Correlation between RPPA expression and clinical features
Thyroid Adenocarcinoma (Primary solid tumor)
15 January 2014 | analyses__2014_01_15
Maintainer Information
Citation Information
doi:10.7908/C1M9074F
Maintained by Juok Cho (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2014): Correlation between RPPA expression and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C1M9074F
Overview
Introduction

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

Summary

Testing the association between 175 genes and 15 clinical features across 217 samples, statistically thresholded by Q value < 0.05, 10 clinical features related to at least one genes.

- 1 gene correlated to 'Time to Death'.

- CHEK1|CHK1_PS345-R-C

- 10 genes correlated to 'AGE'.

- EGFR|EGFR_PY1068-R-V , EEF2|EEF2-R-V , SNAI2|SNAIL-M-C , AKT1 AKT2 AKT3|AKT_PT308-R-V , DVL3|DVL3-R-V , ...

- 5 genes correlated to 'NEOPLASM.DISEASESTAGE'.

- BECN1|BECLIN-G-V , PECAM1|CD31-M-V , CDK1|CDK1-R-V , CASP3|CASPASE-3_ACTIVE-R-C , MAPT|TAU-M-C

- 5 genes correlated to 'PATHOLOGY.T.STAGE'.

- AKT1S1|PRAS40_PT246-R-V , CLDN7|CLAUDIN-7-R-V , DIABLO|SMAC-M-V , AR|AR-R-V , C12ORF5|TIGAR-R-V

- 17 genes correlated to 'PATHOLOGY.N.STAGE'.

- ANXA1|ANNEXIN_I-R-V , SRC|SRC_PY527-R-V , DVL3|DVL3-R-V , PTCH1|PTCH-R-C , BCL2L1|BCL-XL-R-V , ...

- 2 genes correlated to 'PATHOLOGY.M.STAGE'.

- BCL2L1|BCL-XL-R-V , PECAM1|CD31-M-V

- 30 genes correlated to 'HISTOLOGICAL.TYPE'.

- ANXA1|ANNEXIN_I-R-V , FN1|FIBRONECTIN-R-C , PIK3R1|PI3K-P85-R-V , CHEK2|CHK2-M-C , NEK7|NEK7-R-NA , ...

- 6 genes correlated to 'RADIATIONS.RADIATION.REGIMENINDICATION'.

- ERBB2|HER2_PY1248-R-V , DVL3|DVL3-R-V , MET|C-MET-M-C , WWTR1|TAZ_PS89-R-C , ARID1A|ARID1A-M-V , ...

- 6 genes correlated to 'EXTRATHYROIDAL.EXTENSION'.

- EIF4EBP1|4E-BP1-R-V , PIK3CA |PI3K-P110-ALPHA-R-C , BCL2|BCL-2-R-C , PAI-1|PAL-1-M-C , EGFR|EGFR_PY1173-R-C , ...

- 7 genes correlated to 'NUMBER.OF.LYMPH.NODES'.

- PTCH1|PTCH-R-C , MAPK14|P38_MAPK-R-C , DVL3|DVL3-R-V , ANXA1|ANNEXIN_I-R-V , PXN|PAXILLIN-R-V , ...

- No genes correlated to 'GENDER', 'RADIATIONEXPOSURE', 'COMPLETENESS.OF.RESECTION', 'MULTIFOCALITY', and 'TUMOR.SIZE'.

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=1 | shorter survival | N=0 | longer survival | N=1
AGE | Spearman correlation test | N=10 | older | N=6 | younger | N=4
NEOPLASM DISEASESTAGE | ANOVA test | N=5 |  |  |  |
PATHOLOGY T STAGE | Spearman correlation test | N=5 | higher stage | N=1 | lower stage | N=4
PATHOLOGY N STAGE | t test | N=17 | class1 | N=13 | class0 | N=4
PATHOLOGY M STAGE | ANOVA test | N=2 |  |  |  |
GENDER | t test | N=0 |  |  |  |
HISTOLOGICAL TYPE | ANOVA test | N=30 |  |  |  |
RADIATIONS RADIATION REGIMENINDICATION | t test | N=6 | yes | N=4 | no | N=2
RADIATIONEXPOSURE | t test | N=0 |  |  |  |
EXTRATHYROIDAL EXTENSION | ANOVA test | N=6 |  |  |  |
COMPLETENESS OF RESECTION | ANOVA test | N=0 |  |  |  |
NUMBER OF LYMPH NODES | Spearman correlation test | N=7 | higher number.of.lymph.nodes | N=6 | lower number.of.lymph.nodes | N=1
MULTIFOCALITY | t test | N=0 |  |  |  |
TUMOR SIZE | Spearman correlation test | N=0 |  |  |  |

Clinical variable #1: 'Time to Death'

One gene related to 'Time to Death'.

