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 331 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 ,  PPP1R3G|648791 ,  ...

  • 1 gene correlated to 'AGE'.

    • HSD17B2|3294

  • 48 genes correlated to 'GENDER'.

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

  • 23 genes correlated to 'HISTOLOGICAL.TYPE'.

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

  • 14 genes correlated to 'PATHOLOGY.T'.

    • FAM125B|89853 ,  MS4A1|931 ,  PPP1R16B|26051 ,  ZNF671|79891 ,  C14ORF139|79686 ,  ...

  • 6 genes correlated to 'PATHOLOGY.N'.

    • ZNF483|158399 ,  RARS|5917 ,  LOC729020|729020 ,  DAPK2|23604 ,  ZNF337|26152 ,  ...

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

    • ZNF35|7584 ,  ZNF197|10168 ,  RNASEK|440400 ,  NIPA1|123606 ,  ALKBH3|221120 ,  ...

  • 10 genes correlated to 'TUMOR.STAGE'.

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

  • 2 genes correlated to 'NUMBERPACKYEARSSMOKED'.

    • LOC723809|723809 ,  LHFPL3|375612

  • 282 genes correlated to 'TOBACCOSMOKINGHISTORYINDICATOR'.

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

  • 4 genes correlated to 'YEAROFTOBACCOSMOKINGONSET'.

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

  • No genes correlated to 'KARNOFSKY.PERFORMANCE.SCORE', 'RADIATIONS.RADIATION.REGIMENINDICATION', and 'COMPLETENESS.OF.RESECTION'.

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=1 older N=1 younger N=0
GENDER t test N=48 male N=22 female N=26
KARNOFSKY PERFORMANCE SCORE Spearman correlation test   N=0        
HISTOLOGICAL TYPE ANOVA test N=23        
PATHOLOGY T Spearman correlation test N=14 higher pT N=0 lower pT N=14
PATHOLOGY N Spearman correlation test N=6 higher pN N=2 lower pN N=4
PATHOLOGICSPREAD(M) ANOVA test N=77        
TUMOR STAGE Spearman correlation test N=10 higher stage N=3 lower stage N=7
RADIATIONS RADIATION REGIMENINDICATION t test   N=0        
NUMBERPACKYEARSSMOKED Spearman correlation test N=2 higher numberpackyearssmoked N=0 lower numberpackyearssmoked N=2
TOBACCOSMOKINGHISTORYINDICATOR ANOVA test N=282        
YEAROFTOBACCOSMOKINGONSET Spearman correlation test N=4 higher yearoftobaccosmokingonset N=3 lower yearoftobaccosmokingonset N=1
COMPLETENESS OF RESECTION ANOVA test   N=0        
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=9.8)
  censored N = 215
  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 2.853e-07 0.0052 0.366
UCN2|90226 1.35 6.41e-07 0.012 0.636
MYLIP|29116 0.51 1.234e-06 0.023 0.349
DKK1|22943 1.19 2.012e-06 0.037 0.707
PPP1R3G|648791 1.51 2.655e-06 0.049 0.658
LYAR|55646 2.3 2.706e-06 0.05 0.64

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 = 2.85e-07 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) 65.38 (9.8)
  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
HSD17B2|3294 0.2736 1.911e-06 0.035

Figure S2.  Get High-res Image As an example, this figure shows the association of HSD17B2|3294 to 'AGE'. P value = 1.91e-06 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #3: 'GENDER'

48 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 180
  MALE 151
     
  Significant markers N = 48
  Higher in MALE 22
  Higher in FEMALE 26
List of top 10 genes differentially expressed by 'GENDER'

