Correlation between mRNAseq expression and clinical features
Uterine Corpus Endometrioid Carcinoma (Primary solid tumor)
04 October 2018  |  None
Maintainer Information
Maintained by Broad Institute GDAC (Broad Institute of MIT & Harvard)
Overview
Introduction

This pipeline uses various statistical tests to identify mRNAs whose log2 expression levels correlated to selected clinical features. The input file "CPTAC3-UCEC-TP.mRNA_FPKM_log2_protein.coding.txt" is generated in the pipeline mRNAseq_Preprocess in the stddata run.

Summary

Testing the association between 18424 genes and 17 clinical features across 100 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 'HISTOLOGICAL_TYPE'.

    • SENP5|ENSG00000119231.9 ,  ZNF516|ENSG00000101493.9 ,  CERS5|ENSG00000139624.11 ,  IHH|ENSG00000163501.6 ,  GNB5|ENSG00000069966.17 ,  ...

  • 30 genes correlated to 'KARNOFSKY_PERFORMANCE_SCORE'.

    • SLC12A9|ENSG00000146828.16 ,  PDPK1|ENSG00000140992.17 ,  SLC8A2|ENSG00000118160.12 ,  TAF6|ENSG00000106290.13 ,  IRAK1|ENSG00000184216.10 ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • PSG9|ENSG00000183668.16 ,  SEPSECS|ENSG00000109618.10 ,  CARM1|ENSG00000142453.10 ,  KIAA1210|ENSG00000250423.2 ,  TAS2R9|ENSG00000121381.3 ,  ...

  • 30 genes correlated to 'YEARS_TO_BIRTH'.

    • OBSCN|ENSG00000154358.18 ,  ARL4A|ENSG00000122644.11 ,  RASSF6|ENSG00000169435.12 ,  CHP1|ENSG00000187446.10 ,  CHODL|ENSG00000154645.12 ,  ...

  • 30 genes correlated to 'RADIATION_THERAPY'.

    • ZBTB10|ENSG00000205189.10 ,  PSMC3|ENSG00000165916.7 ,  SCYL1|ENSG00000142186.15 ,  BCL7C|ENSG00000099385.10 ,  RAPGEF5|ENSG00000136237.17 ,  ...

  • 30 genes correlated to 'DIABETES'.

    • THOC5|ENSG00000100296.12 ,  UBP1|ENSG00000153560.10 ,  LRP1B|ENSG00000168702.15 ,  CHAMP1|ENSG00000198824.5 ,  ZNF653|ENSG00000161914.8 ,  ...

  • 6 genes correlated to 'NUMBER_PACK_YEARS_SMOKED'.

    • STX1A|ENSG00000106089.10 ,  C14ORF169|ENSG00000170468.7 ,  WIPF2|ENSG00000171475.12 ,  COL17A1|ENSG00000065618.15 ,  AQP4|ENSG00000171885.12 ,  ...

  • 2 genes correlated to 'COUNTRY_OF_ORIGIN'.

    • HBB|ENSG00000244734.2 ,  HBA2|ENSG00000188536.11

  • No genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP', 'FIGO_GRADE', 'MSI', 'PATHOLOGY_N_STAGE', 'PATHOLOGIC_STAGE', 'ETHNICITY', 'RACE', 'BMI', and 'SMOKER'.

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        
HISTOLOGICAL_TYPE Kruskal-Wallis test N=30        
FIGO_GRADE Kruskal-Wallis test   N=0        
KARNOFSKY_PERFORMANCE_SCORE Spearman correlation test N=30 higher score N=10 lower score N=20
MSI Kruskal-Wallis test   N=0        
PATHOLOGY_T_STAGE Spearman correlation test N=30 higher stage N=10 lower stage N=20
PATHOLOGY_N_STAGE Spearman correlation test   N=0        
PATHOLOGIC_STAGE Kruskal-Wallis test   N=0        
YEARS_TO_BIRTH Spearman correlation test N=30 older N=12 younger N=18
ETHNICITY Wilcoxon test   N=0        
RACE Kruskal-Wallis test   N=0        
RADIATION_THERAPY Wilcoxon test N=30 yes N=30 no N=0
DIABETES Wilcoxon test N=30 yes N=30 no N=0
BMI Kruskal-Wallis test   N=0        
NUMBER_PACK_YEARS_SMOKED Spearman correlation test N=6 higher number_pack_years_smoked N=3 lower number_pack_years_smoked N=3
SMOKER Wilcoxon test   N=0        
COUNTRY_OF_ORIGIN Kruskal-Wallis test N=2        
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) 0-130.4 (median=11.6)
  censored N = 95
  death N = 3
     
