Kidney Renal Clear Cell Carcinoma: Correlation between mRNAseq expression and clinical features
Maintained by Juok Cho (Broad Institute)
Overview
Introduction

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

Summary

Testing the association between 18294 genes and 9 clinical features across 469 samples, statistically thresholded by Q value < 0.05, 8 clinical features related to at least one genes.

- 2001 genes correlated to 'Time to Death'.

- COL7A1|1294 , ANKRD56|345079 , B3GNTL1|146712 , DONSON|29980 , FBXL5|26234 , ...

- 13 genes correlated to 'AGE'.

- RANBP17|64901 , WFDC1|58189 , RFPL1S|10740 , PALLD|23022 , UTY|7404 , ...

- 216 genes correlated to 'GENDER'.

- XIST|7503 , PRKY|5616 , NLGN4Y|22829 , TSIX|9383 , RPS4Y1|6192 , ...

- 2273 genes correlated to 'PATHOLOGY.T'.

- NR3C2|4306 , FKBP11|51303 , FAM122A|116224 , TMEM150C|441027 , ZNF132|7691 , ...

- 6 genes correlated to 'PATHOLOGY.N'.

- C11ORF34|349633 , HEMGN|55363 , PITX2|5308 , ATP6V1D|51382 , ATP13A5|344905 , ...

- 217 genes correlated to 'PATHOLOGICSPREAD(M)'.

- GARNL3|84253 , IL20RB|53833 , PLEKHA9|51054 , BIRC5|332 , C22ORF9|23313 , ...

- 2605 genes correlated to 'TUMOR.STAGE'.

- NR3C2|4306 , PLEKHA9|51054 , FKBP11|51303 , FAM122A|116224 , TSPAN7|7102 , ...

- 16 genes correlated to 'NEOADJUVANT.THERAPY'.

- GPR128|84873 , PTPN20B|26095 , USH1C|10083 , HIST1H4D|8360 , SPRY1|10252 , ...

- No genes correlated to 'KARNOFSKY.PERFORMANCE.SCORE'

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 Q value < 0.05.

Clinical feature | Statistical test | Significant genes | Associated with |  | Associated with |
--- | --- | --- | --- | --- | --- | ---
Time to Death | Cox regression test | N=2001 | shorter survival | N=1278 | longer survival | N=723
AGE | Spearman correlation test | N=13 | older | N=2 | younger | N=11
GENDER | t test | N=216 | male | N=131 | female | N=85
KARNOFSKY PERFORMANCE SCORE | Spearman correlation test | N=0 |  |  |  |
PATHOLOGY T | Spearman correlation test | N=2273 | higher pT | N=1236 | lower pT | N=1037
PATHOLOGY N | t test | N=6 | n1 | N=1 | n0 | N=5
PATHOLOGICSPREAD(M) | t test | N=217 | m1 | N=189 | m0 | N=28
TUMOR STAGE | Spearman correlation test | N=2605 | higher stage | N=1412 | lower stage | N=1193
NEOADJUVANT THERAPY | t test | N=16 | yes | N=7 | no | N=9

Clinical variable #1: 'Time to Death'

2001 genes related to 'Time to Death'.

Table S1. Basic characteristics of clinical feature: 'Time to Death'

Time to Death | Duration (Months) | 0.1-111 (median=34.5)
| censored | N = 313
| death | N = 153
| Significant markers | N = 2001
| associated with shorter survival | 1278
| associated with longer survival | 723

List of top 10 genes significantly associated with 'Time to Death' by Cox regression test

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

| HazardRatio | Wald_P | Q | C_index
--- | --- | --- | --- | ---
COL7A1|1294 | 1.31 | 0 | 0 | 0.669
ANKRD56|345079 | 0.71 | 1.11e-16 | 2e-12 | 0.323
B3GNTL1|146712 | 2.3 | 1.11e-16 | 2e-12 | 0.677
DONSON|29980 | 2.6 | 1.11e-16 | 2e-12 | 0.677
FBXL5|26234 | 0.42 | 7.772e-16 | 1.4e-11 | 0.323
SLC16A12|387700 | 0.79 | 8.882e-16 | 1.6e-11 | 0.319
ADAMTS14|140766 | 1.43 | 1.221e-15 | 2.2e-11 | 0.677
RGS17|26575 | 1.43 | 1.776e-15 | 3.2e-11 | 0.66
NUMBL|9253 | 1.82 | 2.331e-15 | 4.3e-11 | 0.681
CCNF|899 | 1.97 | 2.887e-15 | 5.3e-11 | 0.666

Figure S1. Get High-res Image As an example, this figure shows the association of COL7A1|1294 to 'Time to Death'. four curves present the cumulative survival rates of 4 quartile subsets of patients. P value = 0 with univariate Cox regression analysis using continuous log-2 expression values.