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

Time to Death | Duration (Months) | 0.1-158.8 (median=17.4)
| censored | N = 203
| death | N = 13
| Significant markers | N = 1
| associated with shorter survival | 0
| associated with longer survival | 1

List of one gene significantly associated with 'Time to Death' by Cox regression test

Table S2. Get Full Table List of one gene significantly associated with 'Time to Death' by Cox regression test

| HazardRatio | Wald_P | Q | C_index
--- | --- | --- | --- | ---
CHEK1|CHK1_PS345-R-C | 0 | 0.0001013 | 0.018 | 0.206

Figure S1. Get High-res Image As an example, this figure shows the association of CHEK1|CHK1_PS345-R-C to 'Time to Death'. four curves present the cumulative survival rates of 4 quartile subsets of patients. P value = 0.000101 with univariate Cox regression analysis using continuous log-2 expression values.

Clinical variable #2: 'AGE'

10 genes related to 'AGE'.

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

AGE | Mean (SD) | 48.35 (17)
| Significant markers | N = 10
| pos. correlated | 6
| neg. correlated | 4

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

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

| SpearmanCorr | corrP | Q
--- | --- | --- | ---
EGFR|EGFR_PY1068-R-V | 0.2945 | 1.03e-05 | 0.0018
EEF2|EEF2-R-V | -0.2884 | 1.587e-05 | 0.00276
SNAI2|SNAIL-M-C | 0.2833 | 2.266e-05 | 0.00392
AKT1 AKT2 AKT3|AKT_PT308-R-V | 0.28 | 2.863e-05 | 0.00492
DVL3|DVL3-R-V | -0.2711 | 5.209e-05 | 0.00891
MAPK8|JNK_PT183_PT185-R-V | 0.2647 | 7.91e-05 | 0.0134
ATM|ATM-R-C | -0.2631 | 8.736e-05 | 0.0148
AKT1 AKT2 AKT3|AKT_PS473-R-V | 0.2569 | 0.00013 | 0.0218
RAD50|RAD50-M-C | -0.2548 | 0.0001483 | 0.0248
PRKCA |PKC-ALPHA-M-V | 0.2532 | 0.0001633 | 0.0271

Figure S2. Get High-res Image As an example, this figure shows the association of EGFR|EGFR_PY1068-R-V to 'AGE'. P value = 1.03e-05 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #3: 'NEOPLASM.DISEASESTAGE'

5 genes related to 'NEOPLASM.DISEASESTAGE'.

Table S5. Basic characteristics of clinical feature: 'NEOPLASM.DISEASESTAGE'

NEOPLASM.DISEASESTAGE | Labels | N
| STAGE I | 113
| STAGE II | 33
| STAGE III | 45
| STAGE IVA | 20
| STAGE IVC | 4
| Significant markers | N = 5

List of 5 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

Table S6. Get Full Table List of 5 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

| ANOVA_P | Q
--- | --- | ---
BECN1|BECLIN-G-V | 5.216e-07 | 9.13e-05
PECAM1|CD31-M-V | 9.262e-06 | 0.00161
CDK1|CDK1-R-V | 3.499e-05 | 0.00605
CASP3|CASPASE-3_ACTIVE-R-C | 3.589e-05 | 0.00617
MAPT|TAU-M-C | 0.0002862 | 0.0489

Figure S3. Get High-res Image As an example, this figure shows the association of BECN1|BECLIN-G-V to 'NEOPLASM.DISEASESTAGE'. P value = 5.22e-07 with ANOVA analysis.

Clinical variable #4: 'PATHOLOGY.T.STAGE'

5 genes related to 'PATHOLOGY.T.STAGE'.

