Correlation between mRNAseq expression and clinical features
Head and Neck Squamous Cell Carcinoma (Primary solid tumor)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
Maintained by Juok Cho (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2015): Correlation between mRNAseq expression and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C1C53JWM
Overview
Introduction

This pipeline uses various statistical tests to identify mRNAs whose log2 expression levels correlated to selected clinical features.

Summary

Testing the association between 18378 genes and 14 clinical features across 514 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 12 clinical features related to at least one genes.

  • 30 genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP'.

    • ZNF266|10781 ,  AIG1|51390 ,  FRMD5|84978 ,  FGD3|89846 ,  CUL9|23113 ,  ...

  • 30 genes correlated to 'YEARS_TO_BIRTH'.

    • C1ORF103|55791 ,  RNASE3|6037 ,  PER3|8863 ,  MUTED|63915 ,  ABAT|18 ,  ...

  • 30 genes correlated to 'NEOPLASM_DISEASESTAGE'.

    • ZC3HAV1|56829 ,  TRIM25|7706 ,  WDR37|22884 ,  NCOA5|57727 ,  MYD88|4615 ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • C5ORF20|140947 ,  TCEANC|170082 ,  RNPC3|55599 ,  ADM|133 ,  DDIT4|54541 ,  ...

  • 30 genes correlated to 'PATHOLOGY_N_STAGE'.

    • MPZL2|10205 ,  ARHGAP32|9743 ,  SPRR2F|6705 ,  TRIM29|23650 ,  WDR37|22884 ,  ...

  • 7 genes correlated to 'GENDER'.

    • HDHD1A|8226 ,  CYORF15A|246126 ,  CYORF15B|84663 ,  CA5BP|340591 ,  FAM64A|54478 ,  ...

  • 30 genes correlated to 'HISTOLOGICAL_TYPE'.

    • EHD2|30846 ,  NCRNA00201|284702 ,  ACTB|60 ,  NFYB|4801 ,  SUGT1L1|283507 ,  ...

  • 30 genes correlated to 'RADIATIONS_RADIATION_REGIMENINDICATION'.

    • NFATC2|4773 ,  RAD54L2|23132 ,  H3F3A|3020 ,  LIMS1|3987 ,  ZNF827|152485 ,  ...

  • 30 genes correlated to 'NUMBER_PACK_YEARS_SMOKED'.

    • ALDOC|230 ,  SLC5A5|6528 ,  TMSL3|7117 ,  TMTC3|160418 ,  CAND1|55832 ,  ...

  • 30 genes correlated to 'YEAR_OF_TOBACCO_SMOKING_ONSET'.

    • SMAD6|4091 ,  ARSE|415 ,  AREG|374 ,  FMO3|2328 ,  SIPA1L3|23094 ,  ...

  • 30 genes correlated to 'NUMBER_OF_LYMPH_NODES'.

    • NLRX1|79671 ,  MASP1|5648 ,  ARL4C|10123 ,  MPZL2|10205 ,  BCO2|83875 ,  ...

  • 30 genes correlated to 'RACE'.

    • LOC90784|90784 ,  SERHL2|253190 ,  LRRC37A2|474170 ,  MXRA7|439921 ,  ULK4|54986 ,  ...

  • No genes correlated to 'PATHOLOGY_M_STAGE', and 'ETHNICITY'.

