Correlation between gene methylation status and clinical features
Thyroid Adenocarcinoma (Primary solid tumor)
21 April 2013  |  analyses__2013_04_21
Maintainer Information
Citation Information
doi:10.7908/C14J0C3Q
Maintained by Juok Cho (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2013): Thyroid Adenocarcinoma (Primary solid tumor cohort) - 21 April 2013: Correlation between gene methylation status and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C14J0C3Q
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 17071 genes and 14 clinical features across 394 samples, statistically thresholded by Q value < 0.05, 12 clinical features related to at least one genes.

  • 271 genes correlated to 'AGE'.

    • MGA ,  NHLRC1 ,  INA ,  C1ORF59 ,  ZNF518B ,  ...

  • 13 genes correlated to 'GENDER'.

    • UTP14C ,  KIF4B ,  FAM35A ,  WBP11P1 ,  ANKRD20A4 ,  ...

  • 1726 genes correlated to 'HISTOLOGICAL.TYPE'.

    • PON2 ,  LEPR ,  LEPROT ,  XDH ,  EMP1 ,  ...

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

    • KIF15 ,  SIK1 ,  STX17 ,  HSD17B7P2 ,  JMJD1C ,  ...

  • 41 genes correlated to 'RADIATIONEXPOSURE'.

    • CASP12 ,  HESX1 ,  PLOD1 ,  CHEK2 ,  HSCB ,  ...

  • 22 genes correlated to 'DISTANT.METASTASIS'.

    • C1ORF91 ,  MBD1 ,  RPS10 ,  OMP ,  C2ORF34 ,  ...

  • 221 genes correlated to 'EXTRATHYROIDAL.EXTENSION'.

    • OTOS ,  DEFB131 ,  TBX19 ,  PA2G4P4 ,  SLC16A3 ,  ...

  • 603 genes correlated to 'LYMPH.NODE.METASTASIS'.

    • PON2 ,  BMP1 ,  FUT2 ,  MACF1 ,  SREBF1 ,  ...

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

    • ANKRD34B ,  OMP ,  ABCB5 ,  C12ORF54 ,  DNLZ ,  ...

  • 712 genes correlated to 'NUMBER.OF.LYMPH.NODES'.

    • FUT2 ,  TAGLN2 ,  DUSP6 ,  BMP1 ,  MET ,  ...

  • 177 genes correlated to 'NEOPLASM.DISEASESTAGE'.

    • OTOS ,  DEFB131 ,  TBX19 ,  C1ORF91 ,  PA2G4P4 ,  ...

  • 1 gene correlated to 'TUMOR.SIZE'.

    • FOXD4L1

  • No genes correlated to 'Time to Death', and 'MULTIFOCALITY'.

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=0        
AGE Spearman correlation test N=271 older N=270 younger N=1
GENDER t test N=13 male N=7 female N=6
HISTOLOGICAL TYPE ANOVA test N=1726        
RADIATIONS RADIATION REGIMENINDICATION t test N=42 yes N=22 no N=20
RADIATIONEXPOSURE t test N=41 yes N=22 no N=19
DISTANT METASTASIS ANOVA test N=22        
EXTRATHYROIDAL EXTENSION ANOVA test N=221        
LYMPH NODE METASTASIS ANOVA test N=603        
COMPLETENESS OF RESECTION ANOVA test N=8        
NUMBER OF LYMPH NODES Spearman correlation test N=712 higher number.of.lymph.nodes N=18 lower number.of.lymph.nodes N=694
NEOPLASM DISEASESTAGE ANOVA test N=177        
MULTIFOCALITY t test   N=0        
TUMOR SIZE Spearman correlation test N=1 higher tumor.size N=1 lower tumor.size 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 (Months) 0-147.4 (median=9.3)
  censored N = 379
  death N = 10
     
  Significant markers N = 0
Clinical variable #2: 'AGE'

271 genes related to 'AGE'.

