Head and Neck Squamous Cell Carcinoma: Correlation between mRNAseq expression and clinical features
(primary solid tumor cohort)
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 18388 genes and 11 clinical features across 302 samples, statistically thresholded by Q value < 0.05, 6 clinical features related to at least one genes.

- 11 genes correlated to 'Time to Death'.

- CYB5B|80777 , FGD3|89846 , TOMM34|10953 , LOC728989|728989 , TP53INP1|94241 , ...

- 33 genes correlated to 'GENDER'.

- XIST|7503 , ZFY|7544 , PRKY|5616 , RPS4Y1|6192 , DDX3Y|8653 , ...

- 2 genes correlated to 'PATHOLOGY.T'.

- LRRC8A|56262 , MSL3|10943

- 24 genes correlated to 'PATHOLOGY.N'.

- SPRR2F|6705 , TGM1|7051 , SPOCK1|6695 , CRCT1|54544 , PTDSS1|9791 , ...

- 8 genes correlated to 'NUMBERPACKYEARSSMOKED'.

- GLI2|2736 , TMTC3|160418 , DPH3|285381 , B4GALNT3|283358 , ZNRF3|84133 , ...

- 12 genes correlated to 'TOBACCOSMOKINGHISTORYINDICATOR'.

- THAP11|57215 , GPR15|2838 , PCDH7|5099 , CCDC96|257236 , SLC29A2|3177 , ...

- No genes correlated to 'AGE', 'TUMOR.STAGE', 'RADIATIONS.RADIATION.REGIMENINDICATION', 'STOPPEDSMOKINGYEAR', and 'YEAROFTOBACCOSMOKINGONSET'.

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=11 | shorter survival | N=4 | longer survival | N=7
AGE | Spearman correlation test | N=0 |  |  |  |
GENDER | t test | N=33 | male | N=13 | female | N=20
PATHOLOGY T | Spearman correlation test | N=2 | higher pT | N=1 | lower pT | N=1
PATHOLOGY N | Spearman correlation test | N=24 | higher pN | N=11 | lower pN | N=13
TUMOR STAGE | Spearman correlation test | N=0 |  |  |  |
RADIATIONS RADIATION REGIMENINDICATION | t test | N=0 |  |  |  |
NUMBERPACKYEARSSMOKED | Spearman correlation test | N=8 | higher numberpackyearssmoked | N=6 | lower numberpackyearssmoked | N=2
STOPPEDSMOKINGYEAR | Spearman correlation test | N=0 |  |  |  |
TOBACCOSMOKINGHISTORYINDICATOR | ANOVA test | N=12 |  |  |  |
YEAROFTOBACCOSMOKINGONSET | Spearman correlation test | N=0 |  |  |  |

Clinical variable #1: 'Time to Death'

11 genes related to 'Time to Death'.

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

Time to Death | Duration (Months) | 0.1-210.9 (median=14.8)
| censored | N = 179
| death | N = 120
| Significant markers | N = 11
| associated with shorter survival | 4
| associated with longer survival | 7

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
--- | --- | --- | --- | ---
CYB5B|80777 | 2.5 | 2.596e-08 | 0.00048 | 0.63
FGD3|89846 | 0.63 | 7.256e-08 | 0.0013 | 0.335
TOMM34|10953 | 2.3 | 1.419e-07 | 0.0026 | 0.647
LOC728989|728989 | 0.64 | 3.834e-07 | 0.007 | 0.331
TP53INP1|94241 | 0.64 | 7.673e-07 | 0.014 | 0.357
FRMD5|84978 | 1.27 | 7.696e-07 | 0.014 | 0.658
ZNF266|10781 | 0.45 | 1.229e-06 | 0.023 | 0.362
SLC35E2|728661 | 0.57 | 1.757e-06 | 0.032 | 0.381
SLC25A45|283130 | 0.6 | 1.966e-06 | 0.036 | 0.362
POLR2C|5432 | 2.6 | 2.524e-06 | 0.046 | 0.613

Figure S1. Get High-res Image As an example, this figure shows the association of CYB5B|80777 to 'Time to Death'. four curves present the cumulative survival rates of 4 quartile subsets of patients. P value = 2.6e-08 with univariate Cox regression analysis using continuous log-2 expression values.

Clinical variable #2: 'AGE'

No gene related to 'AGE'.

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

AGE | Mean (SD) | 61.05 (12)
| Significant markers | N = 0

Clinical variable #3: 'GENDER'

33 genes related to 'GENDER'.