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=30 shorter survival N=10 longer survival N=20
YEARS_TO_BIRTH Spearman correlation test N=30 older N=16 younger N=14
NEOPLASM_DISEASESTAGE Kruskal-Wallis test N=30        
PATHOLOGY_T_STAGE Spearman correlation test N=30 higher stage N=6 lower stage N=24
PATHOLOGY_N_STAGE Spearman correlation test N=30 higher stage N=3 lower stage N=27
PATHOLOGY_M_STAGE Wilcoxon test   N=0        
GENDER Wilcoxon test N=7 male N=7 female N=0
HISTOLOGICAL_TYPE Kruskal-Wallis test N=30        
RADIATIONS_RADIATION_REGIMENINDICATION Wilcoxon test N=30 yes N=30 no N=0
NUMBER_PACK_YEARS_SMOKED Spearman correlation test N=30 higher number_pack_years_smoked N=25 lower number_pack_years_smoked N=5
YEAR_OF_TOBACCO_SMOKING_ONSET Spearman correlation test N=30 higher year_of_tobacco_smoking_onset N=6 lower year_of_tobacco_smoking_onset N=24
NUMBER_OF_LYMPH_NODES Spearman correlation test N=30 higher number_of_lymph_nodes N=6 lower number_of_lymph_nodes N=24
RACE Kruskal-Wallis test N=30        
ETHNICITY Wilcoxon test   N=0        
Clinical variable #1: 'DAYS_TO_DEATH_OR_LAST_FUP'

30 genes 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) 0.1-211 (median=18.6)
  censored N = 313
  death N = 200
     
  Significant markers N = 30
  associated with shorter survival 10
  associated with longer survival 20
List of top 10 genes differentially expressed by 'DAYS_TO_DEATH_OR_LAST_FUP'

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
ZNF266|10781 0.52 2.494e-08 0.00046 0.382
AIG1|51390 1.7 3.32e-07 0.0024 0.61
FRMD5|84978 1.2 5.129e-07 0.0024 0.623
FGD3|89846 0.72 5.211e-07 0.0024 0.386
CUL9|23113 0.68 1.145e-06 0.0042 0.396
CELSR3|1951 0.8 2.553e-06 0.005 0.394
HPRT1|3251 1.76 2.676e-06 0.005 0.591
ANKMY1|51281 0.59 2.868e-06 0.005 0.401
KIAA1683|80726 0.82 3.005e-06 0.005 0.378
DKK1|22943 1.15 3.097e-06 0.005 0.599
Clinical variable #2: 'YEARS_TO_BIRTH'

30 genes related to 'YEARS_TO_BIRTH'.

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

YEARS_TO_BIRTH Mean (SD) 60.85 (12)
  Significant markers N = 30
  pos. correlated 16
  neg. correlated 14
List of top 10 genes differentially expressed by 'YEARS_TO_BIRTH'

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

SpearmanCorr corrP Q
C1ORF103|55791 -0.2171 6.879e-07 0.0125
RNASE3|6037 0.2602 1.654e-06 0.0125
PER3|8863 -0.2079 2.041e-06 0.0125
MUTED|63915 -0.2027 3.698e-06 0.017
ABAT|18 -0.1981 6.175e-06 0.0227
GPSM2|29899 -0.1916 1.245e-05 0.0311
GABRR1|2569 0.2015 1.338e-05 0.0311
C19ORF76|199800 0.1908 1.354e-05 0.0311
CNTN5|53942 0.2227 1.612e-05 0.0314
TRPM2|7226 0.1881 1.793e-05 0.0314
Clinical variable #3: 'NEOPLASM_DISEASESTAGE'

30 genes related to 'NEOPLASM_DISEASESTAGE'.

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

NEOPLASM_DISEASESTAGE Labels N
  STAGE I 27
  STAGE II 75
  STAGE III 76
  STAGE IVA 253
  STAGE IVB 12
  STAGE IVC 1
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'NEOPLASM_DISEASESTAGE'

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

kruskal_wallis_P Q
ZC3HAV1|56829 4.708e-08 0.000438
TRIM25|7706 4.769e-08 0.000438
WDR37|22884 4.141e-06 0.0254
NCOA5|57727 1.437e-05 0.0584
MYD88|4615 1.589e-05 0.0584
C5ORF20|140947 2.373e-05 0.0702
DDIT4|54541 2.672e-05 0.0702
FUT7|2529 3.882e-05 0.0752
ITPR2|3709 4.049e-05 0.0752
MTHFR|4524 4.091e-05 0.0752
Clinical variable #4: 'PATHOLOGY_T_STAGE'

30 genes related to 'PATHOLOGY_T_STAGE'.