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

T(pos if higher in 'MALE') ttestP Q AUC
PRKY|5616 44.2 6.555e-133 1.2e-128 0.9994
ZFY|7544 52.26 2.118e-108 3.88e-104 0.9979
RPS4Y1|6192 47.24 6.209e-89 1.14e-84 0.9964
XIST|7503 -33.92 8.313e-78 1.52e-73 0.9788
DDX3Y|8653 42.94 7.825e-58 1.43e-53 0.9973
NLGN4Y|22829 25.32 6.128e-44 1.12e-39 0.9911
KDM5D|8284 37.26 7.344e-44 1.35e-39 0.998
USP9Y|8287 36.24 1.355e-41 2.48e-37 0.9995
TSIX|9383 -17.26 3.543e-32 6.49e-28 0.9689
UTY|7404 24.97 4.265e-22 7.81e-18 0.9954

Figure S3.  Get High-res Image As an example, this figure shows the association of PRKY|5616 to 'GENDER'. P value = 6.56e-133 with T-test analysis.

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

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

Table S7.  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'

23 genes related to 'HISTOLOGICAL.TYPE'.

Table S8.  Basic characteristics of clinical feature: 'HISTOLOGICAL.TYPE'

HISTOLOGICAL.TYPE Labels N
  LUNG ACINAR ADENOCARCINOMA 10
  LUNG ADENOCARCINOMA MIXED SUBTYPE 74
  LUNG ADENOCARCINOMA- NOT OTHERWISE SPECIFIED (NOS) 204
  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 = 23
List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

Table S9.  Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

ANOVA_P Q
CREB3L3|84699 1.376e-11 2.52e-07
A4GNT|51146 8.792e-10 1.61e-05
CRH|1392 4.258e-09 7.8e-05
LOC55908|55908 5.806e-09 0.000106
DPCR1|135656 3.164e-08 0.00058
SOX10|6663 5.954e-08 0.00109
SLC22A10|387775 7.248e-08 0.00133
MYO1A|4640 9.326e-08 0.00171
REG4|83998 9.644e-08 0.00177
CA2|760 1.55e-07 0.00284

Figure S4.  Get High-res Image As an example, this figure shows the association of CREB3L3|84699 to 'HISTOLOGICAL.TYPE'. P value = 1.38e-11 with ANOVA analysis.

Clinical variable #6: 'PATHOLOGY.T'

14 genes related to 'PATHOLOGY.T'.

Table S10.  Basic characteristics of clinical feature: 'PATHOLOGY.T'

PATHOLOGY.T Mean (SD) 1.89 (0.76)
  N
  T1 97
  T2 188
  T3 27
  T4 17
     
  Significant markers N = 14
  pos. correlated 0
  neg. correlated 14
List of top 10 genes significantly correlated to 'PATHOLOGY.T' by Spearman correlation test

Table S11.  Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY.T' by Spearman correlation test

SpearmanCorr corrP Q
FAM125B|89853 -0.2919 6.965e-08 0.00128
MS4A1|931 -0.2815 2.174e-07 0.00398
PPP1R16B|26051 -0.2795 2.566e-07 0.0047
ZNF671|79891 -0.2751 4.003e-07 0.00734
C14ORF139|79686 -0.2724 5.254e-07 0.00963
FCRL1|115350 -0.2758 6.12e-07 0.0112
RASGRP2|10235 -0.2693 7.092e-07 0.013
GPR171|29909 -0.266 9.849e-07 0.018
APOBEC2|10930 -0.2643 1.506e-06 0.0276
KIAA0748|9840 -0.2585 2.087e-06 0.0382

Figure S5.  Get High-res Image As an example, this figure shows the association of FAM125B|89853 to 'PATHOLOGY.T'. P value = 6.97e-08 with Spearman correlation analysis.

Clinical variable #7: 'PATHOLOGY.N'

6 genes related to 'PATHOLOGY.N'.