Table S7. Basic characteristics of clinical feature: 'PATHOLOGY.T.STAGE'

PATHOLOGY.T.STAGE | Mean (SD) | 2.2 (0.86)
|  | N
| 1 | 51
| 2 | 81
| 3 | 73
| 4 | 11
| Significant markers | N = 5
| pos. correlated | 1
| neg. correlated | 4

List of 5 genes significantly correlated to 'PATHOLOGY.T.STAGE' by Spearman correlation test

Table S8. Get Full Table List of 5 genes significantly correlated to 'PATHOLOGY.T.STAGE' by Spearman correlation test

| SpearmanCorr | corrP | Q
--- | --- | --- | ---
AKT1S1|PRAS40_PT246-R-V | -0.314 | 2.512e-06 | 0.00044
CLDN7|CLAUDIN-7-R-V | -0.2613 | 0.0001018 | 0.0177
DIABLO|SMAC-M-V | 0.261 | 0.0001043 | 0.018
AR|AR-R-V | -0.2555 | 0.0001466 | 0.0252
C12ORF5|TIGAR-R-V | -0.2447 | 0.0002828 | 0.0484

Figure S4. Get High-res Image As an example, this figure shows the association of AKT1S1|PRAS40_PT246-R-V to 'PATHOLOGY.T.STAGE'. P value = 2.51e-06 with Spearman correlation analysis.

Clinical variable #5: 'PATHOLOGY.N.STAGE'

17 genes related to 'PATHOLOGY.N.STAGE'.

Table S9. Basic characteristics of clinical feature: 'PATHOLOGY.N.STAGE'

PATHOLOGY.N.STAGE | Labels | N
| class0 | 95
| class1 | 93
| Significant markers | N = 17
| Higher in class1 | 13
| Higher in class0 | 4

List of top 10 genes differentially expressed by 'PATHOLOGY.N.STAGE'

Table S10. Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGY.N.STAGE'

| T(pos if higher in 'class1') | ttestP | Q | AUC
--- | --- | --- | --- | ---
ANXA1|ANNEXIN_I-R-V | 6.28 | 2.808e-09 | 4.91e-07 | 0.7282
SRC|SRC_PY527-R-V | -5.63 | 6.809e-08 | 1.18e-05 | 0.7113
DVL3|DVL3-R-V | 5.03 | 1.131e-06 | 0.000196 | 0.6966
PTCH1|PTCH-R-C | 5.03 | 1.19e-06 | 0.000205 | 0.7113
BCL2L1|BCL-XL-R-V | 4.67 | 5.676e-06 | 0.000971 | 0.6739
PXN|PAXILLIN-R-V | 4.63 | 6.945e-06 | 0.00118 | 0.6703
CASP9|CASPASE-9_CLEAVEDD330-R-C | 4.42 | 1.737e-05 | 0.00294 | 0.6732
FN1|FIBRONECTIN-R-C | 4.21 | 3.996e-05 | 0.00671 | 0.6765
VASP|VASP-R-C | 4.21 | 4.004e-05 | 0.00671 | 0.6757
ERBB2|HER2_PY1248-R-V | -4.2 | 4.178e-05 | 0.00693 | 0.6922

Figure S5. Get High-res Image As an example, this figure shows the association of ANXA1|ANNEXIN_I-R-V to 'PATHOLOGY.N.STAGE'. P value = 2.81e-09 with T-test analysis.

Clinical variable #6: 'PATHOLOGY.M.STAGE'

2 genes related to 'PATHOLOGY.M.STAGE'.

Table S11. Basic characteristics of clinical feature: 'PATHOLOGY.M.STAGE'

PATHOLOGY.M.STAGE | Labels | N
| M0 | 114
| M1 | 5
| MX | 97
| Significant markers | N = 2

List of 2 genes differentially expressed by 'PATHOLOGY.M.STAGE'

Table S12. Get Full Table List of 2 genes differentially expressed by 'PATHOLOGY.M.STAGE'

| ANOVA_P | Q
--- | --- | ---
BCL2L1|BCL-XL-R-V | 9.31e-05 | 0.0163
PECAM1|CD31-M-V | 0.0002237 | 0.0389

Figure S6. Get High-res Image As an example, this figure shows the association of BCL2L1|BCL-XL-R-V to 'PATHOLOGY.M.STAGE'. P value = 9.31e-05 with ANOVA analysis.

