Correlation between gene methylation status and clinical features
Skin Cutaneous Melanoma (Metastatic)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
doi:10.7908/C1TM7977
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/C1TM7977
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 19745 genes and 14 clinical features across 359 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 7 clinical features related to at least one genes.

  • 30 genes correlated to 'YEARS_TO_BIRTH'.

    • CMBL ,  RSPO4 ,  ANKRD45 ,  PDGFD ,  NFATC2 ,  ...

  • 30 genes correlated to 'PRIMARY_SITE_OF_DISEASE'.

    • COL1A1 ,  IL32 ,  RBP5 ,  NT5M ,  CD72 ,  ...

  • 6 genes correlated to 'NEOPLASM_DISEASESTAGE'.

    • PTP4A2 ,  CAPN3 ,  CASP8 ,  TNFAIP3 ,  THRB ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • GAL3ST3 ,  FAM100B ,  IQCG ,  C14ORF72 ,  UBE2F ,  ...

  • 30 genes correlated to 'PATHOLOGY_N_STAGE'.

    • PGBD5 ,  CYFIP1 ,  ABCA7 ,  KDM4DL ,  CCNF ,  ...

  • 30 genes correlated to 'BRESLOW_THICKNESS'.

    • HDAC7 ,  FAM100B ,  IKBKE ,  PARP12 ,  ASF1A ,  ...

  • 4 genes correlated to 'GENDER'.

    • KIF4B ,  NICN1__1 ,  ZNF839 ,  NCRNA00116

  • No genes correlated to 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP', 'DAYS_TO_DEATH_OR_LAST_FUP', 'PATHOLOGY_M_STAGE', 'MELANOMA_ULCERATION', 'MELANOMA_PRIMARY_KNOWN', 'RACE', 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_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP Cox regression test   N=0        
DAYS_TO_DEATH_OR_LAST_FUP Cox regression test   N=0        
YEARS_TO_BIRTH Spearman correlation test N=30 older N=30 younger N=0
PRIMARY_SITE_OF_DISEASE Kruskal-Wallis test N=30        
NEOPLASM_DISEASESTAGE Kruskal-Wallis test N=6        
PATHOLOGY_T_STAGE Spearman correlation test N=30 higher stage N=28 lower stage N=2
PATHOLOGY_N_STAGE Spearman correlation test N=30 higher stage N=4 lower stage N=26
PATHOLOGY_M_STAGE Wilcoxon test   N=0        
MELANOMA_ULCERATION Wilcoxon test   N=0        
MELANOMA_PRIMARY_KNOWN Wilcoxon test   N=0        
BRESLOW_THICKNESS Spearman correlation test N=30 higher breslow_thickness N=25 lower breslow_thickness N=5
GENDER Wilcoxon test N=4 male N=4 female N=0
RACE Kruskal-Wallis test   N=0        
ETHNICITY Wilcoxon test   N=0        
Clinical variable #1: 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP'

No gene related to 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP'.

Table S1.  Basic characteristics of clinical feature: 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP'

TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP Duration (Months) 0-346.5 (median=45.9)
  censored N = 121
  death N = 119
     
  Significant markers N = 0
Clinical variable #2: 'DAYS_TO_DEATH_OR_LAST_FUP'

No gene related to 'DAYS_TO_DEATH_OR_LAST_FUP'.

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

DAYS_TO_DEATH_OR_LAST_FUP Duration (Months) 0.2-369.9 (median=50.9)
  censored N = 176
  death N = 182
     
  Significant markers N = 0
Clinical variable #3: '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) 56.21 (16)
  Significant markers N = 30
  pos. correlated 30
  neg. correlated 0
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
CMBL 0.2932 2.189e-08 0.000334
RSPO4 0.2893 3.388e-08 0.000334
ANKRD45 0.2743 1.774e-07 0.000788
PDGFD 0.2734 1.953e-07 0.000788
NFATC2 0.2732 1.995e-07 0.000788
TES 0.269 3.125e-07 0.000885
HIST1H1D 0.2689 3.138e-07 0.000885
PARP12 0.2655 4.475e-07 0.0011
MAMSTR 0.2632 5.677e-07 0.00125
ANKRD18A 0.2575 1.011e-06 0.00181
Clinical variable #4: 'PRIMARY_SITE_OF_DISEASE'

30 genes related to 'PRIMARY_SITE_OF_DISEASE'.

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

PRIMARY_SITE_OF_DISEASE Labels N
  DISTANT METASTASIS 65
  PRIMARY TUMOR 5
  REGIONAL CUTANEOUS OR SUBCUTANEOUS TISSUE 72
  REGIONAL LYMPH NODE 216
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'PRIMARY_SITE_OF_DISEASE'

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

kruskal_wallis_P Q
COL1A1 7.157e-09 5.67e-05
IL32 7.172e-09 5.67e-05
RBP5 8.609e-09 5.67e-05
NT5M 3.138e-08 0.000134
CD72 3.406e-08 0.000134
SNX11 6.379e-08 0.000193
CDK14 8.516e-08 0.000193
ANKRD13A 8.564e-08 0.000193
GRB2 8.81e-08 0.000193
CD3D 1.087e-07 0.000215
Clinical variable #5: 'NEOPLASM_DISEASESTAGE'

6 genes related to 'NEOPLASM_DISEASESTAGE'.

