Correlation between gene methylation status and clinical features
Lung Squamous Cell Carcinoma (Primary solid tumor)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
doi:10.7908/C15M64S2
Maintained by Juok Cho (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2015): Correlation between gene methylation status and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C15M64S2
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 20222 genes and 15 clinical features across 361 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 6 clinical features related to at least one genes.

  • 30 genes correlated to 'YEARS_TO_BIRTH'.

    • KIAA1143 ,  KIF15 ,  C10ORF35 ,  SPRY1 ,  RBP1 ,  ...

  • 30 genes correlated to 'PATHOLOGY_N_STAGE'.

    • SLC12A8 ,  MYH9 ,  LMF2__1 ,  SPTBN5 ,  PTGDR ,  ...

  • 30 genes correlated to 'GENDER'.

    • ALG11__2 ,  UTP14C ,  KIF4B ,  ATP5J ,  GABPA__1 ,  ...

  • 30 genes correlated to 'KARNOFSKY_PERFORMANCE_SCORE'.

    • KLHL9 ,  ZNF326 ,  ZSCAN22 ,  DPY19L4 ,  ARF4 ,  ...

  • 30 genes correlated to 'YEAR_OF_TOBACCO_SMOKING_ONSET'.

    • REXO2 ,  SMARCAL1 ,  C18ORF22 ,  CINP ,  TECPR2 ,  ...

  • 30 genes correlated to 'RACE'.

    • SCAMP5 ,  GFPT1 ,  NARS2 ,  C12ORF10 ,  DSTYK ,  ...

  • No genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP', 'NEOPLASM_DISEASESTAGE', 'PATHOLOGY_T_STAGE', 'PATHOLOGY_M_STAGE', 'HISTOLOGICAL_TYPE', 'RADIATIONS_RADIATION_REGIMENINDICATION', 'NUMBER_PACK_YEARS_SMOKED', 'COMPLETENESS_OF_RESECTION', 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=0        
YEARS_TO_BIRTH Spearman correlation test N=30 older N=5 younger N=25
NEOPLASM_DISEASESTAGE Kruskal-Wallis test   N=0        
PATHOLOGY_T_STAGE Spearman correlation test   N=0        
PATHOLOGY_N_STAGE Spearman correlation test N=30 higher stage N=28 lower stage N=2
PATHOLOGY_M_STAGE Wilcoxon test   N=0        
GENDER Wilcoxon test N=30 male N=30 female N=0
KARNOFSKY_PERFORMANCE_SCORE Spearman correlation test N=30 higher score N=29 lower score N=1
HISTOLOGICAL_TYPE Kruskal-Wallis test   N=0        
RADIATIONS_RADIATION_REGIMENINDICATION Wilcoxon test   N=0        
NUMBER_PACK_YEARS_SMOKED Spearman correlation test   N=0        
YEAR_OF_TOBACCO_SMOKING_ONSET Spearman correlation test N=30 higher year_of_tobacco_smoking_onset N=30 lower year_of_tobacco_smoking_onset N=0
COMPLETENESS_OF_RESECTION Kruskal-Wallis test   N=0        
RACE Kruskal-Wallis test N=30        
ETHNICITY Wilcoxon test   N=0        
Clinical variable #1: 'DAYS_TO_DEATH_OR_LAST_FUP'

No gene 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) 0-174.1 (median=18.7)
  censored N = 218
  death N = 142
     
  Significant markers N = 0
Clinical variable #2: 'YEARS_TO_BIRTH'

30 genes related to 'YEARS_TO_BIRTH'.

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

YEARS_TO_BIRTH Mean (SD) 67.67 (8.7)
  Significant markers N = 30
  pos. correlated 5
  neg. correlated 25
List of top 10 genes differentially expressed by 'YEARS_TO_BIRTH'

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

SpearmanCorr corrP Q
KIAA1143 0.3349 1.137e-10 1.15e-06
KIF15 0.3349 1.137e-10 1.15e-06
C10ORF35 0.2926 2.233e-08 0.000151
SPRY1 -0.28 9.231e-08 0.000467
RBP1 -0.2734 1.882e-07 0.000731
PDGFRL -0.2715 2.303e-07 0.000731
SELP -0.2706 2.53e-07 0.000731
CCDC13 -0.2667 3.805e-07 0.000962
MXRA8 -0.2652 4.46e-07 0.001
EML4 -0.2608 6.967e-07 0.00121
Clinical variable #3: 'NEOPLASM_DISEASESTAGE'

No gene related to 'NEOPLASM_DISEASESTAGE'.