Clinical variable #7: 'GENDER'

No gene related to 'GENDER'.

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

GENDER | Labels | N
| FEMALE | 150
| MALE | 67
| Significant markers | N = 0

Clinical variable #8: 'HISTOLOGICAL.TYPE'

30 genes related to 'HISTOLOGICAL.TYPE'.

Table S14. Basic characteristics of clinical feature: 'HISTOLOGICAL.TYPE'

HISTOLOGICAL.TYPE | Labels | N
| OTHER SPECIFY | 2
| THYROID PAPILLARY CARCINOMA - CLASSICAL/USUAL | 153
| THYROID PAPILLARY CARCINOMA - FOLLICULAR (>= 99% FOLLICULAR PATTERNED) | 52
| THYROID PAPILLARY CARCINOMA - TALL CELL (>= 50% TALL CELL FEATURES) | 10
| Significant markers | N = 30

List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

Table S15. Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

| ANOVA_P | Q
--- | --- | ---
ANXA1|ANNEXIN_I-R-V | 2.158e-14 | 3.78e-12
FN1|FIBRONECTIN-R-C | 1.07e-10 | 1.86e-08
PIK3R1|PI3K-P85-R-V | 5.156e-09 | 8.92e-07
CHEK2|CHK2-M-C | 1.267e-07 | 2.18e-05
NEK7|NEK7-R-NA | 1.801e-07 | 3.08e-05
PXN|PAXILLIN-R-V | 7.578e-07 | 0.000129
XIAP|XIAP-R-C | 9.045e-07 | 0.000153
RAF1|C-RAF_PS338-R-C | 1.708e-06 | 0.000287
ERCC1|ERCC1-M-C | 3.205e-06 | 0.000535
AR|AR-R-V | 4.072e-06 | 0.000676

Figure S7. Get High-res Image As an example, this figure shows the association of ANXA1|ANNEXIN_I-R-V to 'HISTOLOGICAL.TYPE'. P value = 2.16e-14 with ANOVA analysis.

Clinical variable #9: 'RADIATIONS.RADIATION.REGIMENINDICATION'

6 genes related to 'RADIATIONS.RADIATION.REGIMENINDICATION'.

Table S16. Basic characteristics of clinical feature: 'RADIATIONS.RADIATION.REGIMENINDICATION'

RADIATIONS.RADIATION.REGIMENINDICATION | Labels | N
| NO | 13
| YES | 204
| Significant markers | N = 6
| Higher in YES | 4
| Higher in NO | 2

List of 6 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

Table S17. Get Full Table List of 6 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

| T(pos if higher in 'YES') | ttestP | Q | AUC
--- | --- | --- | --- | ---
ERBB2|HER2_PY1248-R-V | 5.04 | 3.645e-05 | 0.00638 | 0.7236
DVL3|DVL3-R-V | -5.43 | 4.392e-05 | 0.00764 | 0.8015
MET|C-MET-M-C | 4.96 | 4.791e-05 | 0.00829 | 0.7051
WWTR1|TAZ_PS89-R-C | 5.06 | 0.0001003 | 0.0173 | 0.7885
ARID1A|ARID1A-M-V | 4.59 | 0.0001297 | 0.0222 | 0.698
BCL2L1|BCL-XL-R-V | -4.81 | 0.000278 | 0.0473 | 0.8311

Figure S8. Get High-res Image As an example, this figure shows the association of ERBB2|HER2_PY1248-R-V to 'RADIATIONS.RADIATION.REGIMENINDICATION'. P value = 3.64e-05 with T-test analysis.

Clinical variable #10: 'RADIATIONEXPOSURE'

No gene related to 'RADIATIONEXPOSURE'.

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

RADIATIONEXPOSURE | Labels | N
| NO | 181
| YES | 11
| Significant markers | N = 0

Clinical variable #11: 'EXTRATHYROIDAL.EXTENSION'

6 genes related to 'EXTRATHYROIDAL.EXTENSION'.