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

GENDER | Labels | N
| FEMALE | 81
| MALE | 221
| Significant markers | N = 33
| Higher in MALE | 13
| Higher in FEMALE | 20

List of top 10 genes differentially expressed by 'GENDER'

Table S5. Get Full Table List of top 10 genes differentially expressed by 'GENDER'

| T(pos if higher in 'MALE') | ttestP | Q | AUC
--- | --- | --- | --- | ---
XIST|7503 | -37.97 | 2.279e-89 | 4.19e-85 | 0.9902
ZFY|7544 | 32.66 | 4.429e-61 | 8.14e-57 | 0.9861
PRKY|5616 | 24.88 | 4.176e-53 | 7.68e-49 | 0.9837
RPS4Y1|6192 | 30.52 | 5.776e-49 | 1.06e-44 | 0.988
DDX3Y|8653 | 27.13 | 1.771e-36 | 3.26e-32 | 0.9802
TSIX|9383 | -17.02 | 4.528e-36 | 8.32e-32 | 0.9642
USP9Y|8287 | 21.72 | 1.36e-26 | 2.5e-22 | 0.9798
KDM5D|8284 | 21.37 | 6.579e-25 | 1.21e-20 | 0.9779
NLGN4Y|22829 | 17.46 | 2.222e-22 | 4.08e-18 | 0.9683
UTY|7404 | 18.71 | 3.739e-21 | 6.87e-17 | 0.9726

Figure S2. Get High-res Image As an example, this figure shows the association of XIST|7503 to 'GENDER'. P value = 2.28e-89 with T-test analysis.

Clinical variable #4: 'PATHOLOGY.T'

2 genes related to 'PATHOLOGY.T'.

Table S6. Basic characteristics of clinical feature: 'PATHOLOGY.T'

PATHOLOGY.T | Mean (SD) | 2.91 (1)
|  | N
| T1 | 23
| T2 | 78
| T3 | 60
| T4 | 101
| Significant markers | N = 2
| pos. correlated | 1
| neg. correlated | 1

List of 2 genes significantly correlated to 'PATHOLOGY.T' by Spearman correlation test

Table S7. Get Full Table List of 2 genes significantly correlated to 'PATHOLOGY.T' by Spearman correlation test

| SpearmanCorr | corrP | Q
--- | --- | --- | ---
LRRC8A|56262 | 0.3223 | 9.538e-08 | 0.00175
MSL3|10943 | -0.2969 | 9.869e-07 | 0.0181

Figure S3. Get High-res Image As an example, this figure shows the association of LRRC8A|56262 to 'PATHOLOGY.T'. P value = 9.54e-08 with Spearman correlation analysis.

Clinical variable #5: 'PATHOLOGY.N'

24 genes related to 'PATHOLOGY.N'.

Table S8. Basic characteristics of clinical feature: 'PATHOLOGY.N'

PATHOLOGY.N | Mean (SD) | 1.03 (0.96)
|  | N
| N0 | 100
| N1 | 32
| N2 | 97
| N3 | 5
| Significant markers | N = 24
| pos. correlated | 11
| neg. correlated | 13

List of top 10 genes significantly correlated to 'PATHOLOGY.N' by Spearman correlation test

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

| SpearmanCorr | corrP | Q
--- | --- | --- | ---
SPRR2F|6705 | -0.3585 | 2.219e-08 | 0.000408
TGM1|7051 | -0.3517 | 3.22e-08 | 0.000592
SPOCK1|6695 | 0.3427 | 7.526e-08 | 0.00138
CRCT1|54544 | -0.3389 | 1.382e-07 | 0.00254
PTDSS1|9791 | 0.3357 | 1.426e-07 | 0.00262
MPZL2|10205 | -0.331 | 2.184e-07 | 0.00401
CNIH3|149111 | 0.3218 | 4.885e-07 | 0.00898
TRMT12|55039 | 0.3215 | 5.019e-07 | 0.00923
SDS|10993 | 0.3196 | 5.892e-07 | 0.0108
ARL4C|10123 | 0.3194 | 5.998e-07 | 0.011

Figure S4. Get High-res Image As an example, this figure shows the association of SPRR2F|6705 to 'PATHOLOGY.N'. P value = 2.22e-08 with Spearman correlation analysis.

Clinical variable #6: 'TUMOR.STAGE'

No gene related to 'TUMOR.STAGE'.