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

NEOPLASM_DISEASESTAGE Labels N
  I OR II NOS 12
  STAGE 0 7
  STAGE I 28
  STAGE IA 18
  STAGE IB 27
  STAGE II 24
  STAGE IIA 14
  STAGE IIB 19
  STAGE IIC 12
  STAGE III 37
  STAGE IIIA 15
  STAGE IIIB 32
  STAGE IIIC 61
  STAGE IV 20
     
  Significant markers N = 6
List of 6 genes differentially expressed by 'NEOPLASM_DISEASESTAGE'

Table S8.  Get Full Table List of 6 genes differentially expressed by 'NEOPLASM_DISEASESTAGE'

kruskal_wallis_P Q
PTP4A2 1.524e-06 0.0301
CAPN3 5.648e-05 0.299
CASP8 6.972e-05 0.299
TNFAIP3 7.493e-05 0.299
THRB 7.927e-05 0.299
FBXO6 9.087e-05 0.299
Clinical variable #6: 'PATHOLOGY_T_STAGE'

30 genes related to 'PATHOLOGY_T_STAGE'.

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

PATHOLOGY_T_STAGE Mean (SD) 2.45 (1.2)
  N
  T0 23
  T1 41
  T2 72
  T3 77
  T4 69
     
  Significant markers N = 30
  pos. correlated 28
  neg. correlated 2
List of top 10 genes differentially expressed by 'PATHOLOGY_T_STAGE'

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

SpearmanCorr corrP Q
GAL3ST3 -0.288 8.715e-07 0.0172
FAM100B 0.269 4.6e-06 0.0313
IQCG 0.267 5.433e-06 0.0313
C14ORF72 0.2649 6.473e-06 0.0313
UBE2F 0.2625 7.931e-06 0.0313
SEMA4D 0.257 1.238e-05 0.0327
HDAC7 0.257 1.245e-05 0.0327
IKBKE 0.2553 1.421e-05 0.0327
TNFSF9 0.2512 1.962e-05 0.0327
TSPAN33 0.2506 2.07e-05 0.0327
Clinical variable #7: 'PATHOLOGY_N_STAGE'

30 genes related to 'PATHOLOGY_N_STAGE'.

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

PATHOLOGY_N_STAGE Mean (SD) 0.9 (1.1)
  N
  N0 169
  N1 64
  N2 38
  N3 49
     
  Significant markers N = 30
  pos. correlated 4
  neg. correlated 26
List of top 10 genes differentially expressed by 'PATHOLOGY_N_STAGE'

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

SpearmanCorr corrP Q
PGBD5 -0.2397 1.464e-05 0.0992
CYFIP1 0.2377 1.734e-05 0.0992
ABCA7 -0.2363 1.945e-05 0.0992
KDM4DL -0.2359 2.009e-05 0.0992
CCNF -0.227 4.147e-05 0.124
SFXN4 -0.2241 5.233e-05 0.124
C10ORF68 -0.2214 6.453e-05 0.124
CCDC7__1 -0.2214 6.453e-05 0.124
C9ORF37 -0.2207 6.856e-05 0.124
EHMT1__1 -0.2207 6.856e-05 0.124
Clinical variable #8: 'PATHOLOGY_M_STAGE'

No gene related to 'PATHOLOGY_M_STAGE'.

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

PATHOLOGY_M_STAGE Labels N
  class0 314
  class1 21
     
  Significant markers N = 0
Clinical variable #9: 'MELANOMA_ULCERATION'

No gene related to 'MELANOMA_ULCERATION'.

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

MELANOMA_ULCERATION Labels N
  NO 132
  YES 89
     
  Significant markers N = 0
Clinical variable #10: 'MELANOMA_PRIMARY_KNOWN'

No gene related to 'MELANOMA_PRIMARY_KNOWN'.

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

MELANOMA_PRIMARY_KNOWN Labels N
  NO 44
  YES 314
     
  Significant markers N = 0
Clinical variable #11: 'BRESLOW_THICKNESS'

30 genes related to 'BRESLOW_THICKNESS'.

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

BRESLOW_THICKNESS Mean (SD) 3.48 (4.7)
  Significant markers N = 30
  pos. correlated 25
  neg. correlated 5
List of top 10 genes differentially expressed by 'BRESLOW_THICKNESS'

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

SpearmanCorr corrP Q
HDAC7 0.2829 3.143e-06 0.0319
FAM100B 0.2816 3.494e-06 0.0319
IKBKE 0.2696 9.228e-06 0.0319
PARP12 0.2693 9.482e-06 0.0319
ASF1A 0.2675 1.096e-05 0.0319
SPATS2L 0.2666 1.172e-05 0.0319
SGK1 -0.2643 1.405e-05 0.0319
IQCG 0.2602 1.922e-05 0.0319
GAL3ST3 -0.2601 1.944e-05 0.0319
ITPRIP 0.26 1.956e-05 0.0319
Clinical variable #12: 'GENDER'

4 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 135
  MALE 224
     
  Significant markers N = 4
  Higher in MALE 4
  Higher in FEMALE 0
List of 4 genes differentially expressed by 'GENDER'

Table S19.  Get Full Table List of 4 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 8433 2.216e-12 4.38e-08 0.7211
NICN1__1 9885 3.891e-08 0.000384 0.6731
ZNF839 10935 1.116e-05 0.0735 0.6384
NCRNA00116 11297 5.989e-05 0.296 0.6264
Clinical variable #13: 'RACE'

No gene related to 'RACE'.

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

RACE Labels N
  ASIAN 5
  BLACK OR AFRICAN AMERICAN 1
  WHITE 345
     
  Significant markers N = 0
Clinical variable #14: 'ETHNICITY'

No gene related to 'ETHNICITY'.

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

ETHNICITY Labels N
  HISPANIC OR LATINO 7
  NOT HISPANIC OR LATINO 345
     
  Significant markers N = 0
Methods & Data
Input

  • Expresson data file = SKCM-TM.meth.by_min_clin_corr.data.txt

  • Clinical data file = SKCM-TM.merged_data.txt

  • Number of patients = 359

  • Number of genes = 19745

  • 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)
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