Table S19. Basic characteristics of clinical feature: 'EXTRATHYROIDAL.EXTENSION'

EXTRATHYROIDAL.EXTENSION | Labels | N
| MINIMAL (T3) | 55
| MODERATE/ADVANCED (T4A) | 10
| NONE | 145
| Significant markers | N = 6

List of 6 genes differentially expressed by 'EXTRATHYROIDAL.EXTENSION'

Table S20. Get Full Table List of 6 genes differentially expressed by 'EXTRATHYROIDAL.EXTENSION'

| ANOVA_P | Q
--- | --- | ---
EIF4EBP1|4E-BP1-R-V | 1.179e-05 | 0.00206
PIK3CA |PI3K-P110-ALPHA-R-C | 4.483e-05 | 0.0078
BCL2|BCL-2-R-C | 7.008e-05 | 0.0121
PAI-1|PAL-1-M-C | 8.137e-05 | 0.014
EGFR|EGFR_PY1173-R-C | 0.0001573 | 0.0269
DIABLO|SMAC-M-V | 0.0001867 | 0.0317

Figure S9. Get High-res Image As an example, this figure shows the association of EIF4EBP1|4E-BP1-R-V to 'EXTRATHYROIDAL.EXTENSION'. P value = 1.18e-05 with ANOVA analysis.

Clinical variable #12: 'COMPLETENESS.OF.RESECTION'

No gene related to 'COMPLETENESS.OF.RESECTION'.

Table S21. Basic characteristics of clinical feature: 'COMPLETENESS.OF.RESECTION'

COMPLETENESS.OF.RESECTION | Labels | N
| R0 | 165
| R1 | 21
| R2 | 2
| RX | 14
| Significant markers | N = 0

Clinical variable #13: 'NUMBER.OF.LYMPH.NODES'

7 genes related to 'NUMBER.OF.LYMPH.NODES'.

Table S22. Basic characteristics of clinical feature: 'NUMBER.OF.LYMPH.NODES'

NUMBER.OF.LYMPH.NODES | Mean (SD) | 3.45 (5.9)
| Significant markers | N = 7
| pos. correlated | 6
| neg. correlated | 1

List of 7 genes significantly correlated to 'NUMBER.OF.LYMPH.NODES' by Spearman correlation test

Table S23. Get Full Table List of 7 genes significantly correlated to 'NUMBER.OF.LYMPH.NODES' by Spearman correlation test

| SpearmanCorr | corrP | Q
--- | --- | --- | ---
PTCH1|PTCH-R-C | 0.3478 | 4.13e-06 | 0.000723
MAPK14|P38_MAPK-R-C | 0.3285 | 1.461e-05 | 0.00254
DVL3|DVL3-R-V | 0.3061 | 5.739e-05 | 0.00993
ANXA1|ANNEXIN_I-R-V | 0.3031 | 6.857e-05 | 0.0118
PXN|PAXILLIN-R-V | 0.2983 | 9.009e-05 | 0.0154
PAI-1|PAL-1-M-C | 0.2804 | 0.0002419 | 0.0411
SRC|SRC_PY527-R-V | -0.2779 | 0.0002767 | 0.0468

Figure S10. Get High-res Image As an example, this figure shows the association of PTCH1|PTCH-R-C to 'NUMBER.OF.LYMPH.NODES'. P value = 4.13e-06 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #14: 'MULTIFOCALITY'

No gene related to 'MULTIFOCALITY'.

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

MULTIFOCALITY | Labels | N
| MULTIFOCAL | 100
| UNIFOCAL | 110
| Significant markers | N = 0

Clinical variable #15: 'TUMOR.SIZE'

No gene related to 'TUMOR.SIZE'.

Table S25. Basic characteristics of clinical feature: 'TUMOR.SIZE'

TUMOR.SIZE | Mean (SD) | 3.28 (1.6)
| Significant markers | N = 0

Methods & Data
Input

- Expresson data file = THCA-TP.rppa.txt

- Clinical data file = THCA-TP.merged_data.txt

- Number of patients = 217

- Number of genes = 175

- Number of clinical features = 15

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

ANOVA analysis

For multi-class clinical features (ordinal or nominal), one-way analysis of variance (Howell 2002) was applied to compare the log2-expression levels between different clinical classes using 'anova' 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

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.

- 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] Howell, D, Statistical Methods for Psychology. (5th ed.), Duxbury Press:324-5 (2002)
[4] Lehmann and Romano, Testing Statistical Hypotheses (3E ed.), New York: Springer. ISBN 0387988645 (2005)
[5] 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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