Correlation between gene methylation status and clinical features
Rectum Adenocarcinoma (Primary solid tumor)
15 January 2014  |  analyses__2014_01_15
Maintainer Information
Citation Information
doi:10.7908/C1RN3693
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/C1RN3693
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 20018 genes and 11 clinical features across 95 samples, statistically thresholded by Q value < 0.05, 6 clinical features related to at least one genes.

  • 274 genes correlated to 'NEOPLASM.DISEASESTAGE'.

    • ADRA2A ,  ADAM11 ,  SNX19 ,  HOXD13 ,  ZNF192 ,  ...

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

    • TUBA3D ,  UQCRB ,  LRRC32 ,  MAST4 ,  CSRP2 ,  ...

  • 3 genes correlated to 'GENDER'.

    • ALG11__2 ,  UTP14C ,  KIF4B

  • 64 genes correlated to 'HISTOLOGICAL.TYPE'.

    • LPAR5 ,  LRRC49__1 ,  PLA2G12B ,  C20ORF56 ,  KIAA0319L__1 ,  ...

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

    • ST8SIA2 ,  RET ,  ZDBF2 ,  SVEP1 ,  ZNF134 ,  ...

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

    • TDRD6 ,  PABPC1L ,  ATRNL1 ,  LOC400891 ,  MPP2 ,  ...

  • No genes correlated to 'Time to Death', 'AGE', 'PATHOLOGY.T.STAGE', '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=0        
NEOPLASM DISEASESTAGE ANOVA test N=274        
PATHOLOGY T STAGE Spearman correlation test   N=0        
PATHOLOGY N STAGE Spearman correlation test   N=0        
PATHOLOGY M STAGE ANOVA test N=7        
GENDER t test N=3 male N=2 female N=1
HISTOLOGICAL TYPE t test N=64 rectal mucinous adenocarcinoma N=37 rectal adenocarcinoma N=27
RADIATIONS RADIATION REGIMENINDICATION t test N=94 yes N=90 no N=4
COMPLETENESS OF RESECTION ANOVA test N=38        
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) 0.2-129.3 (median=12)
  censored N = 78
  death N = 10
     
  Significant markers N = 0
Clinical variable #2: 'AGE'

No gene related to 'AGE'.

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

AGE Mean (SD) 63.33 (12)
  Significant markers N = 0
Clinical variable #3: 'NEOPLASM.DISEASESTAGE'

274 genes related to 'NEOPLASM.DISEASESTAGE'.

Table S3.  Basic characteristics of clinical feature: 'NEOPLASM.DISEASESTAGE'

NEOPLASM.DISEASESTAGE Labels N
  STAGE I 11
  STAGE II 6
  STAGE IIA 18
  STAGE IIB 2
  STAGE IIC 2
  STAGE III 4
  STAGE IIIA 9
  STAGE IIIB 13
  STAGE IIIC 10
  STAGE IV 6
  STAGE IVA 9
     
  Significant markers N = 274
List of top 10 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

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

ANOVA_P Q
ADRA2A 3.934e-33 7.88e-29
ADAM11 1.708e-14 3.42e-10
SNX19 6.253e-13 1.25e-08
HOXD13 3.145e-12 6.29e-08
ZNF192 2.714e-11 5.43e-07
ACBD3 3.939e-11 7.88e-07
C4ORF34 8.905e-11 1.78e-06
GIGYF1 9.181e-11 1.84e-06
FAM25B 1.238e-10 2.48e-06
FAM25C 1.238e-10 2.48e-06

Figure S1.  Get High-res Image As an example, this figure shows the association of ADRA2A to 'NEOPLASM.DISEASESTAGE'. P value = 3.93e-33 with ANOVA analysis.

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

No gene related to 'PATHOLOGY.T.STAGE'.

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

PATHOLOGY.T.STAGE Mean (SD) 2.89 (0.65)
  N
  1 4
  2 13
  3 66
  4 11
     
  Significant markers N = 0
Clinical variable #5: 'PATHOLOGY.N.STAGE'

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

Table S6.  Basic characteristics of clinical feature: 'PATHOLOGY.N.STAGE'

PATHOLOGY.N.STAGE Mean (SD) 0.78 (0.8)
  N
  0 41
  1 30
  2 21
     
  Significant markers N = 0
Clinical variable #6: 'PATHOLOGY.M.STAGE'

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

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

PATHOLOGY.M.STAGE Labels N
  M0 67
  M1 10
  M1A 2
  MX 14
     
  Significant markers N = 7
List of 7 genes differentially expressed by 'PATHOLOGY.M.STAGE'

Table S8.  Get Full Table List of 7 genes differentially expressed by 'PATHOLOGY.M.STAGE'

ANOVA_P Q
TUBA3D 1.65e-12 3.3e-08
UQCRB 4.024e-10 8.06e-06
LRRC32 1.514e-09 3.03e-05
MAST4 1.07e-08 0.000214
CSRP2 2.651e-07 0.00531
CYB5D1 3.424e-07 0.00685
LSMD1 3.424e-07 0.00685

Figure S2.  Get High-res Image As an example, this figure shows the association of TUBA3D to 'PATHOLOGY.M.STAGE'. P value = 1.65e-12 with ANOVA analysis.

