Correlation between RPPA expression and clinical features
Skin Cutaneous Melanoma (Metastatic)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
doi:10.7908/C1251H8K
Maintained by Juok Cho (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2015): Correlation between RPPA expression and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C1251H8K
Overview
Introduction

This pipeline uses various statistical tests to identify RPPAs whose expression levels correlated to selected clinical features.

Summary

Testing the association between 181 genes and 12 clinical features across 169 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 7 clinical features related to at least one genes.

  • 20 genes correlated to 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP'.

    • NA|P27-R-V ,  NA|P27_PT198-R-V ,  NA|BIM-R-V ,  NA|ASNS-R-V ,  NA|GSK3_PS9-R-V ,  ...

  • 30 genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP'.

    • NA|P27-R-V ,  NA|TIGAR-R-V ,  NA|EEF2-R-C ,  NA|ER-ALPHA-R-V ,  NA|BIM-R-V ,  ...

  • 12 genes correlated to 'YEARS_TO_BIRTH'.

    • NA|ERK2-R-E ,  NA|FOXO3A-R-C ,  NA|CD49B-M-V ,  NA|PR-R-V ,  NA|HEREGULIN-R-V ,  ...

  • 30 genes correlated to 'PRIMARY_SITE_OF_DISEASE'.

    • NA|KU80-R-C ,  NA|CASPASE-7_CLEAVEDD198-R-C ,  NA|YB-1-R-V ,  NA|XBP1-G-C ,  NA|LCK-R-V ,  ...

  • 5 genes correlated to 'PATHOLOGY_N_STAGE'.

    • NA|TRANSGLUTAMINASE-M-V ,  NA|PDK1_PS241-R-V ,  NA|SMAD1-R-V ,  NA|S6_PS240_S244-R-V ,  NA|DJ-1-R-E

  • 15 genes correlated to 'MELANOMA_PRIMARY_KNOWN'.

    • NA|TUBERIN_PT1462-R-V ,  NA|TRANSGLUTAMINASE-M-V ,  NA|A-RAF_PS299-R-C ,  NA|MAPK_PT202_Y204-R-V ,  NA|MTOR_PS2448-R-C ,  ...

  • 30 genes correlated to 'BRESLOW_THICKNESS'.

    • NA|IGFBP2-R-V ,  NA|ASNS-R-V ,  NA|SRC_PY416-R-C ,  NA|PKC-DELTA_PS664-R-V ,  NA|ER-ALPHA-R-V ,  ...

  • No genes correlated to 'NEOPLASM_DISEASESTAGE', 'PATHOLOGY_T_STAGE', 'PATHOLOGY_M_STAGE', 'MELANOMA_ULCERATION', and 'GENDER'.

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
TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP Cox regression test N=20 shorter survival N=7 longer survival N=13
DAYS_TO_DEATH_OR_LAST_FUP Cox regression test N=30 shorter survival N=15 longer survival N=15
YEARS_TO_BIRTH Spearman correlation test N=12 older N=4 younger N=8
PRIMARY_SITE_OF_DISEASE Kruskal-Wallis test N=30        
NEOPLASM_DISEASESTAGE Kruskal-Wallis test   N=0        
PATHOLOGY_T_STAGE Spearman correlation test   N=0        
PATHOLOGY_N_STAGE Spearman correlation test N=5 higher stage N=4 lower stage N=1
PATHOLOGY_M_STAGE Wilcoxon test   N=0        
MELANOMA_ULCERATION Wilcoxon test   N=0        
MELANOMA_PRIMARY_KNOWN Wilcoxon test N=15 yes N=15 no N=0
BRESLOW_THICKNESS Spearman correlation test N=30 higher breslow_thickness N=13 lower breslow_thickness N=17
GENDER Wilcoxon test   N=0        
Clinical variable #1: 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP'

20 genes related to 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP'.

Table S1.  Basic characteristics of clinical feature: 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP'

TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP Duration (Months) 0.2-346.5 (median=52.7)
  censored N = 52
  death N = 67
     
  Significant markers N = 20
  associated with shorter survival 7
  associated with longer survival 13
List of top 10 genes differentially expressed by 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP'

Table S2.  Get Full Table List of top 10 genes significantly associated with 'Time from Specimen Diagnosis to Death' by Cox regression test

HazardRatio Wald_P Q C_index
NA|P27-R-V 0.14 0.0004862 0.064 0.362
NA|P27_PT198-R-V 0.1 0.0007071 0.064 0.364
NA|BIM-R-V 0.35 0.002256 0.14 0.379
NA|ASNS-R-V 0.63 0.004649 0.17 0.418
NA|GSK3_PS9-R-V 1.65 0.007004 0.17 0.587
NA|TUBERIN_PT1462-R-V 2.1 0.008216 0.17 0.571
NA|HER3_PY1289-R-C 0.11 0.008503 0.17 0.379
NA|LCK-R-V 0.58 0.008827 0.17 0.422
NA|C-MET_PY1235-R-V 0.08 0.00995 0.17 0.392
NA|AKT-R-V 1.88 0.01084 0.17 0.602
Clinical variable #2: 'DAYS_TO_DEATH_OR_LAST_FUP'

30 genes related to 'DAYS_TO_DEATH_OR_LAST_FUP'.