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

NEOPLASM_DISEASESTAGE Labels N
  STAGE I 3
  STAGE IA 72
  STAGE IB 96
  STAGE II 2
  STAGE IIA 58
  STAGE IIB 69
  STAGE III 3
  STAGE IIIA 46
  STAGE IIIB 6
  STAGE IV 4
     
  Significant markers N = 0
Clinical variable #4: 'PATHOLOGY_T_STAGE'

No gene related to 'PATHOLOGY_T_STAGE'.

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

PATHOLOGY_T_STAGE Mean (SD) 1.98 (0.74)
  N
  T1 89
  T2 202
  T3 58
  T4 12
     
  Significant markers N = 0
Clinical variable #5: 'PATHOLOGY_N_STAGE'

30 genes related to 'PATHOLOGY_N_STAGE'.

Table S6.  Basic characteristics of clinical feature: 'PATHOLOGY_N_STAGE'

PATHOLOGY_N_STAGE Mean (SD) 0.43 (0.64)
  N
  N0 230
  N1 97
  N2 28
     
  Significant markers N = 30
  pos. correlated 28
  neg. correlated 2
List of top 10 genes differentially expressed by 'PATHOLOGY_N_STAGE'

Table S7.  Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY_N_STAGE' by Spearman correlation test

SpearmanCorr corrP Q
SLC12A8 0.2521 1.508e-06 0.0305
MYH9 0.2298 1.225e-05 0.0804
LMF2__1 0.2289 1.331e-05 0.0804
SPTBN5 0.2269 1.591e-05 0.0804
PTGDR 0.2193 3.066e-05 0.124
TAPBP 0.2133 5.091e-05 0.125
ZBTB22 0.2133 5.091e-05 0.125
MST1P2 0.2127 5.349e-05 0.125
VPS36 0.2122 5.569e-05 0.125
MLL 0.2084 7.624e-05 0.125
Clinical variable #6: 'PATHOLOGY_M_STAGE'

No gene related to 'PATHOLOGY_M_STAGE'.

Table S8.  Basic characteristics of clinical feature: 'PATHOLOGY_M_STAGE'

PATHOLOGY_M_STAGE Labels N
  class0 279
  class1 4
     
  Significant markers N = 0
Clinical variable #7: 'GENDER'

30 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 93
  MALE 268
     
  Significant markers N = 30
  Higher in MALE 30
  Higher in FEMALE 0
List of top 10 genes differentially expressed by 'GENDER'

Table S10.  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
ALG11__2 23940 5.397e-40 5.46e-36 0.9605
UTP14C 23940 5.397e-40 5.46e-36 0.9605
KIF4B 3796 1.626e-23 1.1e-19 0.8477
ATP5J 19221 6.476e-15 2.62e-11 0.7712
GABPA__1 19221 6.476e-15 2.62e-11 0.7712
DDX43 6635 1.824e-11 6.15e-08 0.7338
C6ORF108 6695 2.925e-11 8.45e-08 0.7314
RIMBP3 17265 3.05e-08 7.71e-05 0.6927
SEC61G 7734 4.98e-08 0.000112 0.6897
TMEM232 7814 8.332e-08 0.000168 0.6865
Clinical variable #8: 'KARNOFSKY_PERFORMANCE_SCORE'

30 genes related to 'KARNOFSKY_PERFORMANCE_SCORE'.

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

KARNOFSKY_PERFORMANCE_SCORE Mean (SD) 64.57 (38)
  Significant markers N = 30
  pos. correlated 29
  neg. correlated 1
List of top 10 genes differentially expressed by 'KARNOFSKY_PERFORMANCE_SCORE'

Table S12.  Get Full Table List of top 10 genes significantly correlated to 'KARNOFSKY_PERFORMANCE_SCORE' by Spearman correlation test

SpearmanCorr corrP Q
KLHL9 0.65 5.143e-11 1.04e-06
ZNF326 -0.6369 1.644e-10 1.66e-06
ZSCAN22 0.6047 2.252e-09 1.07e-05
DPY19L4 0.6033 2.518e-09 1.07e-05
ARF4 0.6027 2.635e-09 1.07e-05
PMS2L2 0.5959 4.398e-09 1.27e-05
STAG3L1__1 0.5959 4.398e-09 1.27e-05
UEVLD 0.5933 5.306e-09 1.34e-05
RPRD1A 0.5895 7.036e-09 1.58e-05
DCTN5__1 0.5819 1.213e-08 2.23e-05
Clinical variable #9: 'HISTOLOGICAL_TYPE'

No gene related to 'HISTOLOGICAL_TYPE'.

