Lung Adenocarcinoma: 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 18330 genes and 14 clinical features across 324 samples, statistically thresholded by Q value < 0.05, 11 clinical features related to at least one genes.

  • 6 genes correlated to 'Time to Death'.

    • ESYT3|83850 ,  UCN2|90226 ,  MYLIP|29116 ,  DKK1|22943 ,  LYAR|55646 ,  ...

  • 42 genes correlated to 'GENDER'.

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

  • 25 genes correlated to 'HISTOLOGICAL.TYPE'.

    • CREB3L3|84699 ,  A4GNT|51146 ,  LOC55908|55908 ,  CRH|1392 ,  DPCR1|135656 ,  ...

  • 13 genes correlated to 'PATHOLOGY.T'.

    • FAM125B|89853 ,  MS4A1|931 ,  PPP1R16B|26051 ,  GPR171|29909 ,  ZNF671|79891 ,  ...

  • 4 genes correlated to 'PATHOLOGY.N'.

    • RARS|5917 ,  ZNF483|158399 ,  LOC729020|729020 ,  DAPK2|23604

  • 45 genes correlated to 'PATHOLOGICSPREAD(M)'.

    • C19ORF10|56005 ,  MLL5|55904 ,  C12ORF57|113246 ,  PPIG|9360 ,  MPG|4350 ,  ...

  • 8 genes correlated to 'TUMOR.STAGE'.

    • LDHA|3939 ,  ZNF540|163255 ,  ST6GAL1|6480 ,  ACSS1|84532 ,  ZFP3|124961 ,  ...

  • 2 genes correlated to 'NUMBERPACKYEARSSMOKED'.

    • LHFPL3|375612 ,  LOC723809|723809

  • 6 genes correlated to 'STOPPEDSMOKINGYEAR'.

    • GPR15|2838 ,  CCND3|896 ,  STC1|6781 ,  ACOX3|8310 ,  LOXL2|4017 ,  ...

  • 283 genes correlated to 'TOBACCOSMOKINGHISTORYINDICATOR'.

    • GPR15|2838 ,  DBF4B|80174 ,  CHEK1|1111 ,  KIF18B|146909 ,  KNTC1|9735 ,  ...

  • 4 genes correlated to 'YEAROFTOBACCOSMOKINGONSET'.

    • C14ORF118|55668 ,  KLRC4|8302 ,  GPR15|2838 ,  ENTPD3|956

  • No genes correlated to 'AGE', 'KARNOFSKY.PERFORMANCE.SCORE', and 'RADIATIONS.RADIATION.REGIMENINDICATION'.

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=6 shorter survival N=4 longer survival N=2
AGE Spearman correlation test   N=0        
GENDER t test N=42 male N=20 female N=22
KARNOFSKY PERFORMANCE SCORE Spearman correlation test   N=0        
HISTOLOGICAL TYPE ANOVA test N=25        
PATHOLOGY T Spearman correlation test N=13 higher pT N=0 lower pT N=13
PATHOLOGY N Spearman correlation test N=4 higher pN N=2 lower pN N=2
PATHOLOGICSPREAD(M) ANOVA test N=45        
TUMOR STAGE Spearman correlation test N=8 higher stage N=3 lower stage N=5
RADIATIONS RADIATION REGIMENINDICATION t test   N=0        
NUMBERPACKYEARSSMOKED Spearman correlation test N=2 higher numberpackyearssmoked N=0 lower numberpackyearssmoked N=2
STOPPEDSMOKINGYEAR Spearman correlation test N=6 higher stoppedsmokingyear N=4 lower stoppedsmokingyear N=2
TOBACCOSMOKINGHISTORYINDICATOR ANOVA test N=283        
YEAROFTOBACCOSMOKINGONSET Spearman correlation test N=4 higher yearoftobaccosmokingonset N=3 lower yearoftobaccosmokingonset N=1
Clinical variable #1: 'Time to Death'

6 genes related to 'Time to Death'.

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

Time to Death Duration (Months) 0-224 (median=10.1)
  censored N = 208
  death N = 80
     
  Significant markers N = 6
  associated with shorter survival 4
  associated with longer survival 2
List of 6 genes significantly associated with 'Time to Death' by Cox regression test

Table S2.  Get Full Table List of 6 genes significantly associated with 'Time to Death' by Cox regression test

HazardRatio Wald_P Q C_index
ESYT3|83850 0.73 2.917e-07 0.0053 0.365
UCN2|90226 1.35 6.44e-07 0.012 0.636
MYLIP|29116 0.51 1.257e-06 0.023 0.349
DKK1|22943 1.19 1.92e-06 0.035 0.707
LYAR|55646 2.3 2.628e-06 0.048 0.64
PPP1R3G|648791 1.51 2.747e-06 0.05 0.658

