Correlation between gene methylation status and clinical features
Thyroid Adenocarcinoma (Primary solid tumor)
22 February 2013  |  analyses__2013_02_22
Maintainer Information
Citation Information
doi:10.7908/C16H4FPZ
Maintained by Juok Cho (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2013): Correlation between gene methylation status and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C16H4FPZ
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 17090 genes and 13 clinical features across 268 samples, statistically thresholded by Q value < 0.05, 11 clinical features related to at least one genes.

  • 140 genes correlated to 'AGE'.

    • C1ORF59 ,  C7ORF13 ,  NHLRC1 ,  KIF15 ,  ZNF518B ,  ...

  • 11 genes correlated to 'GENDER'.

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

  • 1740 genes correlated to 'HISTOLOGICAL.TYPE'.

    • PON2 ,  CLCF1 ,  EMP1 ,  SH3GL1 ,  SLC35F2 ,  ...

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

    • KIF15 ,  STX17 ,  MAP3K3 ,  SIK1 ,  MYOM2 ,  ...

  • 51 genes correlated to 'RADIATIONEXPOSURE'.

    • ATP5L2 ,  ALKBH2 ,  C1ORF96 ,  CASP12 ,  KIAA0406 ,  ...

  • 33 genes correlated to 'DISTANT.METASTASIS'.

    • GPR153 ,  C12ORF45 ,  DENND1A ,  C1ORF91 ,  C14ORF169 ,  ...

  • 32 genes correlated to 'EXTRATHYROIDAL.EXTENSION'.

    • SNORD97 ,  DYNLRB2 ,  ZNF784 ,  ZNF781 ,  C4ORF43 ,  ...

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

    • PON2 ,  CPNE1 ,  RBM12 ,  MVP ,  SNHG3-RCC1 ,  ...

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

    • DENND1A ,  HPS3 ,  TRRAP ,  ZNF585A ,  ZNF254 ,  ...

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

    • TAGLN2 ,  STARD5 ,  SNHG3-RCC1 ,  FUT2 ,  CPNE1 ,  ...

  • 76 genes correlated to 'NEOPLASM.DISEASESTAGE'.

    • GPR153 ,  C12ORF45 ,  C1ORF91 ,  C2ORF34 ,  C14ORF169 ,  ...

  • No genes correlated to 'MULTIFOCALITY', and 'TUMOR.SIZE'.

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
AGE Spearman correlation test N=140 older N=140 younger N=0
GENDER t test N=11 male N=5 female N=6
HISTOLOGICAL TYPE ANOVA test N=1740        
RADIATIONS RADIATION REGIMENINDICATION t test N=32 yes N=20 no N=12
RADIATIONEXPOSURE t test N=51 yes N=24 no N=27
DISTANT METASTASIS ANOVA test N=33        
EXTRATHYROIDAL EXTENSION ANOVA test N=32        
LYMPH NODE METASTASIS ANOVA test N=300        
COMPLETENESS OF RESECTION ANOVA test N=22        
NUMBER OF LYMPH NODES Spearman correlation test N=523 higher number.of.lymph.nodes N=10 lower number.of.lymph.nodes N=513
NEOPLASM DISEASESTAGE ANOVA test N=76        
MULTIFOCALITY t test   N=0        
TUMOR SIZE Spearman correlation test   N=0        
Clinical variable #1: 'AGE'

140 genes related to 'AGE'.

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

AGE Mean (SD) 46.56 (16)
  Significant markers N = 140
  pos. correlated 140
  neg. correlated 0
List of top 10 genes significantly correlated to 'AGE' by Spearman correlation test

Table S2.  Get Full Table List of top 10 genes significantly correlated to 'AGE' by Spearman correlation test

SpearmanCorr corrP Q
C1ORF59 0.525 2.198e-20 3.76e-16
C7ORF13 0.5113 2.972e-19 5.08e-15
NHLRC1 0.508 5.42e-19 9.26e-15
KIF15 0.5021 1.59e-18 2.72e-14
ZNF518B 0.4823 5.12e-17 8.75e-13
INA 0.4775 1.135e-16 1.94e-12
DLK2 0.4748 1.796e-16 3.07e-12
ACN9 0.4665 6.864e-16 1.17e-11
GNPNAT1 0.4614 1.559e-15 2.66e-11
ZNF274 0.4606 1.778e-15 3.04e-11

Figure S1.  Get High-res Image As an example, this figure shows the association of C1ORF59 to 'AGE'. P value = 2.2e-20 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #2: 'GENDER'

11 genes related to 'GENDER'.