Table S12.  Basic characteristics of clinical feature: 'PATHOLOGY.N'

PATHOLOGY.N Mean (SD) 0.53 (0.77)
  N
  N0 204
  N1 65
  N2 52
  N3 1
     
  Significant markers N = 6
  pos. correlated 2
  neg. correlated 4
List of 6 genes significantly correlated to 'PATHOLOGY.N' by Spearman correlation test

Table S13.  Get Full Table List of 6 genes significantly correlated to 'PATHOLOGY.N' by Spearman correlation test

SpearmanCorr corrP Q
ZNF483|158399 -0.2841 2.157e-07 0.00395
RARS|5917 0.2789 3.665e-07 0.00672
LOC729020|729020 0.2741 5.9e-07 0.0108
DAPK2|23604 -0.2675 1.108e-06 0.0203
ZNF337|26152 -0.2666 1.211e-06 0.0222
CLCN6|1185 -0.2588 2.511e-06 0.046

Figure S6.  Get High-res Image As an example, this figure shows the association of ZNF483|158399 to 'PATHOLOGY.N'. P value = 2.16e-07 with Spearman correlation analysis.

Clinical variable #8: 'PATHOLOGICSPREAD(M)'

77 genes related to 'PATHOLOGICSPREAD(M)'.

Table S14.  Basic characteristics of clinical feature: 'PATHOLOGICSPREAD(M)'

PATHOLOGICSPREAD(M) Labels N
  M0 226
  M1 17
  M1B 1
  MX 79
     
  Significant markers N = 77
List of top 10 genes differentially expressed by 'PATHOLOGICSPREAD(M)'

Table S15.  Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGICSPREAD(M)'

ANOVA_P Q
ZNF35|7584 4.459e-12 8.17e-08
ZNF197|10168 2.305e-11 4.22e-07
RNASEK|440400 9.193e-10 1.68e-05
NIPA1|123606 1.456e-09 2.67e-05
ALKBH3|221120 2.683e-09 4.92e-05
TMEM101|84336 4.766e-09 8.73e-05
MRPS28|28957 5.367e-09 9.84e-05
MGMT|4255 6.417e-09 0.000118
IMPA1|3612 1.432e-08 0.000262
APOA1|335 1.752e-08 0.000321

Figure S7.  Get High-res Image As an example, this figure shows the association of ZNF35|7584 to 'PATHOLOGICSPREAD(M)'. P value = 4.46e-12 with ANOVA analysis.

Clinical variable #9: 'TUMOR.STAGE'

10 genes related to 'TUMOR.STAGE'.

Table S16.  Basic characteristics of clinical feature: 'TUMOR.STAGE'

TUMOR.STAGE Mean (SD) 1.76 (0.94)
  N
  Stage 1 174
  Stage 2 72
  Stage 3 61
  Stage 4 18
     
  Significant markers N = 10
  pos. correlated 3
  neg. correlated 7
List of 10 genes significantly correlated to 'TUMOR.STAGE' by Spearman correlation test

Table S17.  Get Full Table List of 10 genes significantly correlated to 'TUMOR.STAGE' by Spearman correlation test

SpearmanCorr corrP Q
ZNF540|163255 -0.2777 3.626e-07 0.00665
ACSS1|84532 -0.2756 4.462e-07 0.00818
LDHA|3939 0.2732 5.668e-07 0.0104
ZFP3|124961 -0.2653 1.225e-06 0.0225
ST6GAL1|6480 -0.2637 1.421e-06 0.026
FAM117A|81558 -0.2631 1.518e-06 0.0278
RARS|5917 0.2604 1.947e-06 0.0357
C20ORF96|140680 -0.26 2.014e-06 0.0369
RNASE1|6035 -0.2575 2.555e-06 0.0468
ERO1L|30001 0.2568 2.714e-06 0.0497

Figure S8.  Get High-res Image As an example, this figure shows the association of ZNF540|163255 to 'TUMOR.STAGE'. P value = 3.63e-07 with Spearman correlation analysis.

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

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

Table S18.  Basic characteristics of clinical feature: 'RADIATIONS.RADIATION.REGIMENINDICATION'

RADIATIONS.RADIATION.REGIMENINDICATION Labels N
  NO 18
  YES 313
     
  Significant markers N = 0
Clinical variable #11: 'NUMBERPACKYEARSSMOKED'

2 genes related to 'NUMBERPACKYEARSSMOKED'.

