Correlation between gene methylation status and clinical features
Thyroid Adenocarcinoma (Primary solid tumor)
15 July 2014  |  analyses__2014_07_15
Maintainer Information
Citation Information
doi:10.7908/C1V986VN
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/C1V986VN
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 19707 genes and 17 clinical features across 490 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 13 clinical features related to at least one genes.

  • 493 genes correlated to 'AGE'.

    • MGA ,  NHLRC1 ,  INA ,  RANBP17 ,  SYNGR3 ,  ...

  • 407 genes correlated to 'NEOPLASM.DISEASESTAGE'.

    • TBKBP1 ,  MGA ,  INA ,  RANBP17 ,  PDGFB ,  ...

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

    • TBKBP1 ,  GJD3 ,  IFT140 ,  TMEM204 ,  PDGFB ,  ...

  • 1772 genes correlated to 'PATHOLOGY.N.STAGE'.

    • BMP1 ,  ST6GALNAC5 ,  DAGLA ,  CPNE1__1 ,  RBM12__1 ,  ...

  • 2 genes correlated to 'PATHOLOGY.M.STAGE'.

    • IQCD ,  TPCN1

  • 37 genes correlated to 'GENDER'.

    • ALG11__2 ,  UTP14C__1 ,  ETF1 ,  KIF4B ,  FAM35A ,  ...

  • 3081 genes correlated to 'HISTOLOGICAL.TYPE'.

    • LEPR ,  LEPROT ,  PON2 ,  GPR115 ,  XDH ,  ...

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

    • KLHDC1 ,  ZNF845 ,  PPOX ,  C1ORF77 ,  S100A13__1 ,  ...

  • 418 genes correlated to 'EXTRATHYROIDAL.EXTENSION'.

    • NRCAM ,  PDGFB ,  TBKBP1 ,  IFT140 ,  TMEM204 ,  ...

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

    • SLC25A37 ,  NECAB2

  • 1344 genes correlated to 'NUMBER.OF.LYMPH.NODES'.

    • FUT2 ,  TMEM173 ,  MET ,  TAGLN2 ,  MACF1 ,  ...

  • 1 gene correlated to 'TUMOR.SIZE'.

    • TGFBR1

  • 39 genes correlated to 'RACE'.

    • SCAMP5 ,  MRPL36__1 ,  C15ORF53 ,  CDKN2AIP ,  PTGES ,  ...

  • No genes correlated to 'Time to Death', 'RADIATIONEXPOSURE', 'MULTIFOCALITY', 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=493 older N=483 younger N=10
NEOPLASM DISEASESTAGE Kruskal-Wallis test N=407        
PATHOLOGY T STAGE Spearman correlation test N=349 higher stage N=131 lower stage N=218
PATHOLOGY N STAGE Wilcoxon test N=1772 class1 N=1772 class0 N=0
PATHOLOGY M STAGE Kruskal-Wallis test N=2        
GENDER Wilcoxon test N=37 male N=37 female N=0
HISTOLOGICAL TYPE Kruskal-Wallis test N=3081        
RADIATIONS RADIATION REGIMENINDICATION Wilcoxon test N=10 yes N=10 no N=0
RADIATIONEXPOSURE Wilcoxon test   N=0        
EXTRATHYROIDAL EXTENSION Kruskal-Wallis test N=418        
COMPLETENESS OF RESECTION Kruskal-Wallis test N=2        
NUMBER OF LYMPH NODES Spearman correlation test N=1344 higher number.of.lymph.nodes N=46 lower number.of.lymph.nodes N=1298
MULTIFOCALITY Wilcoxon test   N=0        
TUMOR SIZE Spearman correlation test N=1 higher tumor.size N=1 lower tumor.size N=0
RACE Kruskal-Wallis test N=39        
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 (Months) 0-158.8 (median=15.7)
  censored N = 472
  death N = 14
     
  Significant markers N = 0
Clinical variable #2: 'AGE'

493 genes related to 'AGE'.