Table S3.  Basic characteristics of clinical feature: 'GENDER'

GENDER Labels N
  FEMALE 200
  MALE 68
     
  Significant markers N = 11
  Higher in MALE 5
  Higher in FEMALE 6
List of top 10 genes differentially expressed by 'GENDER'

Table S4.  Get Full Table List of top 10 genes differentially expressed by 'GENDER'

T(pos if higher in 'MALE') ttestP Q AUC
UTP14C 32.6 2.583e-88 4.41e-84 0.9965
KIF4B -13.87 2.884e-27 4.93e-23 0.9196
FAM35A -8.87 2.564e-16 4.38e-12 0.8535
WBP11P1 8.11 1.102e-12 1.88e-08 0.8285
ANKRD20A4 7.1 7.022e-11 1.2e-06 0.7546
FRG1B -6.1 4.961e-09 8.48e-05 0.7375
APAF1 -6.01 2.014e-08 0.000344 0.735
CCDC121 5.8 5.564e-08 0.000951 0.7225
MCOLN1 -5.5 1.149e-07 0.00196 0.6805
TUBB4 5.56 1.461e-07 0.0025 0.7246

Figure S2.  Get High-res Image As an example, this figure shows the association of UTP14C to 'GENDER'. P value = 2.58e-88 with T-test analysis.

Clinical variable #3: 'HISTOLOGICAL.TYPE'

1740 genes related to 'HISTOLOGICAL.TYPE'.

Table S5.  Basic characteristics of clinical feature: 'HISTOLOGICAL.TYPE'

HISTOLOGICAL.TYPE Labels N
  OTHER 17
  THYROID PAPILLARY CARCINOMA - CLASSICAL/USUAL 159
  THYROID PAPILLARY CARCINOMA - FOLLICULAR (>= 99% FOLLICULAR PATTERNED) 64
  THYROID PAPILLARY CARCINOMA - TALL CELL (>= 50% TALL CELL FEATURES) 28
     
  Significant markers N = 1740
List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

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

ANOVA_P Q
PON2 1.767e-36 3.02e-32
CLCF1 1.526e-35 2.61e-31
EMP1 5.955e-35 1.02e-30
SH3GL1 2.146e-34 3.67e-30
SLC35F2 7.539e-34 1.29e-29
LY6G6C 1.277e-33 2.18e-29
LOC100126784 1.808e-33 3.09e-29
C8ORF73 2.034e-33 3.47e-29
RELL1 4.903e-33 8.37e-29
AKNA 4.935e-33 8.43e-29

Figure S3.  Get High-res Image As an example, this figure shows the association of PON2 to 'HISTOLOGICAL.TYPE'. P value = 1.77e-36 with ANOVA analysis.

Clinical variable #4: 'RADIATIONS.RADIATION.REGIMENINDICATION'

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

Table S7.  Basic characteristics of clinical feature: 'RADIATIONS.RADIATION.REGIMENINDICATION'

RADIATIONS.RADIATION.REGIMENINDICATION Labels N
  NO 12
  YES 256
     
  Significant markers N = 32
  Higher in YES 20
  Higher in NO 12
List of top 10 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

Table S8.  Get Full Table List of top 10 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

T(pos if higher in 'YES') ttestP Q AUC
KIF15 10.12 6.285e-18 1.07e-13 0.7897
STX17 8.91 6.089e-16 1.04e-11 0.6566
MAP3K3 -11.38 7.004e-14 1.2e-09 0.8805
SIK1 7.61 5.556e-13 9.49e-09 0.7171
MYOM2 6.66 1.001e-09 1.71e-05 0.5189
POMP -7.16 1.193e-09 2.04e-05 0.8428
SNX31 6.27 1.551e-09 2.65e-05 0.7129
GPR120 6.93 1.57e-09 2.68e-05 0.6628
ZNHIT3 6.24 3.481e-09 5.95e-05 0.6224
TAF7 6.32 4.478e-09 7.65e-05 0.6903

Figure S4.  Get High-res Image As an example, this figure shows the association of KIF15 to 'RADIATIONS.RADIATION.REGIMENINDICATION'. P value = 6.29e-18 with T-test analysis.

Clinical variable #5: 'RADIATIONEXPOSURE'

51 genes related to 'RADIATIONEXPOSURE'.