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

DAYS_TO_DEATH_OR_LAST_FUP Duration (Months) 0.2-369.9 (median=54.6)
  censored N = 73
  death N = 95
     
  Significant markers N = 30
  associated with shorter survival 15
  associated with longer survival 15
List of top 10 genes differentially expressed by 'DAYS_TO_DEATH_OR_LAST_FUP'

Table S4.  Get Full Table List of top 10 genes significantly associated with 'Time to Death' by Cox regression test

HazardRatio Wald_P Q C_index
NA|P27-R-V 0.14 2.624e-05 0.0047 0.359
NA|TIGAR-R-V 5.7 0.0002151 0.019 0.595
NA|EEF2-R-C 1.78 0.000309 0.019 0.632
NA|ER-ALPHA-R-V 0.32 0.0016 0.072 0.402
NA|BIM-R-V 0.45 0.00225 0.08 0.406
NA|P27_PT198-R-V 0.17 0.002643 0.08 0.421
NA|4E-BP1_PS65-R-V 2.3 0.004762 0.12 0.57
NA|CYCLIN_D1-R-V 3.2 0.006261 0.14 0.574
NA|AR-R-V 0.28 0.007024 0.14 0.379
NA|GSK3-ALPHA-BETA-M-V 2.9 0.008192 0.15 0.585
Clinical variable #3: 'YEARS_TO_BIRTH'

12 genes related to 'YEARS_TO_BIRTH'.

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

YEARS_TO_BIRTH Mean (SD) 55.28 (16)
  Significant markers N = 12
  pos. correlated 4
  neg. correlated 8
List of top 10 genes differentially expressed by 'YEARS_TO_BIRTH'

Table S6.  Get Full Table List of top 10 genes significantly correlated to 'YEARS_TO_BIRTH' by Spearman correlation test

SpearmanCorr corrP Q
NA|ERK2-R-E 0.2653 0.0005526 0.1
NA|FOXO3A-R-C -0.2366 0.00215 0.195
NA|CD49B-M-V -0.2186 0.004672 0.229
NA|PR-R-V -0.2166 0.005066 0.229
NA|HEREGULIN-R-V -0.2051 0.008042 0.254
NA|IGFBP2-R-V -0.2038 0.008432 0.254
NA|4E-BP1_PT70-R-V 0.1995 0.00996 0.258
NA|RB_PS807_S811-R-V 0.1889 0.01477 0.261
NA|P38_MAPK-R-V 0.188 0.01526 0.261
NA|HER2_PY1248-R-C -0.1872 0.01572 0.261
Clinical variable #4: 'PRIMARY_SITE_OF_DISEASE'

30 genes related to 'PRIMARY_SITE_OF_DISEASE'.

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

PRIMARY_SITE_OF_DISEASE Labels N
  DISTANT METASTASIS 22
  PRIMARY TUMOR 1
  REGIONAL CUTANEOUS OR SUBCUTANEOUS TISSUE 32
  REGIONAL LYMPH NODE 113
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'PRIMARY_SITE_OF_DISEASE'

Table S8.  Get Full Table List of top 10 genes differentially expressed by 'PRIMARY_SITE_OF_DISEASE'

kruskal_wallis_P Q
NA|KU80-R-C 2.424e-05 0.00439
NA|CASPASE-7_CLEAVEDD198-R-C 0.0003002 0.0222
NA|YB-1-R-V 0.0003678 0.0222
NA|XBP1-G-C 0.0005691 0.0258
NA|LCK-R-V 0.0007151 0.0259
NA|AR-R-V 0.002457 0.0741
NA|PCNA-M-C 0.003242 0.0838
NA|CLAUDIN-7-R-V 0.004179 0.0926
NA|SYK-M-V 0.004607 0.0926
NA|HSP70-R-C 0.005701 0.103
Clinical variable #5: 'NEOPLASM_DISEASESTAGE'

No gene related to 'NEOPLASM_DISEASESTAGE'.

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

NEOPLASM_DISEASESTAGE Labels N
  I OR II NOS 8
  STAGE 0 3
  STAGE I 14
  STAGE IA 8
  STAGE IB 17
  STAGE II 7
  STAGE IIA 5
  STAGE IIB 6
  STAGE IIC 3
  STAGE III 20
  STAGE IIIA 5
  STAGE IIIB 15
  STAGE IIIC 27
  STAGE IV 9
     
  Significant markers N = 0
Clinical variable #6: 'PATHOLOGY_T_STAGE'

No gene related to 'PATHOLOGY_T_STAGE'.

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

PATHOLOGY_T_STAGE Mean (SD) 2.3 (1.3)
  N
  T0 15
  T1 21
  T2 37
  T3 28
  T4 31
     
  Significant markers N = 0
Clinical variable #7: 'PATHOLOGY_N_STAGE'

5 genes related to 'PATHOLOGY_N_STAGE'.