Clinical variable #2: 'AGE'

13 genes related to 'AGE'.

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

AGE | Mean (SD) | 60.62 (12)
| Significant markers | N = 13
| pos. correlated | 2
| neg. correlated | 11

List of top 10 genes significantly correlated to 'AGE' by Spearman correlation test

Table S4. Get Full Table List of top 10 genes significantly correlated to 'AGE' by Spearman correlation test

| SpearmanCorr | corrP | Q
--- | --- | --- | ---
RANBP17|64901 | -0.2598 | 1.166e-08 | 0.000213
WFDC1|58189 | -0.2448 | 8.132e-08 | 0.00149
RFPL1S|10740 | -0.2427 | 1.326e-07 | 0.00243
PALLD|23022 | -0.2366 | 2.229e-07 | 0.00408
UTY|7404 | -0.259 | 7.819e-07 | 0.0143
NEFH|4744 | -0.2259 | 7.872e-07 | 0.0144
ZNF780A|284323 | -0.2242 | 9.65e-07 | 0.0176
DIO2|1734 | -0.2226 | 1.18e-06 | 0.0216
FNDC1|84624 | -0.2216 | 1.283e-06 | 0.0235
ZNF610|162963 | -0.2193 | 1.664e-06 | 0.0304

Figure S2. Get High-res Image As an example, this figure shows the association of RANBP17|64901 to 'AGE'. P value = 1.17e-08 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #3: 'GENDER'

216 genes related to 'GENDER'.

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

GENDER | Labels | N
| FEMALE | 162
| MALE | 307
| Significant markers | N = 216
| Higher in MALE | 131
| Higher in FEMALE | 85

List of top 10 genes differentially expressed by 'GENDER'

Table S6. Get Full Table List of top 10 genes differentially expressed by 'GENDER'

| T(pos if higher in 'MALE') | ttestP | Q | AUC
--- | --- | --- | --- | ---
XIST|7503 | -41.65 | 8.192e-153 | 1.5e-148 | 0.9814
PRKY|5616 | 35.38 | 2.013e-94 | 3.68e-90 | 0.973
NLGN4Y|22829 | 32.24 | 8.053e-69 | 1.47e-64 | 0.9727
TSIX|9383 | -23.29 | 1.392e-66 | 2.55e-62 | 0.9657
RPS4Y1|6192 | 32.29 | 2.264e-65 | 4.14e-61 | 0.9799
ZFY|7544 | 31.14 | 8.747e-58 | 1.6e-53 | 0.9723
DDX3Y|8653 | 27.62 | 3.594e-51 | 6.57e-47 | 0.9672
KDM5C|8242 | -16.66 | 8.561e-48 | 1.57e-43 | 0.8963
NCRNA00183|554203 | -16.13 | 7.218e-44 | 1.32e-39 | 0.8643
HAUS7|55559 | 13.78 | 8.192e-36 | 1.5e-31 | 0.8354

Figure S3. Get High-res Image As an example, this figure shows the association of XIST|7503 to 'GENDER'. P value = 8.19e-153 with T-test analysis.

Clinical variable #4: 'KARNOFSKY.PERFORMANCE.SCORE'

No gene related to 'KARNOFSKY.PERFORMANCE.SCORE'.

Table S7. Basic characteristics of clinical feature: 'KARNOFSKY.PERFORMANCE.SCORE'

KARNOFSKY.PERFORMANCE.SCORE | Mean (SD) | 90.97 (19)
| Score | N
| 0 | 1
| 70 | 1
| 80 | 3
| 90 | 9
| 100 | 17
| Significant markers | N = 0

Clinical variable #5: 'PATHOLOGY.T'

2273 genes related to 'PATHOLOGY.T'.