  Significant markers N = 0
Clinical variable #2: 'HISTOLOGICAL_TYPE'

30 genes related to 'HISTOLOGICAL_TYPE'.

Table S2.  Basic characteristics of clinical feature: 'HISTOLOGICAL_TYPE'

HISTOLOGICAL_TYPE Labels N
  CLEAR CELL CARCINOMA 1
  ENDOMETRIOID CARCINOMA 77
  MIXED CELL ADENOCARCINOMA 1
  SEROUS CARCINOMA 21
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'HISTOLOGICAL_TYPE'

Clinical variable #3: 'FIGO_GRADE'

No gene related to 'FIGO_GRADE'.

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

FIGO_GRADE Labels N
  FIGO GRADE 1 32
  FIGO GRADE 2 34
  FIGO GRADE 3 7
     
  Significant markers N = 0
Clinical variable #4: 'KARNOFSKY_PERFORMANCE_SCORE'

30 genes related to 'KARNOFSKY_PERFORMANCE_SCORE'.

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

KARNOFSKY_PERFORMANCE_SCORE Mean (SD) 91.9 (8.5)
  Score N
  60 1
  70 3
  80 1
  90 32
  100 21
     
  Significant markers N = 30
  pos. correlated 10
  neg. correlated 20
List of top 10 genes differentially expressed by 'KARNOFSKY_PERFORMANCE_SCORE'

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

SpearmanCorr corrP Q
SLC12A9|ENSG00000146828.16 -0.5795 1.878e-06 0.0188
PDPK1|ENSG00000140992.17 -0.5656 3.713e-06 0.0188
SLC8A2|ENSG00000118160.12 0.5767 4.063e-06 0.0188
TAF6|ENSG00000106290.13 -0.5581 5.323e-06 0.0188
IRAK1|ENSG00000184216.10 -0.551 7.41e-06 0.0188
DUSP1|ENSG00000120129.5 0.5475 8.698e-06 0.0188
TBL2|ENSG00000106638.14 -0.5461 9.263e-06 0.0188
ANKRD13D|ENSG00000172932.13 -0.5434 1.046e-05 0.0188
POM121|ENSG00000196313.10 -0.5431 1.06e-05 0.0188
UBL3|ENSG00000122042.9 0.5423 1.095e-05 0.0188
Clinical variable #5: 'MSI'

No gene related to 'MSI'.

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

MSI Labels N
  MSI-H 4
  MSI-L 5
  MSS 23
     
  Significant markers N = 0
Clinical variable #6: 'PATHOLOGY_T_STAGE'

30 genes related to 'PATHOLOGY_T_STAGE'.

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

PATHOLOGY_T_STAGE Mean (SD) 1.31 (0.65)
  N
  T1 78
  T2 11
  T3 10
     
  Significant markers N = 30
  pos. correlated 10
  neg. correlated 20
List of top 10 genes differentially expressed by 'PATHOLOGY_T_STAGE'

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

SpearmanCorr corrP Q
PSG9|ENSG00000183668.16 0.6301 2.247e-05 0.167
SEPSECS|ENSG00000109618.10 -0.4099 2.519e-05 0.167
CARM1|ENSG00000142453.10 0.3965 4.848e-05 0.167
KIAA1210|ENSG00000250423.2 -0.3986 5.271e-05 0.167
TAS2R9|ENSG00000121381.3 -0.4257 5.42e-05 0.167
IL11|ENSG00000095752.5 0.3957 6.03e-05 0.167
ELL|ENSG00000105656.11 0.3908 6.346e-05 0.167
SLC27A6|ENSG00000113396.11 -0.3866 8.404e-05 0.173
ZNF641|ENSG00000167528.11 -0.3847 8.46e-05 0.173
PKDCC|ENSG00000162878.11 -0.3717 0.0001521 0.248
Clinical variable #7: 'PATHOLOGY_N_STAGE'

No gene related to 'PATHOLOGY_N_STAGE'.