Figure S1.  Get High-res Image As an example, this figure shows the association of ESYT3|83850 to 'Time to Death'. four curves present the cumulative survival rates of 4 quartile subsets of patients. P value = 2.92e-07 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) 65.43 (9.8)
  Significant markers N = 0
Clinical variable #3: 'GENDER'

42 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 177
  MALE 147
     
  Significant markers N = 42
  Higher in MALE 20
  Higher in FEMALE 22
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
PRKY|5616 44.09 3.498e-131 6.41e-127 0.9994
ZFY|7544 52.14 1.904e-106 3.49e-102 0.9979
RPS4Y1|6192 47.1 3.757e-87 6.88e-83 0.9965
XIST|7503 -35.08 1.118e-79 2.05e-75 0.9842
DDX3Y|8653 43.19 1.531e-57 2.8e-53 0.9973
KDM5D|8284 36.62 3.634e-42 6.66e-38 0.9981
NLGN4Y|22829 24.9 9.35e-42 1.71e-37 0.9917
USP9Y|8287 35.64 6.855e-40 1.26e-35 0.9996
TSIX|9383 -18.62 1.441e-35 2.64e-31 0.9818
UTY|7404 25.08 4.261e-22 7.81e-18 0.9956

Figure S2.  Get High-res Image As an example, this figure shows the association of PRKY|5616 to 'GENDER'. P value = 3.5e-131 with T-test analysis.

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

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

Table S6.  Basic characteristics of clinical feature: 'KARNOFSKY.PERFORMANCE.SCORE'

KARNOFSKY.PERFORMANCE.SCORE Mean (SD) 75.36 (33)
  Significant markers N = 0
Clinical variable #5: 'HISTOLOGICAL.TYPE'

25 genes related to 'HISTOLOGICAL.TYPE'.

Table S7.  Basic characteristics of clinical feature: 'HISTOLOGICAL.TYPE'

HISTOLOGICAL.TYPE Labels N
  LUNG ACINAR ADENOCARCINOMA 10
  LUNG ADENOCARCINOMA MIXED SUBTYPE 73
  LUNG ADENOCARCINOMA- NOT OTHERWISE SPECIFIED (NOS) 198
  LUNG BRONCHIOLOALVEOLAR CARCINOMA MUCINOUS 3
  LUNG BRONCHIOLOALVEOLAR CARCINOMA NONMUCINOUS 14
  LUNG CLEAR CELL ADENOCARCINOMA 2
  LUNG MICROPAPILLARY ADENOCARCINOMA 3
  LUNG MUCINOUS ADENOCARCINOMA 2
  LUNG PAPILLARY ADENOCARCINOMA 13
  LUNG SOLID PATTERN PREDOMINANT ADENOCARCINOMA 2
  MUCINOUS (COLLOID) ADENOCARCINOMA 4
     
  Significant markers N = 25
List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

Table S8.  Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

ANOVA_P Q
CREB3L3|84699 1.536e-11 2.82e-07
A4GNT|51146 1.202e-09 2.2e-05
LOC55908|55908 3.553e-09 6.51e-05
CRH|1392 4.117e-09 7.55e-05
DPCR1|135656 1.818e-08 0.000333
REG4|83998 2.83e-08 0.000519
MYO1A|4640 6.181e-08 0.00113
SOX10|6663 9.508e-08 0.00174
ELOVL5|60481 1.315e-07 0.00241
SLC22A10|387775 1.361e-07 0.00249

Figure S3.  Get High-res Image As an example, this figure shows the association of CREB3L3|84699 to 'HISTOLOGICAL.TYPE'. P value = 1.54e-11 with ANOVA analysis.

Clinical variable #6: 'PATHOLOGY.T'

13 genes related to 'PATHOLOGY.T'.

Table S9.  Basic characteristics of clinical feature: 'PATHOLOGY.T'

PATHOLOGY.T Mean (SD) 1.89 (0.76)
  N
  T1 94
  T2 185
  T3 26
  T4 17
     
  Significant markers N = 13
  pos. correlated 0
  neg. correlated 13
List of top 10 genes significantly correlated to 'PATHOLOGY.T' by Spearman correlation test

Table S10.  Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY.T' by Spearman correlation test

SpearmanCorr corrP Q
FAM125B|89853 -0.2865 1.691e-07 0.0031
MS4A1|931 -0.2825 2.639e-07 0.00484
PPP1R16B|26051 -0.2772 4.342e-07 0.00796
GPR171|29909 -0.2749 5.405e-07 0.00991
ZNF671|79891 -0.2729 6.577e-07 0.0121
FCRL1|115350 -0.275 8.771e-07 0.0161
C14ORF139|79686 -0.2658 1.311e-06 0.024
RASGRP2|10235 -0.2632 1.676e-06 0.0307
STAP1|26228 -0.2617 1.917e-06 0.0351
NELL2|4753 -0.2611 2.029e-06 0.0372

Figure S4.  Get High-res Image As an example, this figure shows the association of FAM125B|89853 to 'PATHOLOGY.T'. P value = 1.69e-07 with Spearman correlation analysis.