Table S8. Basic characteristics of clinical feature: 'PATHOLOGY.T'

PATHOLOGY.T | Mean (SD) | 1.92 (0.97)
|  | N
| T1 | 229
| T2 | 58
| T3 | 171
| T4 | 11
| Significant markers | N = 2273
| pos. correlated | 1236
| neg. correlated | 1037

List of top 10 genes significantly correlated to 'PATHOLOGY.T' by Spearman correlation test

Table S9. Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY.T' by Spearman correlation test

| SpearmanCorr | corrP | Q
--- | --- | --- | ---
NR3C2|4306 | -0.4006 | 1.662e-19 | 3.04e-15
FKBP11|51303 | 0.3783 | 2.095e-17 | 3.83e-13
FAM122A|116224 | -0.3759 | 3.452e-17 | 6.31e-13
TMEM150C|441027 | -0.374 | 5.126e-17 | 9.38e-13
ZNF132|7691 | -0.3721 | 7.623e-17 | 1.39e-12
PLEKHA9|51054 | 0.3714 | 8.655e-17 | 1.58e-12
CCDC121|79635 | -0.3673 | 1.998e-16 | 3.65e-12
FAM160A1|729830 | -0.3665 | 2.357e-16 | 4.31e-12
ACADSB|36 | -0.3654 | 2.926e-16 | 5.35e-12
PTPRB|5787 | -0.3613 | 6.645e-16 | 1.22e-11

Figure S4. Get High-res Image As an example, this figure shows the association of NR3C2|4306 to 'PATHOLOGY.T'. P value = 1.66e-19 with Spearman correlation analysis.

Clinical variable #6: 'PATHOLOGY.N'

6 genes related to 'PATHOLOGY.N'.

Table S10. Basic characteristics of clinical feature: 'PATHOLOGY.N'

PATHOLOGY.N | Labels | N
| N0 | 224
| N1 | 17
| Significant markers | N = 6
| Higher in N1 | 1
| Higher in N0 | 5

List of 6 genes differentially expressed by 'PATHOLOGY.N'

Table S11. Get Full Table List of 6 genes differentially expressed by 'PATHOLOGY.N'

| T(pos if higher in 'N1') | ttestP | Q | AUC
--- | --- | --- | --- | ---
C11ORF34|349633 | -7.8 | 4.243e-09 | 7.76e-05 | 0.7246
HEMGN|55363 | -6.92 | 6.077e-09 | 0.000111 | 0.7661
PITX2|5308 | 7.02 | 1.467e-07 | 0.00268 | 0.7909
ATP6V1D|51382 | -6.11 | 4.424e-07 | 0.00809 | 0.7534
ATP13A5|344905 | -5.94 | 7.995e-07 | 0.0146 | 0.7583
PIGH|5283 | -6.22 | 2.161e-06 | 0.0395 | 0.7957

Figure S5. Get High-res Image As an example, this figure shows the association of C11ORF34|349633 to 'PATHOLOGY.N'. P value = 4.24e-09 with T-test analysis.

Clinical variable #7: 'PATHOLOGICSPREAD(M)'

217 genes related to 'PATHOLOGICSPREAD(M)'.

Table S12. Basic characteristics of clinical feature: 'PATHOLOGICSPREAD(M)'

PATHOLOGICSPREAD(M) | Labels | N
| M0 | 393
| M1 | 76
| Significant markers | N = 217
| Higher in M1 | 189
| Higher in M0 | 28

List of top 10 genes differentially expressed by 'PATHOLOGICSPREAD(M)'

Table S13. Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGICSPREAD(M)'

| T(pos if higher in 'M1') | ttestP | Q | AUC
--- | --- | --- | --- | ---
GARNL3|84253 | -6.98 | 2.217e-10 | 4.06e-06 | 0.7461
IL20RB|53833 | 6.47 | 3.441e-09 | 6.29e-05 | 0.7257
PLEKHA9|51054 | 6.4 | 3.967e-09 | 7.26e-05 | 0.7298
BIRC5|332 | 6.36 | 5.767e-09 | 0.000105 | 0.7221
C22ORF9|23313 | 6.31 | 5.966e-09 | 0.000109 | 0.727
INHBE|83729 | 6.34 | 6.91e-09 | 0.000126 | 0.7218
TYMP|1890 | 6.1 | 1.231e-08 | 0.000225 | 0.7029
NFE2L3|9603 | 6.15 | 1.284e-08 | 0.000235 | 0.7157
OIP5|11339 | 6.15 | 1.349e-08 | 0.000247 | 0.7214
CEP55|55165 | 6.1 | 2.049e-08 | 0.000375 | 0.715

Figure S6. Get High-res Image As an example, this figure shows the association of GARNL3|84253 to 'PATHOLOGICSPREAD(M)'. P value = 2.22e-10 with T-test analysis.