Table S10. Basic characteristics of clinical feature: 'TUMOR.STAGE'

TUMOR.STAGE | Mean (SD) | 3.29 (0.97)
|  | N
| Stage 1 | 16
| Stage 2 | 47
| Stage 3 | 41
| Stage 4 | 153
| Significant markers | N = 0

Clinical variable #7: 'RADIATIONS.RADIATION.REGIMENINDICATION'

No gene related to 'RADIATIONS.RADIATION.REGIMENINDICATION'.

Table S11. Basic characteristics of clinical feature: 'RADIATIONS.RADIATION.REGIMENINDICATION'

RADIATIONS.RADIATION.REGIMENINDICATION | Labels | N
| NO | 75
| YES | 227
| Significant markers | N = 0

Clinical variable #8: 'NUMBERPACKYEARSSMOKED'

8 genes related to 'NUMBERPACKYEARSSMOKED'.

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

NUMBERPACKYEARSSMOKED | Mean (SD) | 49.97 (37)
| Significant markers | N = 8
| pos. correlated | 6
| neg. correlated | 2

List of 8 genes significantly correlated to 'NUMBERPACKYEARSSMOKED' by Spearman correlation test

Table S13. Get Full Table List of 8 genes significantly correlated to 'NUMBERPACKYEARSSMOKED' by Spearman correlation test

| SpearmanCorr | corrP | Q
--- | --- | --- | ---
GLI2|2736 | 0.3843 | 3.463e-07 | 0.00637
TMTC3|160418 | 0.379 | 5.184e-07 | 0.00953
DPH3|285381 | -0.3692 | 1.064e-06 | 0.0196
B4GALNT3|283358 | 0.3683 | 1.136e-06 | 0.0209
ZNRF3|84133 | 0.3631 | 1.639e-06 | 0.0301
KCNQ5|56479 | 0.3601 | 2.025e-06 | 0.0372
GPX2|2877 | 0.3582 | 2.316e-06 | 0.0426
MCOLN1|57192 | -0.356 | 2.698e-06 | 0.0496

Figure S5. Get High-res Image As an example, this figure shows the association of GLI2|2736 to 'NUMBERPACKYEARSSMOKED'. P value = 3.46e-07 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #9: 'STOPPEDSMOKINGYEAR'

No gene related to 'STOPPEDSMOKINGYEAR'.

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

STOPPEDSMOKINGYEAR | Mean (SD) | 1994.58 (14)
| Significant markers | N = 0

Clinical variable #10: 'TOBACCOSMOKINGHISTORYINDICATOR'

12 genes related to 'TOBACCOSMOKINGHISTORYINDICATOR'.

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

TOBACCOSMOKINGHISTORYINDICATOR | Labels | N
| CURRENT REFORMED SMOKER FOR < OR = 15 YEARS | 82
| CURRENT REFORMED SMOKER FOR > 15 YEARS | 53
| CURRENT SMOKER | 98
| LIFELONG NON-SMOKER | 58
| Significant markers | N = 12

List of top 10 genes differentially expressed by 'TOBACCOSMOKINGHISTORYINDICATOR'

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

| ANOVA_P | Q
--- | --- | ---
THAP11|57215 | 8.201e-10 | 1.51e-05
GPR15|2838 | 9.688e-10 | 1.78e-05
PCDH7|5099 | 1.123e-07 | 0.00207
CCDC96|257236 | 2.182e-07 | 0.00401
SLC29A2|3177 | 6.128e-07 | 0.0113
ALDOC|230 | 7.088e-07 | 0.013
DHCR7|1717 | 1.76e-06 | 0.0324
TRIM34|53840 | 1.821e-06 | 0.0335
CST3|1471 | 1.867e-06 | 0.0343
CYTL1|54360 | 1.895e-06 | 0.0348

Figure S6. Get High-res Image As an example, this figure shows the association of THAP11|57215 to 'TOBACCOSMOKINGHISTORYINDICATOR'. P value = 8.2e-10 with ANOVA analysis.

Clinical variable #11: 'YEAROFTOBACCOSMOKINGONSET'

No gene related to 'YEAROFTOBACCOSMOKINGONSET'.

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

YEAROFTOBACCOSMOKINGONSET | Mean (SD) | 1964.54 (12)
| Significant markers | N = 0

Methods & Data
Input

- Expresson data file = HNSC-TP.uncv2.mRNAseq_RSEM_normalized_log2.txt

- Clinical data file = HNSC-TP.clin.merged.picked.txt

- Number of patients = 302

- Number of genes = 18388

- Number of clinical features = 11

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

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

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] Howell, D, Statistical Methods for Psychology. (5th ed.), Duxbury Press:324-5 (2002)
[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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