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

AGE Mean (SD) 47.2 (16)
  Significant markers N = 493
  pos. correlated 483
  neg. correlated 10
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
MGA 0.5263 2.933e-36 5.78e-32
NHLRC1 0.485 2.863e-30 5.64e-26
INA 0.483 5.189e-30 1.02e-25
RANBP17 0.4639 1.608e-27 3.17e-23
SYNGR3 0.4636 1.754e-27 3.46e-23
C1ORF59 0.463 2.119e-27 4.17e-23
ACN9 0.4559 1.619e-26 3.19e-22
OTUD7A 0.4356 4.119e-24 8.11e-20
ZNF518B 0.4318 1.142e-23 2.25e-19
NTNG2 0.4311 1.355e-23 2.67e-19
Clinical variable #3: 'NEOPLASM.DISEASESTAGE'

407 genes related to 'NEOPLASM.DISEASESTAGE'.

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

NEOPLASM.DISEASESTAGE Labels N
  STAGE I 277
  STAGE II 51
  STAGE III 108
  STAGE IV 2
  STAGE IVA 44
  STAGE IVC 6
     
  Significant markers N = 407
List of top 10 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

Table S5.  Get Full Table List of top 10 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

ANOVA_P Q
TBKBP1 3.121e-13 6.15e-09
MGA 6.87e-13 1.35e-08
INA 2.044e-12 4.03e-08
RANBP17 5.786e-12 1.14e-07
PDGFB 3.263e-11 6.43e-07
IFT140 3.673e-11 7.24e-07
TMEM204 3.673e-11 7.24e-07
LOC728392 8.272e-11 1.63e-06
ZNF518B 9.49e-11 1.87e-06
STK40 1.872e-10 3.69e-06
Clinical variable #4: 'PATHOLOGY.T.STAGE'

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

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

PATHOLOGY.T.STAGE Mean (SD) 2.13 (0.88)
  N
  1 140
  2 165
  3 162
  4 21
     
  Significant markers N = 349
  pos. correlated 131
  neg. correlated 218
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
TBKBP1 0.3224 2.908e-13 5.73e-09
GJD3 0.3072 3.978e-12 7.84e-08
IFT140 0.3032 7.832e-12 1.54e-07
TMEM204 0.3032 7.832e-12 1.54e-07
PDGFB 0.2971 2.112e-11 4.16e-07
CKMT2 0.278 4.123e-10 8.12e-06
RNU5D__1 0.278 4.123e-10 8.12e-06
RNU5E__1 0.278 4.123e-10 8.12e-06
PSD3 -0.2766 5.072e-10 9.99e-06
GGT7 0.275 6.457e-10 1.27e-05
Clinical variable #5: 'PATHOLOGY.N.STAGE'

1772 genes related to 'PATHOLOGY.N.STAGE'.

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

PATHOLOGY.N.STAGE Labels N
  class0 223
  class1 219
     
  Significant markers N = 1772
  Higher in class1 1772
  Higher in class0 0
List of top 10 genes differentially expressed by 'PATHOLOGY.N.STAGE'

Table S9.  Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGY.N.STAGE'

W(pos if higher in 'class1') wilcoxontestP Q AUC
BMP1 12610 1.442e-18 2.84e-14 0.7418
ST6GALNAC5 12613 1.471e-18 2.9e-14 0.7417
DAGLA 12625 1.593e-18 3.14e-14 0.7415
CPNE1__1 12705 2.701e-18 5.32e-14 0.7398
RBM12__1 12705 2.701e-18 5.32e-14 0.7398
PON2 12741 3.422e-18 6.74e-14 0.7391
SLC34A2 12749 3.606e-18 7.11e-14 0.7389
MET 12884 8.695e-18 1.71e-13 0.7362
MACF1 12896 9.398e-18 1.85e-13 0.7359
CAPN2 13010 1.959e-17 3.86e-13 0.7336
Clinical variable #6: 'PATHOLOGY.M.STAGE'

2 genes related to 'PATHOLOGY.M.STAGE'.

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

PATHOLOGY.M.STAGE Labels N
  M0 270
  M1 9
  MX 210
     
  Significant markers N = 2
List of 2 genes differentially expressed by 'PATHOLOGY.M.STAGE'

Table S11.  Get Full Table List of 2 genes differentially expressed by 'PATHOLOGY.M.STAGE'

ANOVA_P Q
IQCD 8.968e-06 0.177
TPCN1 8.968e-06 0.177
Clinical variable #7: 'GENDER'

37 genes related to 'GENDER'.