Clinical variable #7: 'PATHOLOGY.N'

4 genes related to 'PATHOLOGY.N'.

Table S11.  Basic characteristics of clinical feature: 'PATHOLOGY.N'

PATHOLOGY.N Mean (SD) 0.55 (0.77)
  N
  N0 197
  N1 65
  N2 52
  N3 1
     
  Significant markers N = 4
  pos. correlated 2
  neg. correlated 2
List of 4 genes significantly correlated to 'PATHOLOGY.N' by Spearman correlation test

Table S12.  Get Full Table List of 4 genes significantly correlated to 'PATHOLOGY.N' by Spearman correlation test

SpearmanCorr corrP Q
RARS|5917 0.2902 1.577e-07 0.00289
ZNF483|158399 -0.2844 2.845e-07 0.00521
LOC729020|729020 0.2725 9.095e-07 0.0167
DAPK2|23604 -0.2643 1.973e-06 0.0362

Figure S5.  Get High-res Image As an example, this figure shows the association of RARS|5917 to 'PATHOLOGY.N'. P value = 1.58e-07 with Spearman correlation analysis.

Clinical variable #8: 'PATHOLOGICSPREAD(M)'

45 genes related to 'PATHOLOGICSPREAD(M)'.

Table S13.  Basic characteristics of clinical feature: 'PATHOLOGICSPREAD(M)'

PATHOLOGICSPREAD(M) Labels N
  M0 225
  M1 17
  MX 74
     
  Significant markers N = 45
List of top 10 genes differentially expressed by 'PATHOLOGICSPREAD(M)'

Table S14.  Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGICSPREAD(M)'

ANOVA_P Q
C19ORF10|56005 1.671e-08 0.000306
MLL5|55904 2.373e-08 0.000435
C12ORF57|113246 3.489e-08 0.000639
PPIG|9360 4.417e-08 0.000809
MPG|4350 5.693e-08 0.00104
SON|6651 8.974e-08 0.00164
C3ORF42|84657 1.052e-07 0.00193
MLST8|64223 1.935e-07 0.00355
ARL6IP4|51329 2.489e-07 0.00456
NCRNA00116|205251 2.501e-07 0.00458

Figure S6.  Get High-res Image As an example, this figure shows the association of C19ORF10|56005 to 'PATHOLOGICSPREAD(M)'. P value = 1.67e-08 with ANOVA analysis.

Clinical variable #9: 'TUMOR.STAGE'

8 genes related to 'TUMOR.STAGE'.

Table S15.  Basic characteristics of clinical feature: 'TUMOR.STAGE'

TUMOR.STAGE Mean (SD) 1.77 (0.94)
  N
  Stage 1 169
  Stage 2 71
  Stage 3 61
  Stage 4 17
     
  Significant markers N = 8
  pos. correlated 3
  neg. correlated 5
List of 8 genes significantly correlated to 'TUMOR.STAGE' by Spearman correlation test

Table S16.  Get Full Table List of 8 genes significantly correlated to 'TUMOR.STAGE' by Spearman correlation test

SpearmanCorr corrP Q
LDHA|3939 0.282 3.167e-07 0.0058
ZNF540|163255 -0.2734 7.375e-07 0.0135
ST6GAL1|6480 -0.2698 1.047e-06 0.0192
ACSS1|84532 -0.2665 1.425e-06 0.0261
ZFP3|124961 -0.2608 2.432e-06 0.0446
ERO1L|30001 0.26 2.612e-06 0.0479
FAM117A|81558 -0.26 2.622e-06 0.048
RARS|5917 0.2596 2.699e-06 0.0494

Figure S7.  Get High-res Image As an example, this figure shows the association of LDHA|3939 to 'TUMOR.STAGE'. P value = 3.17e-07 with Spearman correlation analysis.

Clinical variable #10: 'RADIATIONS.RADIATION.REGIMENINDICATION'

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

Table S17.  Basic characteristics of clinical feature: 'RADIATIONS.RADIATION.REGIMENINDICATION'

RADIATIONS.RADIATION.REGIMENINDICATION Labels N
  NO 18
  YES 306
     
  Significant markers N = 0
Clinical variable #11: 'NUMBERPACKYEARSSMOKED'

2 genes related to 'NUMBERPACKYEARSSMOKED'.

