0006066 0.0135
Clinical variable #5: 'PATHOLOGY_N_STAGE'

22 genes related to 'PATHOLOGY_N_STAGE'.

Table S8.  Basic characteristics of clinical feature: 'PATHOLOGY_N_STAGE'

PATHOLOGY_N_STAGE Mean (SD) 0.54 (0.77)
  N
  N0 225
  N1 72
  N2 58
  N3 1
     
  Significant markers N = 22
  pos. correlated 12
  neg. correlated 10
List of top 10 genes differentially expressed by 'PATHOLOGY_N_STAGE'

Table S9.  Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY_N_STAGE' by Spearman correlation test

SpearmanCorr corrP Q
CDKN1B|P27 -0.1834 0.0005059 0.0601
ACACA|ACC1 0.1812 0.0005925 0.0601
CDKN1B|P27_PT157 -0.1768 0.0008091 0.0601
ARAF|A-RAF_PS299 0.1714 0.001164 0.0649
PDCD4|PDCD4 -0.1667 0.001598 0.0713
BCL2|BCL-2 -0.1602 0.002429 0.0903
ACACA ACACB|ACC_PS79 0.1562 0.003131 0.0997
ANXA1|ANNEXIN-1 0.1517 0.004121 0.115
VHL|VHL 0.1478 0.005211 0.129
TFRC|TFRC 0.1448 0.006201 0.138
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 259
  class1 17
     
  Significant markers N = 0
Clinical variable #7: 'GENDER'

28 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 196
  MALE 169
     
  Significant markers N = 28
  Higher in MALE 28
  Higher in FEMALE 0
List of top 10 genes differentially expressed by 'GENDER'

Table S12.  Get Full Table List of top 10 genes differentially expressed by 'GENDER'. 3 significant gene(s) located in sex chromosomes is(are) filtered out.

W(pos if higher in 'MALE') wilcoxontestP Q AUC
EGFR|EGFR 12166 1.225e-05 0.00183 0.6327
FASN|FASN 20894 1.637e-05 0.00183 0.6308
MTOR|MTOR_PS2448 12822 0.0001989 0.00883 0.6129
BAD|BAD_PS112 12860 0.0002309 0.00883 0.6118
RPS6KA1|P90RSK 12873 0.0002429 0.00883 0.6114
PRKCD|PKC-DELTA_PS664 12888 0.0002574 0.00883 0.6109
HSPA1A|HSP70 20217 0.0002771 0.00883 0.6103
PRKCB|PKC-PAN_BETAII_PS660 13155 0.0007012 0.0184 0.6029
MET|C-MET_PY1235 19820 0.001192 0.0266 0.5984
MAPK14|P38_MAPK 13341 0.001355 0.0268 0.5972
Clinical variable #8: 'RADIATION_THERAPY'

No gene related to 'RADIATION_THERAPY'.

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

RADIATION_THERAPY Labels N
  NO 284
  YES 46
     
  Significant markers N = 0
Clinical variable #9: 'KARNOFSKY_PERFORMANCE_SCORE'

No gene related to 'KARNOFSKY_PERFORMANCE_SCORE'.

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

KARNOFSKY_PERFORMANCE_SCORE Mean (SD) 76.97 (30)
  Significant markers N = 0
Clinical variable #10: 'HISTOLOGICAL_TYPE'

24 genes related to 'HISTOLOGICAL_TYPE'.

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

HISTOLOGICAL_TYPE Labels N
  LUNG ACINAR ADENOCARCINOMA 12
  LUNG ADENOCARCINOMA MIXED SUBTYPE 74
  LUNG ADENOCARCINOMA- NOT OTHERWISE SPECIFIED (NOS) 233
  LUNG BRONCHIOLOALVEOLAR CARCINOMA MUCINOUS 5
  LUNG BRONCHIOLOALVEOLAR CARCINOMA NONMUCINOUS 13
  LUNG CLEAR CELL ADENOCARCINOMA 1
  LUNG MICROPAPILLARY ADENOCARCINOMA 2
  LUNG MUCINOUS ADENOCARCINOMA 2
  LUNG PAPILLARY ADENOCARCINOMA 13
  LUNG SIGNET RING ADENOCARCINOMA 1
  LUNG SOLID PATTERN PREDOMINANT ADENOCARCINOMA 4
  MUCINOUS (COLLOID) CARCINOMA 5
     