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

PATHOLOGY_N_STAGE Mean (SD) 0.22 (0.53)
  N
  N0 46
  N1 6
  N2 3
     
  Significant markers N = 0
Clinical variable #8: 'PATHOLOGIC_STAGE'

No gene related to 'PATHOLOGIC_STAGE'.

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

PATHOLOGIC_STAGE Labels N
  STAGE I 72
  STAGE IA 1
  STAGE IB 1
  STAGE II 8
  STAGE III 15
  STAGE IV 2
  STAGE IVB 1
     
  Significant markers N = 0
Clinical variable #9: 'YEARS_TO_BIRTH'

30 genes related to 'YEARS_TO_BIRTH'.

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

YEARS_TO_BIRTH Mean (SD) 63.56 (10)
  Significant markers N = 30
  pos. correlated 12
  neg. correlated 18
List of top 10 genes differentially expressed by 'YEARS_TO_BIRTH'

Table S13.  Get Full Table List of top 10 genes significantly correlated to 'YEARS_TO_BIRTH' by Spearman correlation test

SpearmanCorr corrP Q
OBSCN|ENSG00000154358.18 0.4509 2.504e-06 0.0461
ARL4A|ENSG00000122644.11 -0.4383 5.1e-06 0.047
RASSF6|ENSG00000169435.12 -0.4087 2.422e-05 0.141
CHP1|ENSG00000187446.10 -0.404 3.069e-05 0.141
CHODL|ENSG00000154645.12 0.3951 4.728e-05 0.146
RNPC3|ENSG00000185946.14 0.3942 4.94e-05 0.146
OGFOD1|ENSG00000087263.15 -0.3904 5.922e-05 0.146
RYR1|ENSG00000196218.10 0.3882 6.581e-05 0.146
HEATR5B|ENSG00000008869.10 -0.3859 7.338e-05 0.146
ZNF879|ENSG00000234284.5 0.3842 7.934e-05 0.146
Clinical variable #10: 'ETHNICITY'

No gene related to 'ETHNICITY'.

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

ETHNICITY Labels N
  HISPANIC OR LATINO 4
  NOT HISPANIC OR LATINO 41
     
  Significant markers N = 0
Clinical variable #11: 'RACE'

No gene related to 'RACE'.

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

RACE Labels N
  ASIAN 1
  BLACK OR AFRICAN AMERICAN 3
  WHITE 58
     
  Significant markers N = 0
Clinical variable #12: 'RADIATION_THERAPY'

30 genes related to 'RADIATION_THERAPY'.

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

RADIATION_THERAPY Labels N
  NO 43
  YES 54
     
  Significant markers N = 30
  Higher in YES 30
  Higher in NO 0
List of top 10 genes differentially expressed by 'RADIATION_THERAPY'

Table S17.  Get Full Table List of top 10 genes differentially expressed by 'RADIATION_THERAPY'

W(pos if higher in 'YES') wilcoxontestP Q AUC
ZBTB10|ENSG00000205189.10 1730 3.654e-05 0.19 0.745
PSMC3|ENSG00000165916.7 1711 6.597e-05 0.19 0.7369
SCYL1|ENSG00000142186.15 1700 9.211e-05 0.19 0.7321
BCL7C|ENSG00000099385.10 1696 0.0001038 0.19 0.7304
RAPGEF5|ENSG00000136237.17 1694 0.0001102 0.19 0.7295
RP11-463D19.2|ENSG00000258677.2 1694 0.0001102 0.19 0.7295
VAT1|ENSG00000108828.14 1690 0.0001241 0.19 0.7278
PSMC1|ENSG00000100764.12 1688 0.0001316 0.19 0.727
ESYT2|ENSG00000117868.14 1688 0.0001316 0.19 0.727
PSMD1|ENSG00000173692.11 1686 0.0001396 0.19 0.7261
Clinical variable #13: 'DIABETES'

30 genes related to 'DIABETES'.