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

NUMBERPACKYEARSSMOKED Mean (SD) 39.72 (26)
  Significant markers N = 2
  pos. correlated 0
  neg. correlated 2
List of 2 genes significantly correlated to 'NUMBERPACKYEARSSMOKED' by Spearman correlation test

Table S19.  Get Full Table List of 2 genes significantly correlated to 'NUMBERPACKYEARSSMOKED' by Spearman correlation test

SpearmanCorr corrP Q
LHFPL3|375612 -0.3346 1.136e-06 0.0208
LOC723809|723809 -0.3251 1.565e-06 0.0287

Figure S8.  Get High-res Image As an example, this figure shows the association of LHFPL3|375612 to 'NUMBERPACKYEARSSMOKED'. P value = 1.14e-06 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #12: 'STOPPEDSMOKINGYEAR'

6 genes related to 'STOPPEDSMOKINGYEAR'.

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

STOPPEDSMOKINGYEAR Mean (SD) 1993.85 (14)
  Significant markers N = 6
  pos. correlated 4
  neg. correlated 2
List of 6 genes significantly correlated to 'STOPPEDSMOKINGYEAR' by Spearman correlation test

Table S21.  Get Full Table List of 6 genes significantly correlated to 'STOPPEDSMOKINGYEAR' by Spearman correlation test

SpearmanCorr corrP Q
GPR15|2838 0.5967 4.001e-16 7.33e-12
CCND3|896 -0.377 6.009e-07 0.011
STC1|6781 0.3667 1.269e-06 0.0233
ACOX3|8310 -0.3666 1.281e-06 0.0235
LOXL2|4017 0.3586 2.244e-06 0.0411
C9ORF25|203259 0.3574 2.44e-06 0.0447

Figure S9.  Get High-res Image As an example, this figure shows the association of GPR15|2838 to 'STOPPEDSMOKINGYEAR'. P value = 4e-16 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #13: 'TOBACCOSMOKINGHISTORYINDICATOR'

283 genes related to 'TOBACCOSMOKINGHISTORYINDICATOR'.

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

TOBACCOSMOKINGHISTORYINDICATOR Labels N
  CURRENT REFORMED SMOKER FOR < OR = 15 YEARS 110
  CURRENT REFORMED SMOKER FOR > 15 YEARS 87
  CURRENT SMOKER 71
  LIFELONG NON-SMOKER 45
     
  Significant markers N = 283
List of top 10 genes differentially expressed by 'TOBACCOSMOKINGHISTORYINDICATOR'

Table S23.  Get Full Table List of top 10 genes differentially expressed by 'TOBACCOSMOKINGHISTORYINDICATOR'

ANOVA_P Q
GPR15|2838 5.989e-16 1.1e-11
DBF4B|80174 4.564e-11 8.36e-07
CHEK1|1111 2.83e-10 5.19e-06
KIF18B|146909 5.035e-10 9.23e-06
KNTC1|9735 1.116e-09 2.05e-05
C20ORF103|24141 1.192e-09 2.18e-05
C15ORF42|90381 1.307e-09 2.4e-05
C9ORF140|89958 1.517e-09 2.78e-05
SKA1|220134 1.528e-09 2.8e-05
PRC1|9055 1.679e-09 3.08e-05

Figure S10.  Get High-res Image As an example, this figure shows the association of GPR15|2838 to 'TOBACCOSMOKINGHISTORYINDICATOR'. P value = 5.99e-16 with ANOVA analysis.

Clinical variable #14: 'YEAROFTOBACCOSMOKINGONSET'

4 genes related to 'YEAROFTOBACCOSMOKINGONSET'.

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

YEAROFTOBACCOSMOKINGONSET Mean (SD) 1964.72 (13)
  Significant markers N = 4
  pos. correlated 3
  neg. correlated 1
List of 4 genes significantly correlated to 'YEAROFTOBACCOSMOKINGONSET' by Spearman correlation test

Table S25.  Get Full Table List of 4 genes significantly correlated to 'YEAROFTOBACCOSMOKINGONSET' by Spearman correlation test

SpearmanCorr corrP Q
C14ORF118|55668 0.3836 4.328e-07 0.00793
KLRC4|8302 0.4209 9.212e-07 0.0169
GPR15|2838 0.3801 1.258e-06 0.0231
ENTPD3|956 -0.3659 1.558e-06 0.0285

Figure S11.  Get High-res Image As an example, this figure shows the association of C14ORF118|55668 to 'YEAROFTOBACCOSMOKINGONSET'. P value = 4.33e-07 with Spearman correlation analysis. The straight line presents the best linear regression.

Methods & Data
Input

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

  • Clinical data file = LUAD-TP.clin.merged.picked.txt

  • Number of patients = 324

  • Number of genes = 18330

  • Number of clinical features = 14

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.

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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