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

AGE Mean (SD) 46.38 (16)
  Significant markers N = 271
  pos. correlated 270
  neg. correlated 1
List of top 10 genes significantly correlated to 'AGE' by Spearman correlation test

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

SpearmanCorr corrP Q
MGA 0.5262 1.91e-29 3.26e-25
NHLRC1 0.5106 1.533e-27 2.62e-23
INA 0.4887 4.853e-25 8.28e-21
C1ORF59 0.4872 7.11e-25 1.21e-20
ZNF518B 0.4757 1.203e-23 2.05e-19
ACN9 0.4633 2.315e-22 3.95e-18
KL 0.452 3.091e-21 5.27e-17
GPR37 0.447 9.377e-21 1.6e-16
SYNGR3 0.4444 1.67e-20 2.85e-16
RANBP17 0.4441 1.781e-20 3.04e-16

Figure S1.  Get High-res Image As an example, this figure shows the association of MGA to 'AGE'. P value = 1.91e-29 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #3: 'GENDER'

13 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 298
  MALE 96
     
  Significant markers N = 13
  Higher in MALE 7
  Higher in FEMALE 6
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
UTP14C 37.91 3.58e-131 6.11e-127 0.994
KIF4B -15.48 1.182e-34 2.02e-30 0.904
FAM35A -11.1 7.059e-24 1.2e-19 0.8604
WBP11P1 8.9 2.529e-15 4.32e-11 0.8193
ANKRD20A4 8.2 3.36e-14 5.74e-10 0.7421
FRG1B -7.09 1.01e-11 1.72e-07 0.7437
CCDC121 6.93 8.155e-11 1.39e-06 0.7184
APAF1 -6.21 3.663e-09 6.25e-05 0.7017
SDHD 6.08 4.08e-09 6.96e-05 0.6997
TMSL3 5.5 7.74e-08 0.00132 0.6378

Figure S2.  Get High-res Image As an example, this figure shows the association of UTP14C to 'GENDER'. P value = 3.58e-131 with T-test analysis.

Clinical variable #4: 'HISTOLOGICAL.TYPE'

1726 genes related to 'HISTOLOGICAL.TYPE'.

Table S6.  Basic characteristics of clinical feature: 'HISTOLOGICAL.TYPE'

HISTOLOGICAL.TYPE Labels N
  OTHER SPECIFY 6
  THYROID PAPILLARY CARCINOMA - CLASSICAL/USUAL 271
  THYROID PAPILLARY CARCINOMA - FOLLICULAR (>= 99% FOLLICULAR PATTERNED) 83
  THYROID PAPILLARY CARCINOMA - TALL CELL (>= 50% TALL CELL FEATURES) 34
     
  Significant markers N = 1726
List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

Table S7.  Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

ANOVA_P Q
PON2 3.76e-35 6.42e-31
LEPR 1.413e-33 2.41e-29
LEPROT 1.413e-33 2.41e-29
XDH 1.262e-32 2.15e-28
EMP1 1.621e-32 2.77e-28
C8ORF73 1.8e-31 3.07e-27
SLC6A12 2.628e-31 4.48e-27
LOC399959 1.093e-30 1.87e-26
SLC35F2 2.179e-30 3.72e-26
LAMP3 3.478e-30 5.93e-26

Figure S3.  Get High-res Image As an example, this figure shows the association of PON2 to 'HISTOLOGICAL.TYPE'. P value = 3.76e-35 with ANOVA analysis.

Clinical variable #5: 'RADIATIONS.RADIATION.REGIMENINDICATION'

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

Table S8.  Basic characteristics of clinical feature: 'RADIATIONS.RADIATION.REGIMENINDICATION'

RADIATIONS.RADIATION.REGIMENINDICATION Labels N
  NO 13
  YES 381
     
  Significant markers N = 42
  Higher in YES 22
  Higher in NO 20
List of top 10 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

Table S9.  Get Full Table List of top 10 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

T(pos if higher in 'YES') ttestP Q AUC
KIF15 10.36 2.16e-21 3.69e-17 0.7854
SIK1 8.56 6.708e-16 1.14e-11 0.6937
STX17 8.92 2.052e-13 3.5e-09 0.6243
HSD17B7P2 8.01 4.562e-13 7.79e-09 0.5803
JMJD1C -9.76 4.878e-12 8.32e-08 0.8082
SNX31 7.13 7.68e-12 1.31e-07 0.6735
MYOM2 7.28 9.697e-11 1.65e-06 0.5439
TAF7 7.1 1.001e-10 1.71e-06 0.6971
HORMAD1 -7.79 5.518e-10 9.42e-06 0.7149
ZNHIT3 6.66 1.106e-09 1.89e-05 0.5843

Figure S4.  Get High-res Image As an example, this figure shows the association of KIF15 to 'RADIATIONS.RADIATION.REGIMENINDICATION'. P value = 2.16e-21 with T-test analysis.

Clinical variable #6: 'RADIATIONEXPOSURE'

41 genes related to 'RADIATIONEXPOSURE'.

Table S10.  Basic characteristics of clinical feature: 'RADIATIONEXPOSURE'

RADIATIONEXPOSURE Labels N
  NO 337
  YES 16
     
  Significant markers N = 41
  Higher in YES 22
  Higher in NO 19
List of top 10 genes differentially expressed by 'RADIATIONEXPOSURE'

Table S11.  Get Full Table List of top 10 genes differentially expressed by 'RADIATIONEXPOSURE'

T(pos if higher in 'YES') ttestP Q AUC
CASP12 -8.01 4.031e-13 6.88e-09 0.6296
HESX1 6.91 2.448e-10 4.18e-06 0.6484
PLOD1 6.61 6.179e-10 1.05e-05 0.6536
CHEK2 -6.38 8.904e-10 1.52e-05 0.5588
HSCB -6.38 8.904e-10 1.52e-05 0.5588
PRMT7 6.24 1.238e-09 2.11e-05 0.5987
PHKB 6.3 4.148e-09 7.08e-05 0.7055
PCNXL3 6.02 4.372e-09 7.46e-05 0.6686
KIFC2 -6.62 5.605e-09 9.56e-05 0.6994
CHST11 6.65 1.681e-08 0.000287 0.6547

Figure S5.  Get High-res Image As an example, this figure shows the association of CASP12 to 'RADIATIONEXPOSURE'. P value = 4.03e-13 with T-test analysis.

Clinical variable #7: 'DISTANT.METASTASIS'

22 genes related to 'DISTANT.METASTASIS'.

Table S12.  Basic characteristics of clinical feature: 'DISTANT.METASTASIS'

DISTANT.METASTASIS Labels N
  M0 217
  M1 6
  MX 170
     
  Significant markers N = 22
List of top 10 genes differentially expressed by 'DISTANT.METASTASIS'

Table S13.  Get Full Table List of top 10 genes differentially expressed by 'DISTANT.METASTASIS'

ANOVA_P Q
C1ORF91 1.491e-17 2.54e-13
MBD1 2.025e-11 3.46e-07
RPS10 1.056e-10 1.8e-06
OMP 1.426e-10 2.43e-06
C2ORF34 3.771e-10 6.44e-06
FOXC1 6.629e-10 1.13e-05
C12ORF45 2.425e-09 4.14e-05
PRPF31 4.124e-09 7.04e-05
NME6 5.829e-09 9.95e-05
GPR153 3.818e-08 0.000651

Figure S6.  Get High-res Image As an example, this figure shows the association of C1ORF91 to 'DISTANT.METASTASIS'. P value = 1.49e-17 with ANOVA analysis.

Clinical variable #8: 'EXTRATHYROIDAL.EXTENSION'

221 genes related to 'EXTRATHYROIDAL.EXTENSION'.