Table S13.  Basic characteristics of clinical feature: 'HISTOLOGICAL_TYPE'

HISTOLOGICAL_TYPE Labels N
  LUNG BASALOID SQUAMOUS CELL CARCINOMA 12
  LUNG CLEAR CELL SQUAMOUS CELL CARCINOMA 1
  LUNG PAPILLARY SQUAMOUS CELL CARICNOMA 5
  LUNG SMALL CELL SQUAMOUS CELL CARCINOMA 1
  LUNG SQUAMOUS CELL CARCINOMA- NOT OTHERWISE SPECIFIED (NOS) 342
     
  Significant markers N = 0
Clinical variable #10: 'RADIATIONS_RADIATION_REGIMENINDICATION'

No gene related to 'RADIATIONS_RADIATION_REGIMENINDICATION'.

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

RADIATIONS_RADIATION_REGIMENINDICATION Labels N
  NO 11
  YES 350
     
  Significant markers N = 0
Clinical variable #11: 'NUMBER_PACK_YEARS_SMOKED'

No gene related to 'NUMBER_PACK_YEARS_SMOKED'.

Table S15.  Basic characteristics of clinical feature: 'NUMBER_PACK_YEARS_SMOKED'

NUMBER_PACK_YEARS_SMOKED Mean (SD) 52.13 (29)
  Significant markers N = 0
Clinical variable #12: 'YEAR_OF_TOBACCO_SMOKING_ONSET'

30 genes related to 'YEAR_OF_TOBACCO_SMOKING_ONSET'.

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

YEAR_OF_TOBACCO_SMOKING_ONSET Mean (SD) 1961.21 (12)
  Significant markers N = 30
  pos. correlated 30
  neg. correlated 0
List of top 10 genes differentially expressed by 'YEAR_OF_TOBACCO_SMOKING_ONSET'

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

SpearmanCorr corrP Q
REXO2 0.3542 2.364e-08 0.000304
SMARCAL1 0.3496 3.666e-08 0.000304
C18ORF22 0.3467 4.83e-08 0.000304
CINP 0.3417 7.716e-08 0.000304
TECPR2 0.3417 7.716e-08 0.000304
GRWD1 0.3401 9.012e-08 0.000304
SEC23B 0.3355 1.368e-07 0.000327
HIGD2A 0.3332 1.694e-07 0.000327
NOP16__1 0.3332 1.694e-07 0.000327
C10ORF119 0.3327 1.768e-07 0.000327
Clinical variable #13: 'COMPLETENESS_OF_RESECTION'

No gene related to 'COMPLETENESS_OF_RESECTION'.

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

COMPLETENESS_OF_RESECTION Labels N
  R0 274
  R1 9
  R2 2
  RX 17
     
  Significant markers N = 0
Clinical variable #14: 'RACE'

30 genes related to 'RACE'.

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

RACE Labels N
  ASIAN 7
  BLACK OR AFRICAN AMERICAN 24
  WHITE 266
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'RACE'

Table S20.  Get Full Table List of top 10 genes differentially expressed by 'RACE'

kruskal_wallis_P Q
SCAMP5 2.615e-08 0.000529
GFPT1 1.033e-07 0.000788
NARS2 1.168e-07 0.000788
C12ORF10 3.581e-07 0.00181
DSTYK 1.061e-06 0.00353
PM20D1 1.515e-06 0.00353
MTR 1.641e-06 0.00353
FAM119B 1.749e-06 0.00353
METTL1 1.749e-06 0.00353
DSG4 1.873e-06 0.00353
Clinical variable #15: 'ETHNICITY'

No gene related to 'ETHNICITY'.

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

ETHNICITY Labels N
  HISPANIC OR LATINO 6
  NOT HISPANIC OR LATINO 231
     
  Significant markers N = 0
Methods & Data
Input

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

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

  • Number of patients = 361

  • Number of genes = 20222

  • Number of clinical features = 15

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)
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