Table S12.  Basic characteristics of clinical feature: 'GENDER'

GENDER Labels N
  FEMALE 360
  MALE 130
     
  Significant markers N = 37
  Higher in MALE 37
  Higher in FEMALE 0
List of top 10 genes differentially expressed by 'GENDER'

Table S13.  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 46584 5.338e-63 1.05e-58 0.9954
UTP14C__1 46584 5.338e-63 1.05e-58 0.9954
ETF1 46175 7.355e-61 1.45e-56 0.9866
KIF4B 4476 1.431e-42 2.82e-38 0.9044
FAM35A 7410 6.982e-31 1.38e-26 0.8417
GLUD1__1 7410 6.982e-31 1.38e-26 0.8417
MTFR1 39063 1.063e-29 2.09e-25 0.8347
WBP11P1 37621 9.001e-25 1.77e-20 0.8039
DACH1 12117 3.542e-16 6.98e-12 0.7411
ANKRD20A4 34669 3.851e-16 7.59e-12 0.7408
Clinical variable #8: 'HISTOLOGICAL.TYPE'

3081 genes related to 'HISTOLOGICAL.TYPE'.

Table S14.  Basic characteristics of clinical feature: 'HISTOLOGICAL.TYPE'

HISTOLOGICAL.TYPE Labels N
  OTHER SPECIFY 9
  THYROID PAPILLARY CARCINOMA - CLASSICAL/USUAL 347
  THYROID PAPILLARY CARCINOMA - FOLLICULAR (>= 99% FOLLICULAR PATTERNED) 99
  THYROID PAPILLARY CARCINOMA - TALL CELL (>= 50% TALL CELL FEATURES) 35
     
  Significant markers N = 3081
List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

Table S15.  Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

ANOVA_P Q
LEPR 1.008e-29 1.99e-25
LEPROT 1.008e-29 1.99e-25
PON2 1.816e-29 3.58e-25
GPR115 2.849e-28 5.61e-24
XDH 9.142e-28 1.8e-23
SLC34A2 2.119e-27 4.18e-23
CAPN2 4.745e-27 9.35e-23
MICAL2 6.296e-27 1.24e-22
C3ORF26__1 8.287e-27 1.63e-22
FILIP1L__1 8.287e-27 1.63e-22
Clinical variable #9: 'RADIATIONS.RADIATION.REGIMENINDICATION'

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

Table S16.  Basic characteristics of clinical feature: 'RADIATIONS.RADIATION.REGIMENINDICATION'

RADIATIONS.RADIATION.REGIMENINDICATION Labels N
  NO 14
  YES 476
     
  Significant markers N = 10
  Higher in YES 10
  Higher in NO 0
List of 10 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

Table S17.  Get Full Table List of 10 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

W(pos if higher in 'YES') wilcoxontestP Q AUC
KLHDC1 897 3.128e-06 0.0616 0.8654
ZNF845 5697 5.95e-06 0.117 0.8549
PPOX 974 6.462e-06 0.127 0.8535
C1ORF77 981 6.752e-06 0.133 0.8528
S100A13__1 981 6.752e-06 0.133 0.8528
ZNF782 981 6.752e-06 0.133 0.8528
COPS8 1003 8.226e-06 0.162 0.8495
C13ORF23 1018 9.402e-06 0.185 0.8472
NHLRC3 1018 9.402e-06 0.185 0.8472
WBP4 1066 1.434e-05 0.282 0.84
Clinical variable #10: 'RADIATIONEXPOSURE'

No gene related to 'RADIATIONEXPOSURE'.

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

RADIATIONEXPOSURE Labels N
  NO 412
  YES 17
     
  Significant markers N = 0
Clinical variable #11: 'EXTRATHYROIDAL.EXTENSION'

418 genes related to 'EXTRATHYROIDAL.EXTENSION'.

Table S19.  Basic characteristics of clinical feature: 'EXTRATHYROIDAL.EXTENSION'

EXTRATHYROIDAL.EXTENSION Labels N
  MINIMAL (T3) 129
  MODERATE/ADVANCED (T4A) 16
  NONE 326
  VERY ADVANCED (T4B) 1
     
  Significant markers N = 418
List of top 10 genes differentially expressed by 'EXTRATHYROIDAL.EXTENSION'

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

ANOVA_P Q
NRCAM 4.956e-13 9.77e-09
PDGFB 2.645e-12 5.21e-08
TBKBP1 3.698e-12 7.29e-08
IFT140 2.102e-11 4.14e-07
TMEM204 2.102e-11 4.14e-07
BBC3 3.011e-11 5.93e-07
SLC34A2 4.097e-11 8.07e-07
MICAL2 4.3e-11 8.47e-07
GPR115 4.558e-11 8.98e-07
COL1A1 7.671e-11 1.51e-06
Clinical variable #12: 'COMPLETENESS.OF.RESECTION'