Clinical variable #8: 'TUMOR.STAGE'

2605 genes related to 'TUMOR.STAGE'.

Table S14. Basic characteristics of clinical feature: 'TUMOR.STAGE'

TUMOR.STAGE | Mean (SD) | 2.11 (1.2)
|  | N
| Stage 1 | 225
| Stage 2 | 47
| Stage 3 | 117
| Stage 4 | 80
| Significant markers | N = 2605
| pos. correlated | 1412
| neg. correlated | 1193

List of top 10 genes significantly correlated to 'TUMOR.STAGE' by Spearman correlation test

Table S15. Get Full Table List of top 10 genes significantly correlated to 'TUMOR.STAGE' by Spearman correlation test

| SpearmanCorr | corrP | Q
--- | --- | --- | ---
NR3C2|4306 | -0.4018 | 1.255e-19 | 2.3e-15
PLEKHA9|51054 | 0.4003 | 1.799e-19 | 3.29e-15
FKBP11|51303 | 0.3926 | 9.788e-19 | 1.79e-14
FAM122A|116224 | -0.3892 | 2.046e-18 | 3.74e-14
TSPAN7|7102 | -0.3764 | 3.131e-17 | 5.73e-13
ACADSB|36 | -0.3713 | 8.819e-17 | 1.61e-12
FAM160A1|729830 | -0.3703 | 1.095e-16 | 2e-12
NOP2|4839 | 0.3702 | 1.111e-16 | 2.03e-12
SYNJ2BP|55333 | -0.3699 | 1.171e-16 | 2.14e-12
ALDH6A1|4329 | -0.3695 | 1.282e-16 | 2.34e-12

Figure S7. Get High-res Image As an example, this figure shows the association of NR3C2|4306 to 'TUMOR.STAGE'. P value = 1.25e-19 with Spearman correlation analysis.

Clinical variable #9: 'NEOADJUVANT.THERAPY'

16 genes related to 'NEOADJUVANT.THERAPY'.

Table S16. Basic characteristics of clinical feature: 'NEOADJUVANT.THERAPY'

NEOADJUVANT.THERAPY | Labels | N
| NO | 5
| YES | 464
| Significant markers | N = 16
| Higher in YES | 7
| Higher in NO | 9

List of top 10 genes differentially expressed by 'NEOADJUVANT.THERAPY'

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

| T(pos if higher in 'YES') | ttestP | Q | AUC
--- | --- | --- | --- | ---
GPR128|84873 | -23.31 | 3.092e-46 | 5.32e-42 | 0.9355
PTPN20B|26095 | -17.07 | 5.488e-20 | 9.43e-16 | 0.8211
USH1C|10083 | -10.67 | 5.068e-15 | 8.71e-11 | 0.8981
HIST1H4D|8360 | -12.87 | 8.909e-13 | 1.53e-08 | 0.8423
SPRY1|10252 | 14.22 | 2.871e-09 | 4.93e-05 | 0.8547
NAPG|8774 | 14.44 | 3.261e-09 | 5.6e-05 | 0.8741
CILP2|148113 | -7.27 | 3.059e-08 | 0.000526 | 0.6936
ZFYVE20|64145 | 17.48 | 3.556e-08 | 0.000611 | 0.9151
RASA3|22821 | 11.73 | 1.034e-07 | 0.00178 | 0.8884
SEMA6A|57556 | -9.8 | 6.457e-07 | 0.0111 | 0.7892

Figure S8. Get High-res Image As an example, this figure shows the association of GPR128|84873 to 'NEOADJUVANT.THERAPY'. P value = 3.09e-46 with T-test analysis.

Methods & Data
Input

- Expresson data file = KIRC.uncv2.mRNAseq_RSEM_normalized_log2.txt

- Clinical data file = KIRC.clin.merged.picked.txt

- Number of patients = 469

- Number of genes = 18294

- Number of clinical features = 9

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

Student's t-test analysis

For two-class clinical features, two-tailed Student's t test with unequal variance (Lehmann and Romano 2005) was applied to compare the log2-expression levels between the two clinical classes using 't.test' function in R

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

This is an experimental feature. The full results of the analysis summarized in this report can be downloaded from the TCGA Data Coordination Center.

- Analysis Results (MD5 checksum)

- Auxiliary Data (MD5 checksum)

- MAGE-TAB File (MD5 checksum)

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] Lehmann and Romano, Testing Statistical Hypotheses (3E ed.), New York: Springer. ISBN 0387988645 (2005)
[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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