Correlation between gene methylation status and clinical features
Skin Cutaneous Melanoma (Metastatic)
15 July 2014  |  analyses__2014_07_15
Maintainer Information
Citation Information
doi:10.7908/C1WM1C6Z
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/C1WM1C6Z
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 19738 genes and 14 clinical features across 285 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 6 clinical features related to at least one genes.

  • 47 genes correlated to 'AGE'.

    • TRPV4 ,  NFATC2 ,  MAMSTR ,  NIPAL2 ,  PARP12 ,  ...

  • 247 genes correlated to 'PRIMARY.SITE.OF.DISEASE'.

    • DCLRE1C ,  CLLU1__1 ,  CLLU1OS__1 ,  PTTG1IP ,  CD3E ,  ...

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

    • FAM100B ,  TUSC1 ,  TNFSF9 ,  IL15 ,  PARP12 ,  ...

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

    • SPHK1 ,  ABCA7

  • 15 genes correlated to 'BRESLOW.THICKNESS'.

    • FAM100B ,  LZTS1 ,  PARP12 ,  ITSN2 ,  SGK1 ,  ...

  • 4 genes correlated to 'GENDER'.

    • ALG11__1 ,  UTP14C ,  KIF4B ,  NICN1__1

  • No genes correlated to 'Time from Specimen Diagnosis to Death', 'Time to Death', 'NEOPLASM.DISEASESTAGE', 'PATHOLOGY.M.STAGE', 'MELANOMA.ULCERATION', 'MELANOMA.PRIMARY.KNOWN', 'RACE', 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 from Specimen Diagnosis to Death Cox regression test   N=0        
Time to Death Cox regression test   N=0        
AGE Spearman correlation test N=47 older N=46 younger N=1
PRIMARY SITE OF DISEASE Kruskal-Wallis test N=247        
NEOPLASM DISEASESTAGE Kruskal-Wallis test   N=0        
PATHOLOGY T STAGE Spearman correlation test N=9 higher stage N=8 lower stage N=1
PATHOLOGY N STAGE Spearman correlation test N=2 higher stage N=0 lower stage N=2
PATHOLOGY M STAGE Kruskal-Wallis test   N=0        
MELANOMA ULCERATION Wilcoxon test   N=0        
MELANOMA PRIMARY KNOWN Wilcoxon test   N=0        
BRESLOW THICKNESS Spearman correlation test N=15 higher breslow.thickness N=11 lower breslow.thickness N=4
GENDER Wilcoxon test N=4 male N=4 female N=0
RACE Kruskal-Wallis test   N=0        
ETHNICITY Wilcoxon test   N=0        
Clinical variable #1: 'Time from Specimen Diagnosis to Death'

No gene related to 'Time from Specimen Diagnosis to Death'.

Table S1.  Basic characteristics of clinical feature: 'Time from Specimen Diagnosis to Death'

Time from Specimen Diagnosis to Death Duration (Months) 0-124.3 (median=14.1)
  censored N = 138
  death N = 134
     
  Significant markers N = 0
Clinical variable #2: 'Time to Death'

No gene related to 'Time to Death'.

Table S2.  Basic characteristics of clinical feature: 'Time to Death'

Time to Death Duration (Months) 0.2-357.4 (median=47.5)
  censored N = 144
  death N = 135
     
  Significant markers N = 0
Clinical variable #3: 'AGE'

47 genes related to 'AGE'.