Table S7.  Basic characteristics of clinical feature: 'PATHOLOGY_T_STAGE'

PATHOLOGY_T_STAGE Mean (SD) 2.87 (1.1)
  N
  T0 1
  T1 48
  T2 132
  T3 98
  T4 173
     
  Significant markers N = 30
  pos. correlated 6
  neg. correlated 24
List of top 10 genes differentially expressed by 'PATHOLOGY_T_STAGE'

Table S8.  Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY_T_STAGE' by Spearman correlation test

SpearmanCorr corrP Q
C5ORF20|140947 -0.3087 2.786e-11 5.12e-07
TCEANC|170082 -0.2906 3.013e-10 2.77e-06
RNPC3|55599 -0.2846 7.143e-10 4.38e-06
ADM|133 0.28 1.378e-09 6.33e-06
DDIT4|54541 0.2729 3.665e-09 9.56e-06
LRRC8A|56262 0.2726 3.837e-09 9.56e-06
TLR10|81793 -0.2739 3.891e-09 9.56e-06
FUT7|2529 -0.2715 4.598e-09 9.56e-06
P2RY13|53829 -0.2709 4.98e-09 9.56e-06
CX3CR1|1524 -0.2712 5.202e-09 9.56e-06
Clinical variable #5: 'PATHOLOGY_N_STAGE'

30 genes related to 'PATHOLOGY_N_STAGE'.

Table S9.  Basic characteristics of clinical feature: 'PATHOLOGY_N_STAGE'

PATHOLOGY_N_STAGE Mean (SD) 1.02 (0.95)
  N
  N0 175
  N1 65
  N2 166
  N3 8
     
  Significant markers N = 30
  pos. correlated 3
  neg. correlated 27
List of top 10 genes differentially expressed by 'PATHOLOGY_N_STAGE'

Table S10.  Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY_N_STAGE' by Spearman correlation test

SpearmanCorr corrP Q
MPZL2|10205 -0.2871 2.694e-09 4.95e-05
ARHGAP32|9743 -0.2726 1.729e-08 0.000125
SPRR2F|6705 -0.2723 2.364e-08 0.000125
TRIM29|23650 -0.2689 2.729e-08 0.000125
WDR37|22884 -0.2604 7.657e-08 0.000218
IL1F5|26525 -0.2602 8.097e-08 0.000218
PDXP|57026 0.2597 8.297e-08 0.000218
TGM1|7051 -0.2576 1.058e-07 0.000243
APOC1|341 0.2562 1.249e-07 0.000244
D4S234E|27065 -0.2557 1.329e-07 0.000244
Clinical variable #6: 'PATHOLOGY_M_STAGE'

No gene related to 'PATHOLOGY_M_STAGE'.

Table S11.  Basic characteristics of clinical feature: 'PATHOLOGY_M_STAGE'

PATHOLOGY_M_STAGE Labels N
  class0 179
  class1 1
     
  Significant markers N = 0
Clinical variable #7: 'GENDER'

7 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 135
  MALE 379
     
  Significant markers N = 7
  Higher in MALE 7
  Higher in FEMALE 0
List of 7 genes differentially expressed by 'GENDER'

Table S13.  Get Full Table List of 7 genes differentially expressed by 'GENDER'. 23 significant gene(s) located in sex chromosomes is(are) filtered out.

W(pos if higher in 'MALE') wilcoxontestP Q AUC
HDHD1A|8226 9999 7.288e-26 1.12e-22 0.8046
CYORF15A|246126 10195 4.533e-18 4.38e-15 0.9989
CYORF15B|84663 9341 1.345e-16 1.18e-13 0.9937
CA5BP|340591 14872 4.919e-13 3.77e-10 0.7093
FAM64A|54478 35824 4.811e-12 3.27e-09 0.7002
ZNF232|7775 35006.5 2.026e-10 1.28e-07 0.6842
CCDC52|152185 34902 3.199e-10 1.96e-07 0.6821
Clinical variable #8: 'HISTOLOGICAL_TYPE'

30 genes related to 'HISTOLOGICAL_TYPE'.