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

DIABETES Labels N
  NO 70
  YES 28
     
  Significant markers N = 30
  Higher in YES 30
  Higher in NO 0
List of top 10 genes differentially expressed by 'DIABETES'

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

W(pos if higher in 'YES') wilcoxontestP Q AUC
THOC5|ENSG00000100296.12 461 4.552e-05 0.2 0.7648
UBP1|ENSG00000153560.10 466 5.387e-05 0.2 0.7622
LRP1B|ENSG00000168702.15 1484 7.51e-05 0.2 0.7571
CHAMP1|ENSG00000198824.5 483 9.442e-05 0.2 0.7536
ZNF653|ENSG00000161914.8 488 0.000111 0.2 0.751
E2F2|ENSG00000007968.6 492 0.0001262 0.2 0.749
KLHL18|ENSG00000114648.10 493 0.0001303 0.2 0.7485
ACOT7|ENSG00000097021.18 494 0.0001345 0.2 0.748
ESYT1|ENSG00000139641.11 494 0.0001345 0.2 0.748
EAF1|ENSG00000144597.12 496 0.0001434 0.2 0.7469
Clinical variable #14: 'BMI'

No gene related to 'BMI'.

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

BMI Labels N
  NORMAL 8
  OBESE 47
  OVERWEIGHT 21
  SEVERELY OBESE 21
  UNDERWEIGHT 3
     
  Significant markers N = 0
Clinical variable #15: 'NUMBER_PACK_YEARS_SMOKED'

6 genes related to 'NUMBER_PACK_YEARS_SMOKED'.

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

NUMBER_PACK_YEARS_SMOKED Mean (SD) 14.48 (12)
  Significant markers N = 6
  pos. correlated 3
  neg. correlated 3
List of 6 genes differentially expressed by 'NUMBER_PACK_YEARS_SMOKED'

Table S22.  Get Full Table List of 6 genes significantly correlated to 'NUMBER_PACK_YEARS_SMOKED' by Spearman correlation test

SpearmanCorr corrP Q
STX1A|ENSG00000106089.10 0.8343 1.677e-05 0.175
C14ORF169|ENSG00000170468.7 -0.826 2.407e-05 0.175
WIPF2|ENSG00000171475.12 0.8219 2.864e-05 0.175
COL17A1|ENSG00000065618.15 0.8136 4.004e-05 0.175
AQP4|ENSG00000171885.12 -0.824 4.762e-05 0.175
AGBL4|ENSG00000186094.15 -0.7981 7.196e-05 0.221
Clinical variable #16: 'SMOKER'

No gene related to 'SMOKER'.

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

SMOKER Labels N
  NON-SMOKER 73
  SMOKER 22
     
  Significant markers N = 0
Clinical variable #17: 'COUNTRY_OF_ORIGIN'

2 genes related to 'COUNTRY_OF_ORIGIN'.

Table S24.  Basic characteristics of clinical feature: 'COUNTRY_OF_ORIGIN'

COUNTRY_OF_ORIGIN Labels N
  MEXICO 2
  POLAND 5
  UKRAINE 32
  UNITED STATES 36
     
  Significant markers N = 2
List of 2 genes differentially expressed by 'COUNTRY_OF_ORIGIN'

Table S25.  Get Full Table List of 2 genes differentially expressed by 'COUNTRY_OF_ORIGIN'

kruskal_wallis_P Q
HBB|ENSG00000244734.2 2.03e-05 0.285
HBA2|ENSG00000188536.11 3.095e-05 0.285
Methods & Data
Input

  • Expresson data file = CPTAC3-UCEC-TP.mRNA_FPKM_log2_protein.coding.txt

  • Clinical data file = CPTAC3-UCEC-TP.clin.merged.picked.txt

  • Number of patients = 100

  • Number of genes = 18424

  • Number of clinical features = 17

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.

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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