  Significant markers N = 24
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
NKX2-1|TTF1 0.000165 0.0305
CCNB1|CYCLIN_B1 0.0002739 0.0305
FN1|FIBRONECTIN 0.002015 0.121
YAP1|YAP_PS127 0.002411 0.121
RPS6KB1|P70S6K 0.002721 0.121
PDCD4|PDCD4 0.004635 0.154
MSH6|MSH6 0.004835 0.154
RAB25|RAB25 0.006013 0.164
PDK1|PDK1 0.006629 0.164
CDH1|E-CADHERIN 0.007661 0.171
Clinical variable #11: 'NUMBER_PACK_YEARS_SMOKED'

No gene related to 'NUMBER_PACK_YEARS_SMOKED'.

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

NUMBER_PACK_YEARS_SMOKED Mean (SD) 41.94 (28)
  Significant markers N = 0
Clinical variable #12: 'YEAR_OF_TOBACCO_SMOKING_ONSET'

30 genes related to 'YEAR_OF_TOBACCO_SMOKING_ONSET'.

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

YEAR_OF_TOBACCO_SMOKING_ONSET Mean (SD) 1964.9 (13)
  Significant markers N = 30
  pos. correlated 16
  neg. correlated 14
List of top 10 genes differentially expressed by 'YEAR_OF_TOBACCO_SMOKING_ONSET'

Table S19.  Get Full Table List of top 10 genes significantly correlated to 'YEAR_OF_TOBACCO_SMOKING_ONSET' by Spearman correlation test

SpearmanCorr corrP Q
CCNB1|CYCLIN_B1 0.2603 0.0001634 0.0201
DIRAS3|ARHI -0.2587 0.0001803 0.0201
EIF4EBP1|4E-BP1_PT70 0.2382 0.0005846 0.0357
CASP7|CASPASE-7_CLEAVEDD198 0.2365 0.0006409 0.0357
EIF4EBP1|4E-BP1 0.2152 0.00194 0.0865
TGM2|TRANSGLUTAMINASE -0.2088 0.002667 0.0991
FOXO3|FOXO3A -0.1955 0.004963 0.124
NAPSA|NAPSIN-A -0.2487 0.004979 0.124
MAPK9|JNK2 -0.1953 0.005021 0.124
SERPINE1|PAI-1 0.192 0.005806 0.129
Clinical variable #13: 'RESIDUAL_TUMOR'

One gene related to 'RESIDUAL_TUMOR'.

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

RESIDUAL_TUMOR Labels N
  R0 235
  R1 10
  R2 3
  RX 21
     
  Significant markers N = 1
List of one gene differentially expressed by 'RESIDUAL_TUMOR'

Table S21.  Get Full Table List of one gene differentially expressed by 'RESIDUAL_TUMOR'

kruskal_wallis_P Q
INPP4B|INPP4B 0.00081 0.181
Clinical variable #14: 'RACE'

No gene related to 'RACE'.

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

RACE Labels N
  ASIAN 5
  BLACK OR AFRICAN AMERICAN 39
  WHITE 275
     
  Significant markers N = 0
Clinical variable #15: 'ETHNICITY'

30 genes related to 'ETHNICITY'.

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

ETHNICITY Labels N
  HISPANIC OR LATINO 6
  NOT HISPANIC OR LATINO 261
     
  Significant markers N = 30
  Higher in NOT HISPANIC OR LATINO 30
  Higher in HISPANIC OR LATINO 0
Methods & Data
Input
  • Expresson data file = LUAD-TP.rppa.txt

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

  • Number of patients = 365

  • Number of genes = 223

  • Number of clinical features = 15

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)