Table S14.  Basic characteristics of clinical feature: 'EXTRATHYROIDAL.EXTENSION'

EXTRATHYROIDAL.EXTENSION Labels N
  MINIMAL (T3) 104
  MODERATE/ADVANCED (T4A) 12
  NONE 260
  VERY ADVANCED (T4B) 1
     
  Significant markers N = 221
List of top 10 genes differentially expressed by 'EXTRATHYROIDAL.EXTENSION'

Table S15.  Get Full Table List of top 10 genes differentially expressed by 'EXTRATHYROIDAL.EXTENSION'

ANOVA_P Q
OTOS 2.971e-68 5.07e-64
DEFB131 3.224e-34 5.5e-30
TBX19 1.516e-32 2.59e-28
PA2G4P4 4.498e-27 7.68e-23
SLC16A3 1.046e-25 1.78e-21
S100A12 3.502e-24 5.98e-20
MTUS2 1.727e-23 2.95e-19
BTBD12 5.936e-19 1.01e-14
TMOD3 7.55e-19 1.29e-14
LOC121838 1.004e-18 1.71e-14

Figure S7.  Get High-res Image As an example, this figure shows the association of OTOS to 'EXTRATHYROIDAL.EXTENSION'. P value = 2.97e-68 with ANOVA analysis.

Clinical variable #9: 'LYMPH.NODE.METASTASIS'

603 genes related to 'LYMPH.NODE.METASTASIS'.

Table S16.  Basic characteristics of clinical feature: 'LYMPH.NODE.METASTASIS'

LYMPH.NODE.METASTASIS Labels N
  N0 185
  N1 42
  N1A 75
  N1B 55
  NX 37
     
  Significant markers N = 603
List of top 10 genes differentially expressed by 'LYMPH.NODE.METASTASIS'

Table S17.  Get Full Table List of top 10 genes differentially expressed by 'LYMPH.NODE.METASTASIS'

ANOVA_P Q
PON2 6.279e-16 1.07e-11
BMP1 3.419e-15 5.84e-11
FUT2 3.537e-14 6.04e-10
MACF1 4.633e-14 7.91e-10
SREBF1 6.802e-14 1.16e-09
XDH 7.279e-14 1.24e-09
MVP 1.452e-13 2.48e-09
TMEM173 1.708e-13 2.91e-09
TIMP2 2.558e-13 4.36e-09
MICAL2 3.445e-13 5.88e-09

Figure S8.  Get High-res Image As an example, this figure shows the association of PON2 to 'LYMPH.NODE.METASTASIS'. P value = 6.28e-16 with ANOVA analysis.

Clinical variable #10: 'COMPLETENESS.OF.RESECTION'

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

Table S18.  Basic characteristics of clinical feature: 'COMPLETENESS.OF.RESECTION'

COMPLETENESS.OF.RESECTION Labels N
  R0 311
  R1 32
  R2 2
  RX 24
     
  Significant markers N = 8
List of 8 genes differentially expressed by 'COMPLETENESS.OF.RESECTION'

Table S19.  Get Full Table List of 8 genes differentially expressed by 'COMPLETENESS.OF.RESECTION'

ANOVA_P Q
ANKRD34B 5.48e-31 9.36e-27
OMP 1.331e-26 2.27e-22
ABCB5 1.457e-10 2.49e-06
C12ORF54 1.209e-07 0.00206
DNLZ 2.111e-07 0.0036
CHUK 3.054e-07 0.00521
TRPA1 4.067e-07 0.00694
ACADL 8.736e-07 0.0149

Figure S9.  Get High-res Image As an example, this figure shows the association of ANKRD34B to 'COMPLETENESS.OF.RESECTION'. P value = 5.48e-31 with ANOVA analysis.

Clinical variable #11: 'NUMBER.OF.LYMPH.NODES'

712 genes related to 'NUMBER.OF.LYMPH.NODES'.

Table S20.  Basic characteristics of clinical feature: 'NUMBER.OF.LYMPH.NODES'

NUMBER.OF.LYMPH.NODES Mean (SD) 3.36 (6)
  Significant markers N = 712
  pos. correlated 18
  neg. correlated 694
List of top 10 genes significantly correlated to 'NUMBER.OF.LYMPH.NODES' by Spearman correlation test

Table S21.  Get Full Table List of top 10 genes significantly correlated to 'NUMBER.OF.LYMPH.NODES' by Spearman correlation test

SpearmanCorr corrP Q
FUT2 -0.4486 2.336e-16 3.99e-12
TAGLN2 -0.4382 1.343e-15 2.29e-11
DUSP6 -0.4356 2.054e-15 3.51e-11
BMP1 -0.4308 4.455e-15 7.6e-11
MET -0.43 5.062e-15 8.64e-11
MACF1 -0.4235 1.423e-14 2.43e-10
TMEM173 -0.4222 1.755e-14 3e-10
SDC4 -0.4165 4.253e-14 7.26e-10
CAPN2 -0.4123 8.039e-14 1.37e-09
DUSP5 -0.412 8.432e-14 1.44e-09

Figure S10.  Get High-res Image As an example, this figure shows the association of FUT2 to 'NUMBER.OF.LYMPH.NODES'. P value = 2.34e-16 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #12: 'NEOPLASM.DISEASESTAGE'

177 genes related to 'NEOPLASM.DISEASESTAGE'.

Table S22.  Basic characteristics of clinical feature: 'NEOPLASM.DISEASESTAGE'

NEOPLASM.DISEASESTAGE Labels N
  STAGE I 225
  STAGE II 43
  STAGE III 86
  STAGE IV 1
  STAGE IVA 32
  STAGE IVC 4
     
  Significant markers N = 177
List of top 10 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

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

ANOVA_P Q
OTOS 2.257e-67 3.85e-63
DEFB131 3.025e-33 5.16e-29
TBX19 1.863e-32 3.18e-28
C1ORF91 5.621e-28 9.59e-24
PA2G4P4 7.255e-27 1.24e-22
MTUS2 4.682e-24 7.99e-20
S100A12 2.56e-23 4.37e-19
SLC16A3 1.124e-22 1.92e-18
ISL2 2.145e-20 3.66e-16
C9ORF46 6.788e-19 1.16e-14

Figure S11.  Get High-res Image As an example, this figure shows the association of OTOS to 'NEOPLASM.DISEASESTAGE'. P value = 2.26e-67 with ANOVA analysis.

Clinical variable #13: 'MULTIFOCALITY'

No gene related to 'MULTIFOCALITY'.

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

MULTIFOCALITY Labels N
  MULTIFOCAL 172
  UNIFOCAL 213
     
  Significant markers N = 0
Clinical variable #14: 'TUMOR.SIZE'

One gene related to 'TUMOR.SIZE'.

Table S25.  Basic characteristics of clinical feature: 'TUMOR.SIZE'

TUMOR.SIZE Mean (SD) 2.91 (1.6)
  Significant markers N = 1
  pos. correlated 1
  neg. correlated 0
List of one gene significantly correlated to 'TUMOR.SIZE' by Spearman correlation test

Table S26.  Get Full Table List of one gene significantly correlated to 'TUMOR.SIZE' by Spearman correlation test

SpearmanCorr corrP Q
FOXD4L1 0.275 8.116e-07 0.0139

Figure S12.  Get High-res Image As an example, this figure shows the association of FOXD4L1 to 'TUMOR.SIZE'. P value = 8.12e-07 with Spearman correlation analysis. The straight line presents the best linear regression.

Methods & Data
Input

  • Expresson data file = THCA-TP.meth.for_correlation.filtered_data.txt

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

  • Number of patients = 394

  • Number of genes = 17071

  • 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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