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

AGE Mean (SD) 55.74 (15)
  Significant markers N = 47
  pos. correlated 46
  neg. correlated 1
List of top 10 genes differentially expressed by 'AGE'

Table S4.  Get Full Table List of top 10 genes significantly correlated to 'AGE' by Spearman correlation test

SpearmanCorr corrP Q
TRPV4 0.3297 1.593e-08 0.000314
NFATC2 0.3001 3.101e-07 0.00612
MAMSTR 0.2945 5.243e-07 0.0103
NIPAL2 0.2929 6.078e-07 0.012
PARP12 0.2895 8.308e-07 0.0164
SP1 0.286 1.139e-06 0.0225
FBXL13__2 0.2849 1.256e-06 0.0248
LRRC17 0.2849 1.256e-06 0.0248
PDGFD 0.284 1.356e-06 0.0268
ALDH1A1 0.2828 1.513e-06 0.0298
Clinical variable #4: 'PRIMARY.SITE.OF.DISEASE'

247 genes related to 'PRIMARY.SITE.OF.DISEASE'.

Table S5.  Basic characteristics of clinical feature: 'PRIMARY.SITE.OF.DISEASE'

PRIMARY.SITE.OF.DISEASE Labels N
  DISTANT METASTASIS 39
  PRIMARY TUMOR 4
  REGIONAL CUTANEOUS OR SUBCUTANEOUS TISSUE 61
  REGIONAL LYMPH NODE 180
     
  Significant markers N = 247
List of top 10 genes differentially expressed by 'PRIMARY.SITE.OF.DISEASE'

Table S6.  Get Full Table List of top 10 genes differentially expressed by 'PRIMARY.SITE.OF.DISEASE'

ANOVA_P Q
DCLRE1C 6.703e-09 0.000132
CLLU1__1 1.145e-08 0.000226
CLLU1OS__1 1.145e-08 0.000226
PTTG1IP 2.686e-08 0.00053
CD3E 2.997e-08 0.000591
KLHL36 3.458e-08 0.000682
ELOVL6 3.49e-08 0.000689
IL32 4.641e-08 0.000916
NT5M 5.689e-08 0.00112
KLF2 5.86e-08 0.00116
Clinical variable #5: 'NEOPLASM.DISEASESTAGE'

No gene related to 'NEOPLASM.DISEASESTAGE'.

Table S7.  Basic characteristics of clinical feature: 'NEOPLASM.DISEASESTAGE'

NEOPLASM.DISEASESTAGE Labels N
  I OR II NOS 10
  STAGE 0 6
  STAGE I 23
  STAGE IA 10
  STAGE IB 25
  STAGE II 17
  STAGE IIA 10
  STAGE IIB 14
  STAGE IIC 10
  STAGE III 32
  STAGE IIIA 14
  STAGE IIIB 24
  STAGE IIIC 49
  STAGE IV 12
     
  Significant markers N = 0
Clinical variable #6: 'PATHOLOGY.T.STAGE'

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

Table S8.  Basic characteristics of clinical feature: 'PATHOLOGY.T.STAGE'

PATHOLOGY.T.STAGE Mean (SD) 2.43 (1.3)
  N
  0 22
  1 31
  2 60
  3 57
  4 58
     
  Significant markers N = 9
  pos. correlated 8
  neg. correlated 1
List of 9 genes differentially expressed by 'PATHOLOGY.T.STAGE'

Table S9.  Get Full Table List of 9 genes significantly correlated to 'PATHOLOGY.T.STAGE' by Spearman correlation test

SpearmanCorr corrP Q
FAM100B 0.3178 9.598e-07 0.0189
TUSC1 -0.3026 3.254e-06 0.0642
TNFSF9 0.2953 5.739e-06 0.113
IL15 0.2882 9.775e-06 0.193
PARP12 0.2877 1.016e-05 0.2
COTL1 0.2863 1.125e-05 0.222
PLEKHB1 0.2859 1.155e-05 0.228
LCN10 0.2854 1.204e-05 0.237
GLIPR1 0.2844 1.289e-05 0.254
Clinical variable #7: 'PATHOLOGY.N.STAGE'

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

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

PATHOLOGY.N.STAGE Mean (SD) 0.88 (1.1)
  N
  0 141
  1 52
  2 34
  3 37
     
  Significant markers N = 2
  pos. correlated 0
  neg. correlated 2
List of 2 genes differentially expressed by 'PATHOLOGY.N.STAGE'

Table S11.  Get Full Table List of 2 genes significantly correlated to 'PATHOLOGY.N.STAGE' by Spearman correlation test

SpearmanCorr corrP Q
SPHK1 -0.2665 1.136e-05 0.224
ABCA7 -0.2657 1.208e-05 0.239
Clinical variable #8: 'PATHOLOGY.M.STAGE'

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

Table S12.  Basic characteristics of clinical feature: 'PATHOLOGY.M.STAGE'

PATHOLOGY.M.STAGE Labels N
  M0 254
  M1 4
  M1A 2
  M1B 2
  M1C 5
     
  Significant markers N = 0
Clinical variable #9: 'MELANOMA.ULCERATION'

No gene related to 'MELANOMA.ULCERATION'.

Table S13.  Basic characteristics of clinical feature: 'MELANOMA.ULCERATION'

MELANOMA.ULCERATION Labels N
  NO 104
  YES 74
     
  Significant markers N = 0
Clinical variable #10: 'MELANOMA.PRIMARY.KNOWN'

No gene related to 'MELANOMA.PRIMARY.KNOWN'.

Table S14.  Basic characteristics of clinical feature: 'MELANOMA.PRIMARY.KNOWN'

MELANOMA.PRIMARY.KNOWN Labels N
  NO 34
  YES 251
     
  Significant markers N = 0
Clinical variable #11: 'BRESLOW.THICKNESS'

15 genes related to 'BRESLOW.THICKNESS'.

Table S15.  Basic characteristics of clinical feature: 'BRESLOW.THICKNESS'

BRESLOW.THICKNESS Mean (SD) 3.58 (4.9)
  Significant markers N = 15
  pos. correlated 11
  neg. correlated 4
List of top 10 genes differentially expressed by 'BRESLOW.THICKNESS'

Table S16.  Get Full Table List of top 10 genes significantly correlated to 'BRESLOW.THICKNESS' by Spearman correlation test

SpearmanCorr corrP Q
FAM100B 0.3492 2.349e-07 0.00464
LZTS1 -0.341 4.655e-07 0.00919
PARP12 0.3366 6.68e-07 0.0132
ITSN2 0.3262 1.517e-06 0.0299
SGK1 -0.3113 4.727e-06 0.0933
ST3GAL1 0.3035 8.348e-06 0.165
SLC45A2 -0.3023 9.103e-06 0.18
C7ORF44 0.3019 9.338e-06 0.184
ABCA9 0.3 1.073e-05 0.212
QDPR -0.3 1.073e-05 0.212
Clinical variable #12: 'GENDER'

4 genes related to 'GENDER'.

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

GENDER Labels N
  FEMALE 110
  MALE 175
     
  Significant markers N = 4
  Higher in MALE 4
  Higher in FEMALE 0
List of 4 genes differentially expressed by 'GENDER'

Table S18.  Get Full Table List of 4 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__1 18053 1.545e-35 3.05e-31 0.9378
UTP14C 18053 1.545e-35 3.05e-31 0.9378
KIF4B 5504 1.177e-09 2.32e-05 0.7141
NICN1__1 6193 4.06e-07 0.00801 0.6783
Clinical variable #13: 'RACE'

No gene related to 'RACE'.

Table S19.  Basic characteristics of clinical feature: 'RACE'

RACE Labels N
  ASIAN 5
  BLACK OR AFRICAN AMERICAN 1
  WHITE 277
     
  Significant markers N = 0
Clinical variable #14: 'ETHNICITY'

No gene related to 'ETHNICITY'.

Table S20.  Basic characteristics of clinical feature: 'ETHNICITY'

ETHNICITY Labels N
  HISPANIC OR LATINO 3
  NOT HISPANIC OR LATINO 276
     
  Significant markers N = 0
Methods & Data
Input

  • Expresson data file = SKCM-TM.meth.by_min_clin_corr.data.txt

  • