Correlation between gene methylation status and clinical features
Stomach Adenocarcinoma (Primary solid tumor)
16 April 2014  |  analyses__2014_04_16
Maintainer Information
Citation Information
doi:10.7908/C1R2102V
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/C1R2102V
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 19730 genes and 11 clinical features across 263 samples, statistically thresholded by Q value < 0.05, 8 clinical features related to at least one genes.

  • 30 genes correlated to 'AGE'.

    • TOP1MT ,  CDCA5 ,  ZFPL1 ,  STARD10 ,  SPRR1A ,  ...

  • 900 genes correlated to 'NEOPLASM.DISEASESTAGE'.

    • DSTYK ,  BMPR1A ,  ABCC4 ,  ALDH6A1 ,  LIN52 ,  ...

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

    • FAM3C ,  PPAP2C ,  MLLT10 ,  PVRL4 ,  NBEAL2 ,  ...

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

    • RAB8A ,  LSM14A ,  YIPF1 ,  MTIF2 ,  LRRFIP1 ,  ...

  • 3 genes correlated to 'GENDER'.

    • KIF4B ,  ALG11__1 ,  UTP14C

  • 102 genes correlated to 'HISTOLOGICAL.TYPE'.

    • CAT ,  MIR568 ,  CREB1 ,  ASB14 ,  PTPN11 ,  ...

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

    • FSCN1 ,  RET ,  CBWD1 ,  HAR1A ,  HAR1B ,  ...

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

    • PTRH1__1 ,  TTC16 ,  YIPF1 ,  TIFA ,  FLJ35220 ,  ...

  • No genes correlated to 'Time to Death', 'PATHOLOGY.N.STAGE', and 'NUMBER.OF.LYMPH.NODES'.

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=30 older N=0 younger N=30
NEOPLASM DISEASESTAGE ANOVA test N=900        
PATHOLOGY T STAGE Spearman correlation test N=421 higher stage N=138 lower stage N=283
PATHOLOGY N STAGE Spearman correlation test   N=0        
PATHOLOGY M STAGE ANOVA test N=47        
GENDER t test N=3 male N=2 female N=1
HISTOLOGICAL TYPE ANOVA test N=102        
RADIATIONS RADIATION REGIMENINDICATION t test N=584 yes N=539 no N=45
COMPLETENESS OF RESECTION ANOVA test N=866        
NUMBER OF LYMPH NODES Spearman correlation 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) 0.1-105.1 (median=9.2)
  censored N = 197
  death N = 55
     
  Significant markers N = 0
Clinical variable #2: 'AGE'

30 genes related to 'AGE'.

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

AGE Mean (SD) 65.41 (11)
  Significant markers N = 30
  pos. correlated 0
  neg. correlated 30
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
TOP1MT -0.3406 2.25e-08 0.000444
CDCA5 -0.3252 1.017e-07 0.00201
ZFPL1 -0.3252 1.017e-07 0.00201
STARD10 -0.3177 2.065e-07 0.00407
SPRR1A -0.3175 2.106e-07 0.00416
KIAA1217 -0.3123 3.375e-07 0.00666
SLC26A3 -0.3087 4.682e-07 0.00923
SLC12A7 -0.2993 1.074e-06 0.0212
ADAM21P1 -0.2986 1.14e-06 0.0225
CHST9 -0.2985 1.264e-06 0.0249

Figure S1.  Get High-res Image As an example, this figure shows the association of TOP1MT to 'AGE'. P value = 2.25e-08 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #3: 'NEOPLASM.DISEASESTAGE'

900 genes related to 'NEOPLASM.DISEASESTAGE'.

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

NEOPLASM.DISEASESTAGE Labels N
  STAGE I 2
  STAGE IA 9
  STAGE IB 23
  STAGE II 24
  STAGE IIA 33
  STAGE IIB 44
  STAGE III 2
  STAGE IIIA 43
  STAGE IIIB 38
  STAGE IIIC 27
  STAGE IV 18
     
  Significant markers N = 900
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
DSTYK 4.848e-30 9.57e-26
BMPR1A 3.681e-22 7.26e-18
ABCC4 1.069e-18 2.11e-14
ALDH6A1 6.509e-18 1.28e-13
LIN52 6.509e-18 1.28e-13
NBPF1 1.18e-17 2.33e-13
ZNF792 1.478e-14 2.91e-10
ALG9 8.627e-13 1.7e-08
SMAD1 1.602e-12 3.16e-08
ZNF398 4.294e-12 8.47e-08

Figure S2.  Get High-res Image As an example, this figure shows the association of DSTYK to 'NEOPLASM.DISEASESTAGE'. P value = 4.85e-30 with ANOVA analysis.

Clinical variable #4: 'PATHOLOGY.T.STAGE'

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

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

PATHOLOGY.T.STAGE Mean (SD) 2.97 (0.83)
  N
  1 11
  2 61
  3 116
  4 75
     
  Significant markers N = 421
  pos. correlated 138
  neg. correlated 283
List of top 10 genes significantly correlated to 'PATHOLOGY.T.STAGE' by Spearman correlation test

Table S7.  Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY.T.STAGE' by Spearman correlation test

SpearmanCorr corrP Q
FAM3C -0.3644 1.117e-09 2.2e-05
PPAP2C 0.3637 1.204e-09 2.38e-05
MLLT10 -0.3586 2.12e-09 4.18e-05
PVRL4 0.3561 2.799e-09 5.52e-05
NBEAL2 0.3546 3.302e-09 6.51e-05
C4ORF29 -0.3519 4.386e-09 8.65e-05
MFSD8 -0.3519 4.386e-09 8.65e-05
RPL24 -0.3518 4.45e-09 8.78e-05
TTC19__1 -0.3509 4.892e-09 9.65e-05
ZSWIM7__1 -0.3509 4.892e-09 9.65e-05

Figure S3.  Get High-res Image As an example, this figure shows the association of FAM3C to 'PATHOLOGY.T.STAGE'. P value = 1.12e-09 with Spearman correlation analysis.

Clinical variable #5: 'PATHOLOGY.N.STAGE'

No gene related to 'PATHOLOGY.N.STAGE'.

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

PATHOLOGY.N.STAGE Mean (SD) 1.23 (1.1)
  N
  0 92
  1 69
  2 49
  3 52
     
  Significant markers N = 0
Clinical variable #6: 'PATHOLOGY.M.STAGE'

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

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

PATHOLOGY.M.STAGE Labels N
  M0 238
  M1 13
  MX 12
     
  Significant markers N = 47
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
RAB8A 1.038e-08 0.000205
LSM14A 1.394e-08 0.000275
YIPF1 1.72e-08 0.000339
MTIF2 2.321e-08 0.000458
LRRFIP1 2.533e-08 5e-04
FDX1 3.363e-08 0.000663
TIFA 4.672e-08 0.000922
CYP4V2 4.866e-08 0.00096
SLC25A2 1.283e-07 0.00253
FLJ35220 1.343e-07 0.00265

Figure S4.  Get High-res Image As an example, this figure shows the association of RAB8A to 'PATHOLOGY.M.STAGE'. P value = 1.04e-08 with ANOVA analysis.

Clinical variable #7: 'GENDER'

3 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 100
  MALE 163
     
  Significant markers N = 3
  Higher in MALE 2
  Higher in FEMALE 1
List of 3 genes differentially expressed by 'GENDER'

Table S12.  Get Full Table List of 3 genes differentially expressed by 'GENDER'

T(pos if higher in 'MALE') ttestP Q AUC
KIF4B -12.64 9.769e-29 1.93e-24 0.8609
ALG11__1 13.95 1.359e-26 2.68e-22 0.9433
UTP14C 13.95 1.359e-26 2.68e-22 0.9433

Figure S5.  Get High-res Image As an example, this figure shows the association of KIF4B to 'GENDER'. P value = 9.77e-29 with T-test analysis.

Clinical variable #8: 'HISTOLOGICAL.TYPE'

102 genes related to 'HISTOLOGICAL.TYPE'.

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

HISTOLOGICAL.TYPE Labels N
  STOMACH ADENOCARCINOMA DIFFUSE TYPE 49
  STOMACH ADENOCARCINOMA NOT OTHERWISE SPECIFIED (NOS) 115
  STOMACH INTESTINAL ADENOCARCINOMA NOT OTHERWISE SPECIFIED (NOS) 36
  STOMACH INTESTINAL ADENOCARCINOMA TUBULAR TYPE 40
  STOMACH INTESTINAL ADENOCARCINOMA  MUCINOUS TYPE 14
  STOMACH INTESTINAL ADENOCARCINOMA  PAPILLARY TYPE 6
  STOMACH ADENOCARCINOMA SIGNET RING TYPE 3
     
  Significant markers N = 102
List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

Table S14.  Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

ANOVA_P Q
CAT 1.161e-14 2.29e-10
MIR568 1.735e-13 3.42e-09
CREB1 4.66e-11 9.19e-07
ASB14 1.717e-09 3.39e-05
PTPN11 5.608e-09 0.000111
SLC23A1 8.569e-09 0.000169
BRDT 1.803e-08 0.000356
BAD__1 1.843e-08 0.000363
GPR137__1 1.843e-08 0.000363
NGEF 2.021e-08 0.000399

Figure S6.  Get High-res Image As an example, this figure shows the association of CAT to 'HISTOLOGICAL.TYPE'. P value = 1.16e-14 with ANOVA analysis.

Clinical variable #9: 'RADIATIONS.RADIATION.REGIMENINDICATION'

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

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

RADIATIONS.RADIATION.REGIMENINDICATION Labels N
  NO 7
  YES 256
     
  Significant markers N = 584
  Higher in YES 539
  Higher in NO 45
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'

T(pos if higher in 'YES') ttestP Q AUC
FSCN1 14.7 9.048e-36 1.79e-31 0.8086
RET 13.77 3.266e-32 6.44e-28 0.8092
CBWD1 15.29 3.943e-31 7.78e-27 0.9319
HAR1A 12.8 5.297e-25 1.05e-20 0.8175
HAR1B 12.8 5.297e-25 1.05e-20 0.8175
HAR1A__1 11.4 7.149e-24 1.41e-19 0.649
HAR1B__1 11.4 7.149e-24 1.41e-19 0.649
TSPAN5 11.1 1.079e-23 2.13e-19 0.7517
MAP1LC3A 10.88 7.34e-23 1.45e-18 0.5971
DMC1 10.85 8.724e-23 1.72e-18 0.7779

Figure S7.  Get High-res Image As an example, this figure shows the association of FSCN1 to 'RADIATIONS.RADIATION.REGIMENINDICATION'. P value = 9.05e-36 with T-test analysis.

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

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

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

COMPLETENESS.OF.RESECTION Labels N
  R0 230
  R1 9
  R2 5
     
  Significant markers N = 866
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
PTRH1__1 6.944e-21 1.37e-16
TTC16 6.944e-21 1.37e-16
YIPF1 1.518e-18 3e-14
TIFA 2.055e-18 4.05e-14
FLJ35220 6.776e-18 1.34e-13
LOC100294362 6.776e-18 1.34e-13
BCAS3 6.03e-17 1.19e-12
TH1L 7.905e-17 1.56e-12
FDX1 8.222e-17 1.62e-12
TTC4 1.898e-16 3.74e-12

Figure S8.  Get High-res Image As an example, this figure shows the association of PTRH1__1 to 'COMPLETENESS.OF.RESECTION'. P value = 6.94e-21 with ANOVA analysis.

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

No gene related to 'NUMBER.OF.LYMPH.NODES'.

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

NUMBER.OF.LYMPH.NODES Mean (SD) 4.81 (7.3)
  Significant markers N = 0
Methods & Data
Input

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

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

  • Number of patients = 263

  • Number of genes = 19730

  • Number of clinical features = 11

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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