Correlation between mRNAseq expression and clinical features
Head and Neck Squamous Cell Carcinoma (Primary solid tumor)
15 January 2014  |  analyses__2014_01_15
Maintainer Information
Citation Information
doi:10.7908/C1KW5DGF
Maintained by Juok Cho (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2014): Correlation between mRNAseq expression and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C1KW5DGF
Overview
Introduction

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

Summary

Testing the association between 18339 genes and 12 clinical features across 360 samples, statistically thresholded by Q value < 0.05, 10 clinical features related to at least one genes.

  • 17 genes correlated to 'Time to Death'.

    • FGD3|89846 ,  CYB5B|80777 ,  TP53INP1|94241 ,  LOC728989|728989 ,  SLC25A45|283130 ,  ...

  • 1 gene correlated to 'AGE'.

    • RNASE3|6037

  • 11 genes correlated to 'PATHOLOGY.T.STAGE'.

    • LRRC8A|56262 ,  WDR37|22884 ,  MSL3|10943 ,  TCEANC|170082 ,  C6ORF62|81688 ,  ...

  • 20 genes correlated to 'PATHOLOGY.N.STAGE'.

    • TGM1|7051 ,  APOC1|341 ,  MPZL2|10205 ,  SPRR2F|6705 ,  PDXP|57026 ,  ...

  • 10 genes correlated to 'PATHOLOGY.M.STAGE'.

    • SNHG12|85028 ,  SNHG3|8420 ,  TIAL1|7073 ,  NSUN5P2|260294 ,  METT11D1|64745 ,  ...

  • 61 genes correlated to 'GENDER'.

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

  • 88 genes correlated to 'HISTOLOGICAL.TYPE'.

    • LOC100190940|100190940 ,  GPR45|11250 ,  DQX1|165545 ,  MAL2|114569 ,  THBS3|7059 ,  ...

  • 4 genes correlated to 'RADIATIONS.RADIATION.REGIMENINDICATION'.

    • NFATC2|4773 ,  CTDSP2|10106 ,  IRAK3|11213 ,  ITPRIPL2|162073

  • 52 genes correlated to 'NUMBERPACKYEARSSMOKED'.

    • TMTC3|160418 ,  DPH3|285381 ,  KLHL13|90293 ,  C12ORF66|144577 ,  GLI2|2736 ,  ...

  • 31 genes correlated to 'NUMBER.OF.LYMPH.NODES'.

    • ARL4C|10123 ,  MPZL2|10205 ,  TGM1|7051 ,  PPEF1|5475 ,  ALS2CL|259173 ,  ...

  • No genes correlated to 'NEOPLASM.DISEASESTAGE', 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=17 shorter survival N=10 longer survival N=7
AGE Spearman correlation test N=1 older N=1 younger N=0
NEOPLASM DISEASESTAGE ANOVA test   N=0        
PATHOLOGY T STAGE Spearman correlation test N=11 higher stage N=2 lower stage N=9
PATHOLOGY N STAGE Spearman correlation test N=20 higher stage N=8 lower stage N=12
PATHOLOGY M STAGE t test N=10 mx N=10 m0 N=0
GENDER t test N=61 male N=27 female N=34
HISTOLOGICAL TYPE ANOVA test N=88        
RADIATIONS RADIATION REGIMENINDICATION t test N=4 yes N=0 no N=4
NUMBERPACKYEARSSMOKED Spearman correlation test N=52 higher numberpackyearssmoked N=43 lower numberpackyearssmoked N=9
YEAROFTOBACCOSMOKINGONSET Spearman correlation test   N=0        
NUMBER OF LYMPH NODES Spearman correlation test N=31 higher number.of.lymph.nodes N=11 lower number.of.lymph.nodes N=20
Clinical variable #1: 'Time to Death'

17 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=16.1)
  censored N = 219
  death N = 137
     
  Significant markers N = 17
  associated with shorter survival 10
  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
FGD3|89846 0.65 4.847e-08 0.00089 0.346
CYB5B|80777 2.3 7.119e-08 0.0013 0.624
TP53INP1|94241 0.63 2.863e-07 0.0052 0.361
LOC728989|728989 0.67 3.763e-07 0.0069 0.361
SLC25A45|283130 0.6 5.526e-07 0.01 0.368
POLR2C|5432 2.5 7.137e-07 0.013 0.62
TOMM34|10953 2.1 7.628e-07 0.014 0.637
FRMD5|84978 1.24 8.11e-07 0.015 0.648
DKK1|22943 1.19 8.979e-07 0.016 0.633
SLC35E2|728661 0.58 1.114e-06 0.02 0.4

Figure S1.  Get High-res Image As an example, this figure shows the association of FGD3|89846 to 'Time to Death'. four curves present the cumulative survival rates of 4 quartile subsets of patients. P value = 4.85e-08 with univariate Cox regression analysis using continuous log-2 expression values.

Clinical variable #2: 'AGE'

One gene related to 'AGE'.

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

AGE Mean (SD) 60.63 (12)
  Significant markers N = 1
  pos. correlated 1
  neg. correlated 0
List of one gene significantly correlated to 'AGE' by Spearman correlation test

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

SpearmanCorr corrP Q
RNASE3|6037 0.3188 5.973e-07 0.011

Figure S2.  Get High-res Image As an example, this figure shows the association of RNASE3|6037 to 'AGE'. P value = 5.97e-07 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #3: 'NEOPLASM.DISEASESTAGE'

No gene related to 'NEOPLASM.DISEASESTAGE'.

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

NEOPLASM.DISEASESTAGE Labels N
  STAGE I 23
  STAGE II 54
  STAGE III 58
  STAGE IVA 168
  STAGE IVB 6
     
  Significant markers N = 0
Clinical variable #4: 'PATHOLOGY.T.STAGE'

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

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

PATHOLOGY.T.STAGE Mean (SD) 2.85 (1)
  N
  1 35
  2 91
  3 74
  4 114
     
  Significant markers N = 11
  pos. correlated 2
  neg. correlated 9
List of top 10 genes significantly correlated to 'PATHOLOGY.T.STAGE' by Spearman correlation test

Table S7.  Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY.T.STAGE' by Spearman correlation test

SpearmanCorr corrP Q
LRRC8A|56262 0.322 5.214e-09 9.56e-05
WDR37|22884 -0.3011 5.288e-08 0.00097
MSL3|10943 -0.2977 7.565e-08 0.00139
TCEANC|170082 -0.2815 3.957e-07 0.00725
C6ORF62|81688 -0.2788 5.128e-07 0.0094
CX3CR1|1524 -0.2775 5.864e-07 0.0108
HIST1H1E|3008 0.2745 8.11e-07 0.0149
ZNF547|284306 -0.2653 1.856e-06 0.034
PKNOX1|5316 -0.2633 2.243e-06 0.0411
C14ORF139|79686 -0.2629 2.328e-06 0.0427

Figure S3.  Get High-res Image As an example, this figure shows the association of LRRC8A|56262 to 'PATHOLOGY.T.STAGE'. P value = 5.21e-09 with Spearman correlation analysis.

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

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

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

PATHOLOGY.N.STAGE Mean (SD) 1.02 (0.95)
  N
  0 118
  1 44
  2 114
  3 5
     
  Significant markers N = 20
  pos. correlated 8
  neg. correlated 12
List of top 10 genes significantly correlated to 'PATHOLOGY.N.STAGE' by Spearman correlation test

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

SpearmanCorr corrP Q
TGM1|7051 -0.3121 9.189e-08 0.00169
APOC1|341 0.3066 1.574e-07 0.00289
MPZL2|10205 -0.3064 1.606e-07 0.00295
SPRR2F|6705 -0.3004 3.671e-07 0.00673
PDXP|57026 0.2947 4.911e-07 0.009
CRCT1|54544 -0.2961 5.194e-07 0.00952
PTDSS1|9791 0.2886 8.608e-07 0.0158
PRSS12|8492 -0.2885 8.66e-07 0.0159
ALS2CL|259173 -0.2842 1.273e-06 0.0233
MAF1|84232 0.2842 1.277e-06 0.0234

Figure S4.  Get High-res Image As an example, this figure shows the association of TGM1|7051 to 'PATHOLOGY.N.STAGE'. P value = 9.19e-08 with Spearman correlation analysis.

