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'

Table S3. Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL_TYPE'

| kruskal_wallis_P | Q
--- | --- | ---
SENP5|ENSG00000119231.9 | 2.716e-07 | 0.00439
ZNF516|ENSG00000101493.9 | 5.838e-07 | 0.00439
CERS5|ENSG00000139624.11 | 7.155e-07 | 0.00439
IHH|ENSG00000163501.6 | 1.215e-06 | 0.00559
GNB5|ENSG00000069966.17 | 1.566e-06 | 0.00577
CR2|ENSG00000117322.15 | 1.923e-06 | 0.00591
NR1I2|ENSG00000144852.15 | 2.583e-06 | 0.0068
TRIM46|ENSG00000163462.16 | 3.248e-06 | 0.0069
OPA1|ENSG00000198836.7 | 3.37e-06 | 0.0069
S100A1|ENSG00000160678.10 | 4.99e-06 | 0.0085

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.

- There are also useful links about clinical features.

- CDE Browser

- Data dictionary for clinical data

- NCI wiki - Biospecimen and Clinical XSD Files Specification

- 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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