Correlation between gene methylation status and clinical features
Head and Neck Squamous Cell Carcinoma (Primary solid tumor)
17 October 2014  |  analyses__2014_10_17
Maintainer Information
Citation Information
doi:10.7908/C1DV1HS9
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/C1DV1HS9
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 20185 genes and 13 clinical features across 494 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 10 clinical features related to at least one genes.

  • 14 genes correlated to 'AGE'.

    • KIAA1143 ,  KIF15 ,  TRIM45 ,  FIGNL1 ,  SOX10 ,  ...

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

    • MAP4K4 ,  SMURF1 ,  ABL2 ,  C5ORF38 ,  IRX2 ,  ...

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

    • AVPI1 ,  DSG1 ,  SLC47A2 ,  C19ORF66__1 ,  FAM185A ,  ...

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

    • METTL3 ,  CDKN2D ,  C19ORF2 ,  LOC729156 ,  ABCB9 ,  ...

  • 178 genes correlated to 'GENDER'.

    • KIF4B ,  FRG1B ,  MRPL32 ,  PSMA2__1 ,  NCRNA00116 ,  ...

  • 7 genes correlated to 'HISTOLOGICAL.TYPE'.

    • CALML3 ,  RPP21 ,  ARHGAP23 ,  ARSG ,  HAUS8 ,  ...

  • 1094 genes correlated to 'RADIATIONS.RADIATION.REGIMENINDICATION'.

    • HSPB1 ,  RUFY3 ,  NFS1 ,  ROMO1 ,  SNRNP40 ,  ...

  • 21 genes correlated to 'NUMBERPACKYEARSSMOKED'.

    • KLF6 ,  DCAF17 ,  METTL8 ,  SCN9A ,  LOC401093 ,  ...

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

    • HSPB3 ,  FAM185A ,  SLC13A4 ,  P2RY6 ,  DSG1 ,  ...

  • 13 genes correlated to 'RACE'.

    • GPBAR1 ,  ATAD3A ,  WBSCR27 ,  LOC100133161 ,  TP53 ,  ...

  • No genes correlated to 'Time to Death', 'NEOPLASM.DISEASESTAGE', 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=14 older N=12 younger N=2
NEOPLASM DISEASESTAGE Kruskal-Wallis test   N=0        
PATHOLOGY T STAGE Spearman correlation test N=47 higher stage N=2 lower stage N=45
PATHOLOGY N STAGE Spearman correlation test N=10 higher stage N=10 lower stage N=0
PATHOLOGY M STAGE Kruskal-Wallis test N=14        
GENDER Wilcoxon test N=178 male N=178 female N=0
HISTOLOGICAL TYPE Kruskal-Wallis test N=7        
RADIATIONS RADIATION REGIMENINDICATION Wilcoxon test N=1094 yes N=1094 no N=0
NUMBERPACKYEARSSMOKED Spearman correlation test N=21 higher numberpackyearssmoked N=2 lower numberpackyearssmoked N=19
NUMBER OF LYMPH NODES Spearman correlation test N=57 higher number.of.lymph.nodes N=57 lower number.of.lymph.nodes N=0
RACE Kruskal-Wallis test N=13        
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 (Years) 2-5480 (median=717.5)
  censored N = 304
  death N = 116
     
  Significant markers N = 0
Clinical variable #2: 'AGE'

14 genes related to 'AGE'.

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

AGE Mean (SD) 60.8 (12)
  Significant markers N = 14
  pos. correlated 12
  neg. correlated 2
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
KIAA1143 0.2795 2.691e-10 5.43e-06
KIF15 0.2795 2.691e-10 5.43e-06
TRIM45 0.223 5.67e-07 0.0114
FIGNL1 0.2198 8.249e-07 0.0166
SOX10 0.2111 2.25e-06 0.0454
ZNF274 0.2088 2.921e-06 0.059
CHMP6 -0.1995 8.034e-06 0.162
INPP5F 0.1993 8.25e-06 0.166
RETNLB 0.1973 1.023e-05 0.206
SOX12 0.1969 1.058e-05 0.214
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 26
  STAGE II 76
  STAGE III 74
  STAGE IVA 240
  STAGE IVB 12
  STAGE IVC 1
     
  Significant markers N = 0
Clinical variable #4: 'PATHOLOGY.T.STAGE'

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

Table S5.  Basic characteristics of clinical feature: 'PATHOLOGY.T.STAGE'

PATHOLOGY.T.STAGE Mean (SD) 2.86 (1)
  N
  0 1
  1 46
  2 130
  3 95
  4 164
     
  Significant markers N = 47
  pos. correlated 2
  neg. correlated 45
List of top 10 genes differentially expressed by 'PATHOLOGY.T.STAGE'

Table S6.  Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY.T.STAGE' by Spearman correlation test

SpearmanCorr corrP Q
MAP4K4 -0.2559 6.041e-08 0.00122
SMURF1 -0.2494 1.311e-07 0.00265
ABL2 -0.2388 4.54e-07 0.00916
C5ORF38 -0.2369 5.634e-07 0.0114
IRX2 -0.2369 5.634e-07 0.0114
SDCCAG8 -0.2367 5.778e-07 0.0117
COG5 -0.2361 6.142e-07 0.0124
DUS4L -0.2361 6.142e-07 0.0124
GSTP1 -0.229 1.35e-06 0.0272
KCNK1 -0.2284 1.444e-06 0.0291
Clinical variable #5: 'PATHOLOGY.N.STAGE'

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

Table S7.  Basic characteristics of clinical feature: 'PATHOLOGY.N.STAGE'

PATHOLOGY.N.STAGE Mean (SD) 1 (0.95)
  N
  0 171
  1 63
  2 156
  3 8
     
  Significant markers N = 10
  pos. correlated 10
  neg. correlated 0
List of 10 genes differentially expressed by 'PATHOLOGY.N.STAGE'

Table S8.  Get Full Table List of 10 genes significantly correlated to 'PATHOLOGY.N.STAGE' by Spearman correlation test

SpearmanCorr corrP Q
AVPI1 0.2568 2.056e-07 0.00415
DSG1 0.2536 2.944e-07 0.00594
SLC47A2 0.253 3.144e-07 0.00635
C19ORF66__1 0.2401 1.26e-06 0.0254
FAM185A 0.2374 1.665e-06 0.0336
EFEMP1 0.234 2.37e-06 0.0478
GLB1L3 0.2225 7.454e-06 0.15
MAFB 0.2197 9.671e-06 0.195
CFB 0.2187 1.067e-05 0.215
KRT80 0.2155 1.487e-05 0.3
Clinical variable #6: 'PATHOLOGY.M.STAGE'

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

Table S9.  Basic characteristics of clinical feature: 'PATHOLOGY.M.STAGE'

PATHOLOGY.M.STAGE Labels N
  M0 168
  M1 1
  MX 58
     
  Significant markers N = 14
List of top 10 genes differentially expressed by 'PATHOLOGY.M.STAGE'

Table S10.  Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGY.M.STAGE'

ANOVA_P Q
METTL3 3.409e-07 0.00688
CDKN2D 9.25e-07 0.0187
C19ORF2 1.789e-06 0.0361
LOC729156 2.634e-06 0.0532
ABCB9 2.687e-06 0.0542
OGFOD2__1 2.687e-06 0.0542
LPXN 2.783e-06 0.0562
ZFP91 2.783e-06 0.0562
ZFP91-CNTF 2.783e-06 0.0562
C19ORF42 7.125e-06 0.144
Clinical variable #7: 'GENDER'

178 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 134
  MALE 360
     
  Significant markers N = 178
  Higher in MALE 178
  Higher in FEMALE 0
List of top 10 genes differentially expressed by 'GENDER'

Table S12.  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
KIF4B 7240 5.364e-33 1.08e-28 0.8499
FRG1B 11387 1.78e-19 3.59e-15 0.764
MRPL32 12584 2.898e-16 5.85e-12 0.7391
PSMA2__1 12584 2.898e-16 5.85e-12 0.7391
NCRNA00116 14338 4.088e-12 8.25e-08 0.7028
NPDC1 14576 1.33e-11 2.68e-07 0.6978
CCDC121__1 14986 9.498e-11 1.92e-06 0.6893
GPN1__1 14986 9.498e-11 1.92e-06 0.6893
ZNF839 15451 7.992e-10 1.61e-05 0.6797
NDUFA13 15455 8.136e-10 1.64e-05 0.6796
Clinical variable #8: 'HISTOLOGICAL.TYPE'

7 genes related to 'HISTOLOGICAL.TYPE'.

Table S13.  Basic characteristics of clinical feature: 'HISTOLOGICAL.TYPE'

HISTOLOGICAL.TYPE Labels N
  HEAD AND NECK SQUAMOUS CELL CARCINOMA 483
  HEAD AND NECK SQUAMOUS CELL CARCINOMA SPINDLE CELL VARIANT 1
  HEAD AND NECK SQUAMOUS CELL CARCINOMA BASALOID TYPE 10
     
  Significant markers N = 7
List of 7 genes differentially expressed by 'HISTOLOGICAL.TYPE'

Table S14.  Get Full Table List of 7 genes differentially expressed by 'HISTOLOGICAL.TYPE'

ANOVA_P Q
CALML3 1.114e-05 0.225
RPP21 1.197e-05 0.242
ARHGAP23 1.268e-05 0.256
ARSG 1.286e-05 0.259
HAUS8 1.283e-05 0.259
MYO9B__1 1.283e-05 0.259
CBX4 1.33e-05 0.268
Clinical variable #9: 'RADIATIONS.RADIATION.REGIMENINDICATION'

1094 genes related to 'RADIATIONS.RADIATION.REGIMENINDICATION'.