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

RADIATIONEXPOSURE Labels N
  NO 223
  YES 10
     
  Significant markers N = 51
  Higher in YES 24
  Higher in NO 27
List of top 10 genes differentially expressed by 'RADIATIONEXPOSURE'

Table S10.  Get Full Table List of top 10 genes differentially expressed by 'RADIATIONEXPOSURE'

T(pos if higher in 'YES') ttestP Q AUC
ATP5L2 8.46 3.404e-15 5.82e-11 0.7762
ALKBH2 -8.15 2.332e-14 3.98e-10 0.7996
C1ORF96 8.65 3.892e-14 6.65e-10 0.6691
CASP12 -7.51 2.33e-11 3.98e-07 0.6924
KIAA0406 -8.78 4.695e-11 8.02e-07 0.7525
NKX2-2 -7.11 6.453e-11 1.1e-06 0.7453
VTN 7.34 4.704e-10 8.04e-06 0.6839
NAP1L1 -6.48 6.324e-10 1.08e-05 0.6744
RPL18 -6.7 6.703e-10 1.14e-05 0.752
DCUN1D2 6.79 8.564e-10 1.46e-05 0.7592

Figure S5.  Get High-res Image As an example, this figure shows the association of ATP5L2 to 'RADIATIONEXPOSURE'. P value = 3.4e-15 with T-test analysis.

Clinical variable #6: 'DISTANT.METASTASIS'

33 genes related to 'DISTANT.METASTASIS'.

Table S11.  Basic characteristics of clinical feature: 'DISTANT.METASTASIS'

DISTANT.METASTASIS Labels N
  M0 122
  M1 3
  MX 142
     
  Significant markers N = 33
List of top 10 genes differentially expressed by 'DISTANT.METASTASIS'

Table S12.  Get Full Table List of top 10 genes differentially expressed by 'DISTANT.METASTASIS'

ANOVA_P Q
GPR153 9.495e-16 1.62e-11
C12ORF45 1.396e-15 2.39e-11
DENND1A 6.389e-15 1.09e-10
C1ORF91 1.655e-14 2.83e-10
C14ORF169 2.155e-13 3.68e-09
C2ORF34 2.751e-13 4.7e-09
RPS10 5.116e-13 8.74e-09
TMEM161A 1.256e-11 2.15e-07
ADAM9 4.165e-10 7.11e-06
ZP3 8.038e-10 1.37e-05

Figure S6.  Get High-res Image As an example, this figure shows the association of GPR153 to 'DISTANT.METASTASIS'. P value = 9.5e-16 with ANOVA analysis.

Clinical variable #7: 'EXTRATHYROIDAL.EXTENSION'

32 genes related to 'EXTRATHYROIDAL.EXTENSION'.

Table S13.  Basic characteristics of clinical feature: 'EXTRATHYROIDAL.EXTENSION'

EXTRATHYROIDAL.EXTENSION Labels N
  MINIMAL (T3) 62
  MODERATE/ADVANCED (T4A) 4
  NONE 188
     
  Significant markers N = 32
List of top 10 genes differentially expressed by 'EXTRATHYROIDAL.EXTENSION'

Table S14.  Get Full Table List of top 10 genes differentially expressed by 'EXTRATHYROIDAL.EXTENSION'

ANOVA_P Q
SNORD97 4.343e-14 7.42e-10
DYNLRB2 2.745e-13 4.69e-09
ZNF784 1.168e-10 2e-06
ZNF781 1.755e-10 3e-06
C4ORF43 2.707e-10 4.62e-06
MRPL55 4.832e-10 8.26e-06
B4GALT7 2.195e-09 3.75e-05
KCNA5 4.312e-09 7.37e-05
HIGD2B 4.699e-09 8.03e-05
PIAS2 6.657e-09 0.000114

Figure S7.  Get High-res Image As an example, this figure shows the association of SNORD97 to 'EXTRATHYROIDAL.EXTENSION'. P value = 4.34e-14 with ANOVA analysis.

Clinical variable #8: 'LYMPH.NODE.METASTASIS'

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

Table S15.  Basic characteristics of clinical feature: 'LYMPH.NODE.METASTASIS'

LYMPH.NODE.METASTASIS Labels N
  N0 131
  N1 14
  N1A 56
  N1B 40
  NX 27
     
  Significant markers N = 300
List of top 10 genes differentially expressed by 'LYMPH.NODE.METASTASIS'

Table S16.  Get Full Table List of top 10 genes differentially expressed by 'LYMPH.NODE.METASTASIS'

ANOVA_P Q
PON2 1.229e-11 2.1e-07
CPNE1 1.496e-11 2.56e-07
RBM12 1.496e-11 2.56e-07
MVP 1.82e-11 3.11e-07
SNHG3-RCC1 2.119e-11 3.62e-07
BMP1 1.975e-10 3.37e-06
TAGLN2 2.139e-10 3.65e-06
LYPD1 2.834e-10 4.84e-06
STARD5 3.045e-10 5.2e-06
DIAPH1 3.195e-10 5.46e-06

Figure S8.  Get High-res Image As an example, this figure shows the association of PON2 to 'LYMPH.NODE.METASTASIS'. P value = 1.23e-11 with ANOVA analysis.

