Correlation between gene methylation status and clinical features
Lung Adenocarcinoma (Primary solid tumor)
15 July 2014  |  analyses__2014_07_15
Maintainer Information
Citation Information
doi:10.7908/C12V2DX4
Maintained by Juok Cho (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2014): Correlation between gene methylation status and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C12V2DX4
Overview
Introduction

This pipeline uses various statistical tests to identify genes whose promoter methylation levels correlated to selected clinical features.

Summary

Testing the association between 19992 genes and 14 clinical features across 409 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 11 clinical features related to at least one genes.

  • 19 genes correlated to 'AGE'.

    • KIAA1143 ,  KIF15 ,  BMP8A ,  CLEC5A ,  NHLRC1 ,  ...

  • 1 gene correlated to 'NEOPLASM.DISEASESTAGE'.

    • NOLC1

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

    • ACBD5 ,  TACC2 ,  DDX21 ,  SLC41A3 ,  PRDM15 ,  ...

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

    • POLR2J3__1 ,  GPRIN2 ,  MRPS17 ,  POP7 ,  VAMP1 ,  ...

  • 189 genes correlated to 'GENDER'.

    • KIF4B ,  EIF4A1 ,  SNORA48 ,  ATP5J ,  GABPA ,  ...

  • 1 gene correlated to 'KARNOFSKY.PERFORMANCE.SCORE'.

    • CCDC80

  • 25 genes correlated to 'HISTOLOGICAL.TYPE'.

    • LOC150622 ,  IQGAP1 ,  TRIM8 ,  ZMIZ1 ,  RILP ,  ...

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

    • C18ORF54 ,  DNAJC5 ,  MRPS23 ,  EIF5A

  • 5 genes correlated to 'NUMBERPACKYEARSSMOKED'.

    • FAM128A__1 ,  LOC150776__1 ,  BHMT2 ,  DMGDH ,  LOC284798

  • 3 genes correlated to 'COMPLETENESS.OF.RESECTION'.

    • APBB3 ,  SLC35A4 ,  CDC23

  • 13 genes correlated to 'RACE'.

    • GPBAR1 ,  CRYZ__1 ,  TYW3__1 ,  LOC253039 ,  PSMD5 ,  ...

  • No genes correlated to 'Time to Death', '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
Time to Death Cox regression test   N=0        
AGE Spearman correlation test N=19 older N=10 younger N=9
NEOPLASM DISEASESTAGE Kruskal-Wallis test N=1        
PATHOLOGY T STAGE Spearman correlation test N=43 higher stage N=15 lower stage N=28
PATHOLOGY N STAGE Spearman correlation test N=11 higher stage N=2 lower stage N=9
PATHOLOGY M STAGE Kruskal-Wallis test   N=0        
GENDER Wilcoxon test N=189 male N=189 female N=0
KARNOFSKY PERFORMANCE SCORE Spearman correlation test N=1 higher score N=1 lower score N=0
HISTOLOGICAL TYPE Kruskal-Wallis test N=25        
RADIATIONS RADIATION REGIMENINDICATION Wilcoxon test N=4 yes N=4 no N=0
NUMBERPACKYEARSSMOKED Spearman correlation test N=5 higher numberpackyearssmoked N=0 lower numberpackyearssmoked N=5
COMPLETENESS OF RESECTION Kruskal-Wallis test N=3        
RACE Kruskal-Wallis test N=13        
ETHNICITY Wilcoxon test   N=0        
Clinical variable #1: 'Time to Death'

No gene related to 'Time to Death'.

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

Time to Death Duration (Years) 1-2696 (median=415)
  censored N = 289
  death N = 68
     
  Significant markers N = 0
Clinical variable #2: 'AGE'

19 genes related to 'AGE'.

Table S2.  Basic characteristics of clinical feature: 'AGE'

AGE Mean (SD) 65.25 (10)
  Significant markers N = 19
  pos. correlated 10
  neg. correlated 9
List of top 10 genes differentially expressed by 'AGE'

Table S3.  Get Full Table List of top 10 genes significantly correlated to 'AGE' by Spearman correlation test

SpearmanCorr corrP Q
KIAA1143 0.277 3.881e-08 0.000776
KIF15 0.277 3.881e-08 0.000776
BMP8A 0.2696 9.113e-08 0.00182
CLEC5A 0.2554 4.333e-07 0.00866
NHLRC1 0.2524 5.99e-07 0.012
B4GALNT4 0.252 6.243e-07 0.0125
LOC148696 -0.2413 1.881e-06 0.0376
ELOVL2 0.2363 3.124e-06 0.0624
UBE2L6 -0.2309 5.264e-06 0.105
LEAP2 -0.2295 6.013e-06 0.12
Clinical variable #3: 'NEOPLASM.DISEASESTAGE'

One gene related to 'NEOPLASM.DISEASESTAGE'.