Table S15.  Basic characteristics of clinical feature: 'RADIATIONS.RADIATION.REGIMENINDICATION'

RADIATIONS.RADIATION.REGIMENINDICATION Labels N
  NO 81
  YES 413
     
  Significant markers N = 1094
  Higher in YES 1094
  Higher in NO 0
List of top 10 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

Table S16.  Get Full Table List of top 10 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

W(pos if higher in 'YES') wilcoxontestP Q AUC
HSPB1 7644 1.065e-14 2.15e-10 0.7715
RUFY3 7928 6.912e-14 1.4e-09 0.763
NFS1 8187 3.62e-13 7.31e-09 0.7553
ROMO1 8187 3.62e-13 7.31e-09 0.7553
SNRNP40 8243 5.146e-13 1.04e-08 0.7536
ZCCHC17 8243 5.146e-13 1.04e-08 0.7536
SNX22 8295 7.12e-13 1.44e-08 0.752
HMMR 8317 8.164e-13 1.65e-08 0.7514
NUDCD2 8317 8.164e-13 1.65e-08 0.7514
EIF4E2__1 8341 9.473e-13 1.91e-08 0.7507
Clinical variable #10: 'NUMBERPACKYEARSSMOKED'

21 genes related to 'NUMBERPACKYEARSSMOKED'.

Table S17.  Basic characteristics of clinical feature: 'NUMBERPACKYEARSSMOKED'

NUMBERPACKYEARSSMOKED Mean (SD) 45.66 (36)
  Significant markers N = 21
  pos. correlated 2
  neg. correlated 19
List of top 10 genes differentially expressed by 'NUMBERPACKYEARSSMOKED'

Table S18.  Get Full Table List of top 10 genes significantly correlated to 'NUMBERPACKYEARSSMOKED' by Spearman correlation test

SpearmanCorr corrP Q
KLF6 0.2847 1.457e-06 0.0294
DCAF17 -0.2779 2.633e-06 0.0531
METTL8 -0.2779 2.633e-06 0.0531
SCN9A -0.2779 2.644e-06 0.0534
LOC401093 -0.273 4.004e-06 0.0808
MBNL1__1 -0.273 4.004e-06 0.0808
SELT -0.2703 5.036e-06 0.102
ARMC8__1 -0.2682 5.996e-06 0.121
THAP2 -0.2675 6.339e-06 0.128
ZFC3H1 -0.2675 6.339e-06 0.128
Clinical variable #11: 'NUMBER.OF.LYMPH.NODES'

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

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

NUMBER.OF.LYMPH.NODES Mean (SD) 2.18 (4.4)
  Significant markers N = 57
  pos. correlated 57
  neg. correlated 0
List of top 10 genes differentially expressed by 'NUMBER.OF.LYMPH.NODES'

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

SpearmanCorr corrP Q
HSPB3 0.2824 1.579e-08 0.000319
FAM185A 0.2766 3.158e-08 0.000637
SLC13A4 0.2686 8.086e-08 0.00163
P2RY6 0.2632 1.492e-07 0.00301
DSG1 0.2623 1.642e-07 0.00331
AVPI1 0.2584 2.542e-07 0.00513
NBLA00301 0.2533 4.443e-07 0.00897
SLC47A2 0.2517 5.26e-07 0.0106
C9ORF139 0.2517 5.281e-07 0.0107
FUT7 0.2517 5.281e-07 0.0107
Clinical variable #12: 'RACE'

13 genes related to 'RACE'.

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

RACE Labels N
  AMERICAN INDIAN OR ALASKA NATIVE 2
  ASIAN 11
  BLACK OR AFRICAN AMERICAN 44
  WHITE 421
     
  Significant markers N = 13
List of top 10 genes differentially expressed by 'RACE'

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

ANOVA_P Q
GPBAR1 2.36e-11 4.76e-07
ATAD3A 3.182e-07 0.00642
WBSCR27 6.408e-07 0.0129
LOC100133161 1.081e-06 0.0218
TP53 1.083e-06 0.0219
WRAP53 1.083e-06 0.0219
MFN2 2.048e-06 0.0413
EIF2AK4 2.239e-06 0.0452
EIF3D 2.489e-06 0.0502
LOC253039 2.947e-06 0.0594
Clinical variable #13: 'ETHNICITY'

No gene related to 'ETHNICITY'.

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

ETHNICITY Labels N
  HISPANIC OR LATINO 24
  NOT HISPANIC OR LATINO 437
     
  Significant markers N = 0
Methods & Data
Input

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

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

  • Number of patients = 494

  • Number of genes = 20185

  • Number of clinical features = 13

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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