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

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

Table S10.  Basic characteristics of clinical feature: 'PATHOLOGY.M.STAGE'

PATHOLOGY.M.STAGE Labels N
  M0 83
  MX 20
     
  Significant markers N = 10
  Higher in MX 10
  Higher in M0 0
List of 10 genes differentially expressed by 'PATHOLOGY.M.STAGE'

Table S11.  Get Full Table List of 10 genes differentially expressed by 'PATHOLOGY.M.STAGE'

T(pos if higher in 'MX') ttestP Q AUC
SNHG12|85028 6.72 1.54e-08 0.000282 0.8223
SNHG3|8420 6.14 1.313e-07 0.00241 0.8072
TIAL1|7073 5.98 2.196e-07 0.00403 0.8169
NSUN5P2|260294 5.68 5.714e-07 0.0105 0.7843
METT11D1|64745 5.54 6.752e-07 0.0124 0.7873
SNHG1|23642 5.61 9.244e-07 0.0169 0.7831
CCNL2|81669 5.42 9.633e-07 0.0177 0.7717
RABGGTB|5876 5.75 9.653e-07 0.0177 0.8006
ACYP1|97 5.66 1.473e-06 0.027 0.812
NSUN5P1|155400 5.39 1.934e-06 0.0354 0.7765

Figure S5.  Get High-res Image As an example, this figure shows the association of SNHG12|85028 to 'PATHOLOGY.M.STAGE'. P value = 1.54e-08 with T-test analysis.

Clinical variable #7: 'GENDER'

61 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 101
  MALE 259
     
  Significant markers N = 61
  Higher in MALE 27
  Higher in FEMALE 34
List of top 10 genes differentially expressed by 'GENDER'

Table S13.  Get Full Table List of top 10 genes differentially expressed by 'GENDER'

T(pos if higher in 'MALE') ttestP Q AUC
XIST|7503 -46.91 2.402e-130 4.4e-126 0.9981
ZFY|7544 44.1 5.468e-108 1e-103 0.9961
PRKY|5616 31.42 3.973e-82 7.28e-78 0.9937
RPS4Y1|6192 41.27 8.587e-74 1.57e-69 0.9998
DDX3Y|8653 41.68 1.521e-67 2.79e-63 0.9963
USP9Y|8287 36.03 3.816e-56 7e-52 0.9983
KDM5D|8284 36.63 3.922e-50 7.19e-46 0.9979
UTY|7404 33.38 2.594e-48 4.75e-44 0.9943
TSIX|9383 -18.09 5.707e-42 1.05e-37 0.9671
NLGN4Y|22829 21.14 3.216e-28 5.89e-24 0.9834

Figure S6.  Get High-res Image As an example, this figure shows the association of XIST|7503 to 'GENDER'. P value = 2.4e-130 with T-test analysis.

Clinical variable #8: 'HISTOLOGICAL.TYPE'

88 genes related to 'HISTOLOGICAL.TYPE'.

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

HISTOLOGICAL.TYPE Labels N
  HEAD AND NECK SQUAMOUS CELL CARCINOMA 355
  HEAD AND NECK SQUAMOUS CELL CARCINOMA SPINDLE CELL VARIANT 1
  HEAD AND NECK SQUAMOUS CELL CARCINOMA BASALOID TYPE 4
     
  Significant markers N = 88
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
LOC100190940|100190940 7.962e-14 1.46e-09
GPR45|11250 3.386e-13 6.2e-09
DQX1|165545 4.12e-13 7.54e-09
MAL2|114569 1.305e-11 2.39e-07
THBS3|7059 2.21e-11 4.04e-07
MAP7D3|79649 6.773e-11 1.24e-06
POU3F2|5454 1.349e-10 2.47e-06
MARVELD2|153562 2.574e-10 4.71e-06
EHD2|30846 5.593e-10 1.02e-05
TOM1L1|10040 6.731e-10 1.23e-05

Figure S7.  Get High-res Image As an example, this figure shows the association of LOC100190940|100190940 to 'HISTOLOGICAL.TYPE'. P value = 7.96e-14 with ANOVA analysis.