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

HISTOLOGICAL_TYPE Labels N
  HEAD AND NECK SQUAMOUS CELL CARCINOMA 503
  HEAD AND NECK SQUAMOUS CELL CARCINOMA SPINDLE CELL VARIANT 1
  HEAD AND NECK SQUAMOUS CELL CARCINOMA BASALOID TYPE 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'

kruskal_wallis_P Q
EHD2|30846 1.924e-06 0.0156
NCRNA00201|284702 3.699e-06 0.0156
ACTB|60 4.652e-06 0.0156
NFYB|4801 4.661e-06 0.0156
SUGT1L1|283507 6.572e-06 0.0156
RALGPS1|9649 1.002e-05 0.0156
KIAA0907|22889 1.081e-05 0.0156
GNRHR2|114814 1.155e-05 0.0156
RCOR3|55758 1.166e-05 0.0156
C1ORF77|26097 1.262e-05 0.0156
Clinical variable #9: 'RADIATIONS_RADIATION_REGIMENINDICATION'

30 genes related to 'RADIATIONS_RADIATION_REGIMENINDICATION'.

Table S16.  Basic characteristics of clinical feature: 'RADIATIONS_RADIATION_REGIMENINDICATION'

RADIATIONS_RADIATION_REGIMENINDICATION Labels N
  NO 83
  YES 431
     
  Significant markers N = 30
  Higher in YES 30
  Higher in NO 0
List of top 10 genes differentially expressed by 'RADIATIONS_RADIATION_REGIMENINDICATION'

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

W(pos if higher in 'YES') wilcoxontestP Q AUC
NFATC2|4773 8156 5.24e-14 9.63e-10 0.7626
RAD54L2|23132 9192 2.273e-12 1.73e-08 0.743
H3F3A|3020 26535 2.962e-12 1.73e-08 0.7418
LIMS1|3987 9280 3.768e-12 1.73e-08 0.7406
ZNF827|152485 9352 6.481e-12 2.38e-08 0.738
NHSL2|340527 9367.5 1.054e-11 3.23e-08 0.7357
ATPIF1|93974 26235 1.613e-11 3.91e-08 0.7334
UHMK1|127933 9552 1.743e-11 3.91e-08 0.733
IL6ST|3572 9569 1.915e-11 3.91e-08 0.7325
ZNF366|167465 9264 2.73e-11 5.02e-08 0.7323
Clinical variable #10: 'NUMBER_PACK_YEARS_SMOKED'

30 genes related to 'NUMBER_PACK_YEARS_SMOKED'.

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

NUMBER_PACK_YEARS_SMOKED Mean (SD) 45.19 (35)
  Significant markers N = 30
  pos. correlated 25
  neg. correlated 5
List of top 10 genes differentially expressed by 'NUMBER_PACK_YEARS_SMOKED'

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

SpearmanCorr corrP Q
ALDOC|230 0.2878 6.175e-07 0.00478
SLC5A5|6528 0.2993 7.253e-07 0.00478
TMSL3|7117 -0.2844 8.498e-07 0.00478
TMTC3|160418 0.2822 1.041e-06 0.00478
CAND1|55832 0.2788 1.416e-06 0.00521
C12ORF66|144577 0.2763 1.767e-06 0.00541
LASS6|253782 0.265 4.741e-06 0.0102
GSR|2936 0.2646 4.923e-06 0.0102
UNC119B|84747 0.2644 5.016e-06 0.0102
DPH3|285381 -0.2629 5.688e-06 0.0104
Clinical variable #11: 'YEAR_OF_TOBACCO_SMOKING_ONSET'

30 genes related to 'YEAR_OF_TOBACCO_SMOKING_ONSET'.

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

YEAR_OF_TOBACCO_SMOKING_ONSET Mean (SD) 1967.2 (13)
  Significant markers N = 30
  pos. correlated 6
  neg. correlated 24
List of top 10 genes differentially expressed by 'YEAR_OF_TOBACCO_SMOKING_ONSET'

Table S21.  Get Full Table List of top 10 genes significantly correlated to 'YEAR_OF_TOBACCO_SMOKING_ONSET' by Spearman correlation test

SpearmanCorr corrP Q
SMAD6|4091 -0.2732 3.8e-06 0.0434
ARSE|415 -0.2705 5.356e-06 0.0434
AREG|374 0.2657 7.09e-06 0.0434
FMO3|2328 -0.2556 1.598e-05 0.0531
SIPA1L3|23094 -0.2547 1.72e-05 0.0531
TNFSF4|7292 -0.2543 1.774e-05 0.0531
ST8SIA4|7903 -0.2526 2.024e-05 0.0531
GJA5|2702 -0.2482 2.844e-05 0.059
MSR1|4481 -0.2458 3.431e-05 0.059
GRP|2922 -0.2612 3.467e-05 0.059
Clinical variable #12: 'NUMBER_OF_LYMPH_NODES'

30 genes related to 'NUMBER_OF_LYMPH_NODES'.

Table S22.  Basic characteristics of clinical feature: 'NUMBER_OF_LYMPH_NODES'

NUMBER_OF_LYMPH_NODES Mean (SD) 2.2 (4.3)
  Significant markers N = 30
  pos. correlated 6
  neg. correlated 24
List of top 10 genes differentially expressed by 'NUMBER_OF_LYMPH_NODES'

Table S23.  Get Full Table List of top 10 genes significantly correlated to 'NUMBER_OF_LYMPH_NODES' by Spearman correlation test

SpearmanCorr corrP Q
NLRX1|79671 -0.2739 2.685e-08 0.000378
MASP1|5648 -0.2672 6.233e-08 0.000378
ARL4C|10123 0.266 6.911e-08 0.000378
MPZL2|10205 -0.2645 8.218e-08 0.000378
BCO2|83875 -0.256 2.159e-07 0.000794
SLC5A10|125206 -0.2525 3.326e-07 0.000913
TRIM29|23650 -0.2505 4.017e-07 0.000913
PPEF1|5475 0.25 4.686e-07 0.000913
WDR37|22884 -0.2489 4.744e-07 0.000913
IL1F5|26525 -0.2481 5.371e-07 0.000913
Clinical variable #13: 'RACE'

30 genes related to 'RACE'.

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

RACE Labels N
  AMERICAN INDIAN OR ALASKA NATIVE 2
  ASIAN 11
  BLACK OR AFRICAN AMERICAN 45
  WHITE 439
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'RACE'

Table S25.  Get Full Table List of top 10 genes differentially expressed by 'RACE'

kruskal_wallis_P Q
LOC90784|90784 9.904e-09 0.000182
SERHL2|253190 7.8e-08 0.000717
LRRC37A2|474170 2.46e-07 0.00151
MXRA7|439921 3.454e-07 0.00159
ULK4|54986 4.858e-07 0.00179
GSTM1|2944 1.149e-06 0.00352
GCAT|23464 2.984e-06 0.0062
CRYBB2|1415 3.569e-06 0.0062
SERPINC1|462 3.894e-06 0.0062
POLR2J2|246721 3.964e-06 0.0062
Clinical variable #14: 'ETHNICITY'

No gene related to 'ETHNICITY'.

Table S26.  Basic characteristics of clinical feature: 'ETHNICITY'

ETHNICITY Labels N
  HISPANIC OR LATINO 24
  NOT HISPANIC OR LATINO 453
     
  Significant markers N = 0
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 = 514

  • Number of genes = 18378

  • Number of clinical features = 14

Selected clinical features
  • For clinical features selected for this analysis and their value conozzle.versions, please find a documentation on selected CDEs .

  • 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, 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

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.

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] 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)