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

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

COMPLETENESS.OF.RESECTION Labels N
  R0 376
  R1 50
  R2 4
  RX 29
     
  Significant markers N = 2
List of 2 genes differentially expressed by 'COMPLETENESS.OF.RESECTION'

Table S22.  Get Full Table List of 2 genes differentially expressed by 'COMPLETENESS.OF.RESECTION'

ANOVA_P Q
SLC25A37 6.078e-06 0.12
NECAB2 9.816e-06 0.193
Clinical variable #13: 'NUMBER.OF.LYMPH.NODES'

1344 genes related to 'NUMBER.OF.LYMPH.NODES'.

Table S23.  Basic characteristics of clinical feature: 'NUMBER.OF.LYMPH.NODES'

NUMBER.OF.LYMPH.NODES Mean (SD) 3.53 (6.2)
  Significant markers N = 1344
  pos. correlated 46
  neg. correlated 1298
List of top 10 genes differentially expressed by 'NUMBER.OF.LYMPH.NODES'

Table S24.  Get Full Table List of top 10 genes significantly correlated to 'NUMBER.OF.LYMPH.NODES' by Spearman correlation test

SpearmanCorr corrP Q
FUT2 -0.4303 6.426e-19 1.27e-14
TMEM173 -0.4239 2.349e-18 4.63e-14
MET -0.4236 2.493e-18 4.91e-14
TAGLN2 -0.4156 1.223e-17 2.41e-13
MACF1 -0.4146 1.513e-17 2.98e-13
HDAC9 -0.414 1.691e-17 3.33e-13
CAPN2 -0.4091 4.362e-17 8.59e-13
CPNE1__1 -0.4076 5.807e-17 1.14e-12
RBM12__1 -0.4076 5.807e-17 1.14e-12
SMURF1 -0.4047 1e-16 1.97e-12
Clinical variable #14: 'MULTIFOCALITY'

No gene related to 'MULTIFOCALITY'.

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

MULTIFOCALITY Labels N
  MULTIFOCAL 222
  UNIFOCAL 258
     
  Significant markers N = 0
Clinical variable #15: 'TUMOR.SIZE'

One gene related to 'TUMOR.SIZE'.

Table S26.  Basic characteristics of clinical feature: 'TUMOR.SIZE'

TUMOR.SIZE Mean (SD) 2.96 (1.6)
  Significant markers N = 1
  pos. correlated 1
  neg. correlated 0
List of one gene differentially expressed by 'TUMOR.SIZE'

Table S27.  Get Full Table List of one gene significantly correlated to 'TUMOR.SIZE' by Spearman correlation test

SpearmanCorr corrP Q
TGFBR1 0.2263 6.208e-06 0.122
Clinical variable #16: 'RACE'

39 genes related to 'RACE'.

Table S28.  Basic characteristics of clinical feature: 'RACE'

RACE Labels N
  AMERICAN INDIAN OR ALASKA NATIVE 1
  ASIAN 49
  BLACK OR AFRICAN AMERICAN 22
  WHITE 319
     
  Significant markers N = 39
List of top 10 genes differentially expressed by 'RACE'

Table S29.  Get Full Table List of top 10 genes differentially expressed by 'RACE'

ANOVA_P Q
SCAMP5 5.467e-14 1.08e-09
MRPL36__1 6.667e-12 1.31e-07
C15ORF53 2.405e-10 4.74e-06
CDKN2AIP 3.575e-10 7.04e-06
PTGES 3.867e-09 7.62e-05
CLTC 8.422e-09 0.000166
LOC100133161 9.194e-08 0.00181
EGOT 9.377e-08 0.00185
ITPR1 9.377e-08 0.00185
RFWD3 9.984e-08 0.00197
Clinical variable #17: 'ETHNICITY'

No gene related to 'ETHNICITY'.

Table S30.  Basic characteristics of clinical feature: 'ETHNICITY'

ETHNICITY Labels N
  HISPANIC OR LATINO 38
  NOT HISPANIC OR LATINO 344
     
  Significant markers N = 0
Methods & Data
Input

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

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

  • Number of patients = 490

  • Number of genes = 19707

  • Number of clinical features = 17

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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