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

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

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

RADIATIONS.RADIATION.REGIMENINDICATION Labels N
  NO 76
  YES 284
     
  Significant markers N = 4
  Higher in YES 0
  Higher in NO 4
List of 4 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

Table S17.  Get Full Table List of 4 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

T(pos if higher in 'YES') ttestP Q AUC
NFATC2|4773 -5.84 3.554e-08 0.000652 0.7015
CTDSP2|10106 -5.14 1.065e-06 0.0195 0.6821
IRAK3|11213 -4.94 2.11e-06 0.0387 0.6724
ITPRIPL2|162073 -4.93 2.342e-06 0.0429 0.6611

Figure S8.  Get High-res Image As an example, this figure shows the association of NFATC2|4773 to 'RADIATIONS.RADIATION.REGIMENINDICATION'. P value = 3.55e-08 with T-test analysis.

Clinical variable #10: 'NUMBERPACKYEARSSMOKED'

52 genes related to 'NUMBERPACKYEARSSMOKED'.

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

NUMBERPACKYEARSSMOKED Mean (SD) 47.52 (39)
  Significant markers N = 52
  pos. correlated 43
  neg. correlated 9
List of top 10 genes significantly correlated to 'NUMBERPACKYEARSSMOKED' by Spearman correlation test

Table S19.  Get Full Table List of top 10 genes significantly correlated to 'NUMBERPACKYEARSSMOKED' by Spearman correlation test

SpearmanCorr corrP Q
TMTC3|160418 0.4033 2.021e-09 3.71e-05
DPH3|285381 -0.3761 2.727e-08 5e-04
KLHL13|90293 0.3718 4.044e-08 0.000742
C12ORF66|144577 0.3696 4.938e-08 0.000905
GLI2|2736 0.3691 5.167e-08 0.000947
LASS6|253782 0.3685 5.444e-08 0.000998
TMSL3|7117 -0.3659 6.853e-08 0.00126
LRP4|4038 0.3637 8.283e-08 0.00152
ATPIF1|93974 -0.3579 1.375e-07 0.00252
ZNF462|58499 0.3575 1.418e-07 0.0026

Figure S9.  Get High-res Image As an example, this figure shows the association of TMTC3|160418 to 'NUMBERPACKYEARSSMOKED'. P value = 2.02e-09 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #11: 'YEAROFTOBACCOSMOKINGONSET'

No gene related to 'YEAROFTOBACCOSMOKINGONSET'.

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

YEAROFTOBACCOSMOKINGONSET Mean (SD) 1966.18 (13)
  Significant markers N = 0
Clinical variable #12: 'NUMBER.OF.LYMPH.NODES'

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

Table S21.  Basic characteristics of clinical feature: 'NUMBER.OF.LYMPH.NODES'

NUMBER.OF.LYMPH.NODES Mean (SD) 2.54 (5)
  Significant markers N = 31
  pos. correlated 11
  neg. correlated 20
List of top 10 genes significantly correlated to 'NUMBER.OF.LYMPH.NODES' by Spearman correlation test

Table S22.  Get Full Table List of top 10 genes significantly correlated to 'NUMBER.OF.LYMPH.NODES' by Spearman correlation test

SpearmanCorr corrP Q
ARL4C|10123 0.3534 2.174e-09 3.99e-05
MPZL2|10205 -0.3214 6.289e-08 0.00115
TGM1|7051 -0.316 1.072e-07 0.00197
PPEF1|5475 0.3104 2.15e-07 0.00394
ALS2CL|259173 -0.3068 2.566e-07 0.0047
GDPD3|79153 -0.306 2.791e-07 0.00512
SLC13A4|26266 -0.3036 3.846e-07 0.00705
SERPINB2|5055 -0.3014 4.282e-07 0.00785
GSC|145258 0.3002 5.247e-07 0.00962
APOE|348 0.2981 5.756e-07 0.0106

Figure S10.  Get High-res Image As an example, this figure shows the association of ARL4C|10123 to 'NUMBER.OF.LYMPH.NODES'. P value = 2.17e-09 with Spearman correlation analysis. The straight line presents the best linear regression.

Methods & Data
Input

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

  • Clinical data file = HNSC-TP.merged_data.txt

  • Number of patients = 360

  • Number of genes = 18339

  • Number of clinical features = 12

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.

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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