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

PATHOLOGY_N_STAGE Mean (SD) 0.89 (1.1)
  N
  N0 85
  N1 24
  N2 26
  N3 21
     
  Significant markers N = 5
  pos. correlated 4
  neg. correlated 1
List of 5 genes differentially expressed by 'PATHOLOGY_N_STAGE'

Table S12.  Get Full Table List of 5 genes significantly correlated to 'PATHOLOGY_N_STAGE' by Spearman correlation test

SpearmanCorr corrP Q
NA|TRANSGLUTAMINASE-M-V 0.316 5.847e-05 0.0106
NA|PDK1_PS241-R-V 0.2352 0.003122 0.25
NA|SMAD1-R-V -0.2284 0.004137 0.25
NA|S6_PS240_S244-R-V 0.2137 0.007404 0.289
NA|DJ-1-R-E 0.2117 0.007986 0.289
Clinical variable #8: 'PATHOLOGY_M_STAGE'

No gene related to 'PATHOLOGY_M_STAGE'.

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

PATHOLOGY_M_STAGE Labels N
  class0 149
  class1 10
     
  Significant markers N = 0
Clinical variable #9: 'MELANOMA_ULCERATION'

No gene related to 'MELANOMA_ULCERATION'.

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

MELANOMA_ULCERATION Labels N
  NO 65
  YES 37
     
  Significant markers N = 0
Clinical variable #10: 'MELANOMA_PRIMARY_KNOWN'

15 genes related to 'MELANOMA_PRIMARY_KNOWN'.

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

MELANOMA_PRIMARY_KNOWN Labels N
  NO 25
  YES 144
     
  Significant markers N = 15
  Higher in YES 15
  Higher in NO 0
List of top 10 genes differentially expressed by 'MELANOMA_PRIMARY_KNOWN'

Table S16.  Get Full Table List of top 10 genes differentially expressed by 'MELANOMA_PRIMARY_KNOWN'

W(pos if higher in 'YES') wilcoxontestP Q AUC
NA|TUBERIN_PT1462-R-V 2493 0.002166 0.206 0.6925
NA|TRANSGLUTAMINASE-M-V 1155 0.004319 0.206 0.6792
NA|A-RAF_PS299-R-C 2444 0.004379 0.206 0.6789
NA|MAPK_PT202_Y204-R-V 2435 0.00496 0.206 0.6764
NA|MTOR_PS2448-R-C 2425 0.005686 0.206 0.6736
NA|SRC_PY527-R-V 2411 0.006865 0.207 0.6697
NA|AKT_PS473-R-V 2351 0.01478 0.268 0.6531
NA|FOXO3A_PS318_S321-R-C 2343 0.0163 0.268 0.6508
NA|PDK1_PS241-R-V 1260 0.0169 0.268 0.65
NA|HER2_PY1248-R-C 1277 0.02069 0.268 0.6453
Clinical variable #11: 'BRESLOW_THICKNESS'

30 genes related to 'BRESLOW_THICKNESS'.

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

BRESLOW_THICKNESS Mean (SD) 3.38 (5.3)
  Significant markers N = 30
  pos. correlated 13
  neg. correlated 17
List of top 10 genes differentially expressed by 'BRESLOW_THICKNESS'

Table S18.  Get Full Table List of top 10 genes significantly correlated to 'BRESLOW_THICKNESS' by Spearman correlation test

SpearmanCorr corrP Q
NA|IGFBP2-R-V -0.306 0.0007136 0.116
NA|ASNS-R-V -0.2919 0.001278 0.116
NA|SRC_PY416-R-C -0.2714 0.002826 0.133
NA|PKC-DELTA_PS664-R-V -0.2669 0.00334 0.133
NA|ER-ALPHA-R-V -0.2644 0.00367 0.133
NA|MRE11-R-C -0.2501 0.006092 0.156
NA|4E-BP1_PT70-R-V 0.2495 0.00622 0.156
NA|GSK3-ALPHA-BETA-M-V 0.2432 0.007693 0.156
NA|CD49B-M-V -0.241 0.00828 0.156
NA|AKT-R-V 0.2399 0.008591 0.156
Clinical variable #12: 'GENDER'

No gene related to 'GENDER'.

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

GENDER Labels N
  FEMALE 64
  MALE 105
     
  Significant markers N = 0
Methods & Data
Input

  • Expresson data file = SKCM-TM.rppa.txt

  • Clinical data file = SKCM-TM.merged_data.txt

  • Number of patients = 169

  • Number of genes = 181

  • Number of clinical features = 12

Selected clinical features

  • For clinical features selected for this analysis and their value conozzle.versions, please find a documentation on selected CDEs .

  • 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, Wald's test in univariate Cox regression analysis with proportional hazards model (Andersen and Gill 1982) was used to estimate the P values using the 'coxph' function in R. Kaplan-Meier survival curves were plot using the four quartile subgroups of patients based on expression levels

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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