Table S19.  Basic characteristics of clinical feature: 'NUMBERPACKYEARSSMOKED'

NUMBERPACKYEARSSMOKED Mean (SD) 40.01 (26)
  Significant markers N = 2
  pos. correlated 0
  neg. correlated 2
List of 2 genes significantly correlated to 'NUMBERPACKYEARSSMOKED' by Spearman correlation test

Table S20.  Get Full Table List of 2 genes significantly correlated to 'NUMBERPACKYEARSSMOKED' by Spearman correlation test

SpearmanCorr corrP Q
LOC723809|723809 -0.3325 6.824e-07 0.0125
LHFPL3|375612 -0.3355 8.267e-07 0.0152

Figure S9.  Get High-res Image As an example, this figure shows the association of LOC723809|723809 to 'NUMBERPACKYEARSSMOKED'. P value = 6.82e-07 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #12: 'TOBACCOSMOKINGHISTORYINDICATOR'

282 genes related to 'TOBACCOSMOKINGHISTORYINDICATOR'.

Table S21.  Basic characteristics of clinical feature: 'TOBACCOSMOKINGHISTORYINDICATOR'

TOBACCOSMOKINGHISTORYINDICATOR Labels N
  CURRENT REFORMED SMOKER FOR < OR = 15 YEARS 114
  CURRENT REFORMED SMOKER FOR > 15 YEARS 87
  CURRENT SMOKER 73
  LIFELONG NON-SMOKER 46
     
  Significant markers N = 282
List of top 10 genes differentially expressed by 'TOBACCOSMOKINGHISTORYINDICATOR'

Table S22.  Get Full Table List of top 10 genes differentially expressed by 'TOBACCOSMOKINGHISTORYINDICATOR'

ANOVA_P Q
GPR15|2838 8.529e-17 1.56e-12
DBF4B|80174 2.707e-11 4.96e-07
CHEK1|1111 2.882e-10 5.28e-06
KIF18B|146909 3.187e-10 5.84e-06
KNTC1|9735 4.185e-10 7.67e-06
C15ORF42|90381 5.769e-10 1.06e-05
C9ORF140|89958 7.955e-10 1.46e-05
LMNB2|84823 8.808e-10 1.61e-05
PRC1|9055 9.845e-10 1.8e-05
RAD54L|8438 1.205e-09 2.21e-05

Figure S10.  Get High-res Image As an example, this figure shows the association of GPR15|2838 to 'TOBACCOSMOKINGHISTORYINDICATOR'. P value = 8.53e-17 with ANOVA analysis.

Clinical variable #13: 'YEAROFTOBACCOSMOKINGONSET'

4 genes related to 'YEAROFTOBACCOSMOKINGONSET'.

Table S23.  Basic characteristics of clinical feature: 'YEAROFTOBACCOSMOKINGONSET'

YEAROFTOBACCOSMOKINGONSET Mean (SD) 1964.9 (13)
  Significant markers N = 4
  pos. correlated 3
  neg. correlated 1
List of 4 genes significantly correlated to 'YEAROFTOBACCOSMOKINGONSET' by Spearman correlation test

Table S24.  Get Full Table List of 4 genes significantly correlated to 'YEAROFTOBACCOSMOKINGONSET' by Spearman correlation test

SpearmanCorr corrP Q
KLRC4|8302 0.4247 5.274e-07 0.00967
ENTPD3|956 -0.3718 6.99e-07 0.0128
C14ORF118|55668 0.3617 1.452e-06 0.0266
GPR15|2838 0.3674 2.046e-06 0.0375

Figure S11.  Get High-res Image As an example, this figure shows the association of KLRC4|8302 to 'YEAROFTOBACCOSMOKINGONSET'. P value = 5.27e-07 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #14: 'COMPLETENESS.OF.RESECTION'

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

Table S25.  Basic characteristics of clinical feature: 'COMPLETENESS.OF.RESECTION'

COMPLETENESS.OF.RESECTION Labels N
  R0 183
  R1 9
  R2 4
  RX 11
     
  Significant markers N = 0
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 = 331

  • 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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