Table S4.  Basic characteristics of clinical feature: 'NEOPLASM.DISEASESTAGE'

NEOPLASM.DISEASESTAGE Labels N
  STAGE I 4
  STAGE IA 98
  STAGE IB 117
  STAGE IIA 43
  STAGE IIB 59
  STAGE IIIA 59
  STAGE IIIB 9
  STAGE IV 19
     
  Significant markers N = 1
List of one gene differentially expressed by 'NEOPLASM.DISEASESTAGE'

Table S5.  Get Full Table List of one gene differentially expressed by 'NEOPLASM.DISEASESTAGE'

ANOVA_P Q
NOLC1 3.969e-06 0.0794
Clinical variable #4: 'PATHOLOGY.T.STAGE'

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

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

PATHOLOGY.T.STAGE Mean (SD) 1.85 (0.73)
  N
  1 128
  2 227
  3 36
  4 15
     
  Significant markers N = 43
  pos. correlated 15
  neg. correlated 28
List of top 10 genes differentially expressed by 'PATHOLOGY.T.STAGE'

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

SpearmanCorr corrP Q
ACBD5 -0.2802 9.259e-09 0.000185
TACC2 -0.2661 5.243e-08 0.00105
DDX21 -0.2563 1.642e-07 0.00328
SLC41A3 -0.2556 1.781e-07 0.00356
PRDM15 0.252 2.676e-07 0.00535
NME1-NME2 -0.2502 3.268e-07 0.00653
NME2 -0.2502 3.268e-07 0.00653
AFMID -0.247 4.682e-07 0.00936
TK1 -0.247 4.682e-07 0.00936
GLT1D1 0.2465 4.907e-07 0.00981
Clinical variable #5: 'PATHOLOGY.N.STAGE'

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

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

PATHOLOGY.N.STAGE Mean (SD) 0.5 (0.76)
  N
  0 262
  1 75
  2 62
  3 1
     
  Significant markers N = 11
  pos. correlated 2
  neg. correlated 9
List of top 10 genes differentially expressed by 'PATHOLOGY.N.STAGE'

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

SpearmanCorr corrP Q
POLR2J3__1 -0.2408 1.099e-06 0.022
GPRIN2 0.2308 3.102e-06 0.062
MRPS17 -0.2275 4.324e-06 0.0864
POP7 -0.2266 4.729e-06 0.0945
VAMP1 0.2227 6.897e-06 0.138
LZIC -0.2211 8.081e-06 0.162
NMNAT1 -0.2211 8.081e-06 0.162
TMEM209 -0.2192 9.676e-06 0.193
MYADM -0.2192 9.724e-06 0.194
WDR75 -0.2169 1.206e-05 0.241
Clinical variable #6: 'PATHOLOGY.M.STAGE'

No gene related to 'PATHOLOGY.M.STAGE'.

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

PATHOLOGY.M.STAGE Labels N
  M0 265
  M1 12
  M1A 1
  M1B 4
  MX 123
     
  Significant markers N = 0
Clinical variable #7: 'GENDER'

189 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 219
  MALE 190
     
  Significant markers N = 189
  Higher in MALE 189
  Higher in FEMALE 0
List of top 10 genes differentially expressed by 'GENDER'

Table S12.  Get Full Table List of top 10 genes differentially expressed by 'GENDER'. 0 significant gene(s) located in sex chromosomes is(are) filtered out.

W(pos if higher in 'MALE') wilcoxontestP Q AUC
KIF4B 6423 1.685e-33 3.37e-29 0.8456
EIF4A1 9081 8.169e-23 1.63e-18 0.7818
SNORA48 9081 8.169e-23 1.63e-18 0.7818
ATP5J 30267 2.101e-15 4.2e-11 0.7274
GABPA 30267 2.101e-15 4.2e-11 0.7274
RWDD2B 11386 2.808e-15 5.61e-11 0.7264
FUBP3 11578 1.009e-14 2.02e-10 0.7217
LOC100272217 11578 1.009e-14 2.02e-10 0.7217
COX7C 11640 1.516e-14 3.03e-10 0.7203
RNASEH2C 29913 2.2e-14 4.4e-10 0.7189
Clinical variable #8: 'KARNOFSKY.PERFORMANCE.SCORE'

One gene related to 'KARNOFSKY.PERFORMANCE.SCORE'.

Table S13.  Basic characteristics of clinical feature: 'KARNOFSKY.PERFORMANCE.SCORE'

KARNOFSKY.PERFORMANCE.SCORE Mean (SD) 84 (22)
  Significant markers N = 1
  pos. correlated 1
  neg. correlated 0
List of one gene differentially expressed by 'KARNOFSKY.PERFORMANCE.SCORE'

Table S14.  Get Full Table List of one gene significantly correlated to 'KARNOFSKY.PERFORMANCE.SCORE' by Spearman correlation test

SpearmanCorr corrP Q
CCDC80 0.4889 8.575e-06 0.171
Clinical variable #9: 'HISTOLOGICAL.TYPE'

25 genes related to 'HISTOLOGICAL.TYPE'.

Table S15.  Basic characteristics of clinical feature: 'HISTOLOGICAL.TYPE'

HISTOLOGICAL.TYPE Labels N
  LUNG ACINAR ADENOCARCINOMA 13
  LUNG ADENOCARCINOMA MIXED SUBTYPE 79
  LUNG ADENOCARCINOMA- NOT OTHERWISE SPECIFIED (NOS) 258
  LUNG BRONCHIOLOALVEOLAR CARCINOMA MUCINOUS 4
  LUNG BRONCHIOLOALVEOLAR CARCINOMA NONMUCINOUS 19
  LUNG CLEAR CELL ADENOCARCINOMA 1
  LUNG MICROPAPILLARY ADENOCARCINOMA 3
  LUNG MUCINOUS ADENOCARCINOMA 2
  LUNG PAPILLARY ADENOCARCINOMA 18
  LUNG SIGNET RING ADENOCARCINOMA 1
  LUNG SOLID PATTERN PREDOMINANT ADENOCARCINOMA 4
  MUCINOUS (COLLOID) CARCINOMA 7
     
  Significant markers N = 25
List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

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

ANOVA_P Q
LOC150622 9.758e-09 0.000195
IQGAP1 1.231e-06 0.0246
TRIM8 3.202e-06 0.064
ZMIZ1 3.817e-06 0.0763
RILP 4.484e-06 0.0896
FAM46B 5.07e-06 0.101
SHISA4 6.018e-06 0.12
CPEB3 6.14e-06 0.123
ARMC9 7.032e-06 0.141
AVPI1 7.065e-06 0.141
Clinical variable #10: 'RADIATIONS.RADIATION.REGIMENINDICATION'

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

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

RADIATIONS.RADIATION.REGIMENINDICATION Labels N
  NO 18
  YES 391
     
  Significant markers N = 4
  Higher in YES 4
  Higher in NO 0
List of 4 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

Table S18.  Get Full Table List of 4 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

W(pos if higher in 'YES') wilcoxontestP Q AUC
C18ORF54 5709 6.971e-06 0.139 0.8132
DNAJC5 1322 7.491e-06 0.15 0.8122
MRPS23 5714 7.635e-06 0.153 0.8119
EIF5A 5659 1.283e-05 0.256 0.8041
Clinical variable #11: 'NUMBERPACKYEARSSMOKED'

5 genes related to 'NUMBERPACKYEARSSMOKED'.

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

NUMBERPACKYEARSSMOKED Mean (SD) 41.17 (27)
  Significant markers N = 5
  pos. correlated 0
  neg. correlated 5
List of 5 genes differentially expressed by 'NUMBERPACKYEARSSMOKED'

Table S20.  Get Full Table List of 5 genes significantly correlated to 'NUMBERPACKYEARSSMOKED' by Spearman correlation test

SpearmanCorr corrP Q
FAM128A__1 -0.3066 1.745e-07 0.00349
LOC150776__1 -0.3066 1.745e-07 0.00349
BHMT2 -0.2661 6.592e-06 0.132
DMGDH -0.2661 6.592e-06 0.132
LOC284798 -0.2578 1.301e-05 0.26
Clinical variable #12: 'COMPLETENESS.OF.RESECTION'

3 genes related to 'COMPLETENESS.OF.RESECTION'.

Table S21.  Basic characteristics of clinical feature: 'COMPLETENESS.OF.RESECTION'

COMPLETENESS.OF.RESECTION Labels N
  R0 272
  R1 10
  R2 1
  RX 16
     
  Significant markers N = 3
List of 3 genes differentially expressed by 'COMPLETENESS.OF.RESECTION'

Table S22.  Get Full Table List of 3 genes differentially expressed by 'COMPLETENESS.OF.RESECTION'

ANOVA_P Q
APBB3 7.202e-07 0.0144
SLC35A4 7.202e-07 0.0144
CDC23 1.513e-06 0.0302
Clinical variable #13: 'RACE'

13 genes related to 'RACE'.

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

RACE Labels N
  ASIAN 5
  BLACK OR AFRICAN AMERICAN 29
  WHITE 326
     
  Significant markers N = 13
List of top 10 genes differentially expressed by 'RACE'

Table S24.  Get Full Table List of top 10 genes differentially expressed by 'RACE'

ANOVA_P Q
GPBAR1 2.477e-08 0.000495
CRYZ__1 5.564e-07 0.0111
TYW3__1 5.564e-07 0.0111
LOC253039 1.084e-06 0.0217
PSMD5 1.084e-06 0.0217
LOC100133161 1.283e-06 0.0256
CS 2.768e-06 0.0553
RGPD5 3.286e-06 0.0657
RGPD8 3.286e-06 0.0657
WBSCR27 4.137e-06 0.0827
Clinical variable #14: 'ETHNICITY'

No gene related to 'ETHNICITY'.

Table S25.  Basic characteristics of clinical feature: 'ETHNICITY'

ETHNICITY Labels N
  HISPANIC OR LATINO 7
  NOT HISPANIC OR LATINO 297
     
  Significant markers N = 0
Methods & Data
Input

  • Expresson data file = LUAD-TP.meth.by_min_clin_corr.data.txt

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

  • Number of patients = 409

  • Number of genes = 19992

  • 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

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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