Clinical variable #7: 'GENDER'

3 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 42
  MALE 53
     
  Significant markers N = 3
  Higher in MALE 2
  Higher in FEMALE 1
List of 3 genes differentially expressed by 'GENDER'

Table S10.  Get Full Table List of 3 genes differentially expressed by 'GENDER'

T(pos if higher in 'MALE') ttestP Q AUC
ALG11__2 10.51 1.773e-14 3.55e-10 0.9438
UTP14C 10.51 1.773e-14 3.55e-10 0.9438
KIF4B -5.63 2.616e-07 0.00524 0.7996

Figure S3.  Get High-res Image As an example, this figure shows the association of ALG11__2 to 'GENDER'. P value = 1.77e-14 with T-test analysis.

Clinical variable #8: 'HISTOLOGICAL.TYPE'

64 genes related to 'HISTOLOGICAL.TYPE'.

Table S11.  Basic characteristics of clinical feature: 'HISTOLOGICAL.TYPE'

HISTOLOGICAL.TYPE Labels N
  RECTAL ADENOCARCINOMA 87
  RECTAL MUCINOUS ADENOCARCINOMA 6
     
  Significant markers N = 64
  Higher in RECTAL MUCINOUS ADENOCARCINOMA 37
  Higher in RECTAL ADENOCARCINOMA 27
List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

Table S12.  Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

T(pos if higher in 'RECTAL MUCINOUS ADENOCARCINOMA') ttestP Q AUC
LPAR5 9.24 7.503e-14 1.5e-09 0.8678
LRRC49__1 8.53 3.14e-13 6.28e-09 0.933
PLA2G12B 9.55 3.521e-13 7.05e-09 0.8295
C20ORF56 -7.67 1.839e-11 3.68e-07 0.8467
KIAA0319L__1 -9.74 4.834e-11 9.68e-07 0.8678
OIT3 7.16 3.2e-10 6.4e-06 0.8985
ABCB11 7.14 4.126e-10 8.26e-06 0.7548
C8ORF84 -8.17 6.278e-10 1.26e-05 0.8199
ARFGAP1 6.94 7.503e-10 1.5e-05 0.7969
VPS37B -10.44 7.592e-10 1.52e-05 0.9275

Figure S4.  Get High-res Image As an example, this figure shows the association of LPAR5 to 'HISTOLOGICAL.TYPE'. P value = 7.5e-14 with T-test analysis.

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

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

Table S13.  Basic characteristics of clinical feature: 'RADIATIONS.RADIATION.REGIMENINDICATION'

RADIATIONS.RADIATION.REGIMENINDICATION Labels N
  NO 5
  YES 90
     
  Significant markers N = 94
  Higher in YES 90
  Higher in NO 4
List of top 10 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

Table S14.  Get Full Table List of top 10 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

T(pos if higher in 'YES') ttestP Q AUC
ST8SIA2 12.25 1.38e-20 2.76e-16 0.8933
RET 9.48 2.925e-15 5.86e-11 0.8711
ZDBF2 9.43 5.148e-15 1.03e-10 0.8644
SVEP1 10.41 5.889e-15 1.18e-10 0.8578
ZNF134 8.15 1.924e-12 3.85e-08 0.7756
MIR548N__3 7.77 1.152e-11 2.31e-07 0.8222
PLEKHA3 7.77 1.152e-11 2.31e-07 0.8222
INHA__1 7.62 2.597e-11 5.2e-07 0.7422
OBSL1__1 7.62 2.597e-11 5.2e-07 0.7422
MEOX2 7.79 3.18e-11 6.36e-07 0.8044

Figure S5.  Get High-res Image As an example, this figure shows the association of ST8SIA2 to 'RADIATIONS.RADIATION.REGIMENINDICATION'. P value = 1.38e-20 with T-test analysis.

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

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

Table S15.  Basic characteristics of clinical feature: 'COMPLETENESS.OF.RESECTION'

COMPLETENESS.OF.RESECTION Labels N
  R0 64
  R1 2
  R2 2
  RX 4
     
  Significant markers N = 38
List of top 10 genes differentially expressed by 'COMPLETENESS.OF.RESECTION'

Table S16.  Get Full Table List of top 10 genes differentially expressed by 'COMPLETENESS.OF.RESECTION'

ANOVA_P Q
TDRD6 7.484e-12 1.5e-07
PABPC1L 1.21e-10 2.42e-06
ATRNL1 5.433e-10 1.09e-05
LOC400891 1.475e-09 2.95e-05
MPP2 2.095e-09 4.19e-05
FRMPD1 5.53e-09 0.000111
FLJ39582 1.169e-08 0.000234
THAP7 1.169e-08 0.000234
ABCA11P__1 1.715e-08 0.000343
ZNF721__1 1.715e-08 0.000343

Figure S6.  Get High-res Image As an example, this figure shows the association of TDRD6 to 'COMPLETENESS.OF.RESECTION'. P value = 7.48e-12 with ANOVA analysis.

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

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

Table S17.  Basic characteristics of clinical feature: 'NUMBER.OF.LYMPH.NODES'

NUMBER.OF.LYMPH.NODES Mean (SD) 3.12 (5.7)
  Significant markers N = 0
Methods & Data
Input

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

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

  • Number of patients = 95

  • Number of genes = 20018

  • 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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