Clinical variable #9: 'COMPLETENESS.OF.RESECTION'

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

Table S17.  Basic characteristics of clinical feature: 'COMPLETENESS.OF.RESECTION'

COMPLETENESS.OF.RESECTION Labels N
  R0 210
  R1 17
  R2 1
  RX 19
     
  Significant markers N = 22
List of top 10 genes differentially expressed by 'COMPLETENESS.OF.RESECTION'

Table S18.  Get Full Table List of top 10 genes differentially expressed by 'COMPLETENESS.OF.RESECTION'

ANOVA_P Q
DENND1A 8.044e-60 1.37e-55
HPS3 6.574e-21 1.12e-16
TRRAP 2.711e-18 4.63e-14
ZNF585A 2.916e-13 4.98e-09
ZNF254 2.238e-12 3.82e-08
C18ORF2 4.791e-11 8.19e-07
PCDH18 9.887e-11 1.69e-06
LOC728743 2.089e-10 3.57e-06
TYW3 1.724e-09 2.94e-05
AVIL 2.42e-08 0.000413

Figure S9.  Get High-res Image As an example, this figure shows the association of DENND1A to 'COMPLETENESS.OF.RESECTION'. P value = 8.04e-60 with ANOVA analysis.

Clinical variable #10: 'NUMBER.OF.LYMPH.NODES'

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

Table S19.  Basic characteristics of clinical feature: 'NUMBER.OF.LYMPH.NODES'

NUMBER.OF.LYMPH.NODES Mean (SD) 2.87 (5.3)
  Significant markers N = 523
  pos. correlated 10
  neg. correlated 513
List of top 10 genes significantly correlated to 'NUMBER.OF.LYMPH.NODES' by Spearman correlation test

Table S20.  Get Full Table List of top 10 genes significantly correlated to 'NUMBER.OF.LYMPH.NODES' by Spearman correlation test

SpearmanCorr corrP Q
TAGLN2 -0.4741 2.811e-13 4.8e-09
STARD5 -0.4689 5.521e-13 9.44e-09
SNHG3-RCC1 -0.4673 6.732e-13 1.15e-08
FUT2 -0.4624 1.249e-12 2.13e-08
CPNE1 -0.4513 4.917e-12 8.4e-08
RBM12 -0.4513 4.917e-12 8.4e-08
MVP -0.447 8.285e-12 1.42e-07
AGFG1 -0.4461 9.17e-12 1.57e-07
EPHA4 -0.4439 1.197e-11 2.04e-07
MET -0.4438 1.207e-11 2.06e-07

Figure S10.  Get High-res Image As an example, this figure shows the association of TAGLN2 to 'NUMBER.OF.LYMPH.NODES'. P value = 2.81e-13 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #11: 'NEOPLASM.DISEASESTAGE'

76 genes related to 'NEOPLASM.DISEASESTAGE'.

Table S21.  Basic characteristics of clinical feature: 'NEOPLASM.DISEASESTAGE'

NEOPLASM.DISEASESTAGE Labels N
  STAGE I 152
  STAGE II 31
  STAGE III 58
  STAGE IVA 24
  STAGE IVC 2
     
  Significant markers N = 76
List of top 10 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

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

ANOVA_P Q
GPR153 3.946e-25 6.74e-21
C12ORF45 1.831e-23 3.13e-19
C1ORF91 3.284e-23 5.61e-19
C2ORF34 3.47e-22 5.93e-18
C14ORF169 1.604e-20 2.74e-16
RPS10 3.484e-19 5.95e-15
ZP3 7.673e-15 1.31e-10
THAP11 8.429e-14 1.44e-09
ADAM9 6.381e-13 1.09e-08
ZNF202 6.449e-13 1.1e-08

Figure S11.  Get High-res Image As an example, this figure shows the association of GPR153 to 'NEOPLASM.DISEASESTAGE'. P value = 3.95e-25 with ANOVA analysis.

Clinical variable #12: 'MULTIFOCALITY'

No gene related to 'MULTIFOCALITY'.

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

MULTIFOCALITY Labels N
  MULTIFOCAL 132
  UNIFOCAL 127
     
  Significant markers N = 0
Clinical variable #13: 'TUMOR.SIZE'

No gene related to 'TUMOR.SIZE'.

Table S24.  Basic characteristics of clinical feature: 'TUMOR.SIZE'

TUMOR.SIZE Mean (SD) 2.74 (1.5)
  Significant markers N = 0
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 = 268

  • Number of genes = 17090

  • Number of clinical features = 13

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] Spearman, C, The proof and measurement of association between two things, Amer. J. Psychol 15:72-101 (1904)
[2] Lehmann and Romano, Testing Statistical Hypotheses (3E ed.), New York: Springer. ISBN 0387988645 (2005)
[3] Howell, D, Statistical Methods for Psychology. (5th ed.), Duxbury Press:324-5 (2002)
[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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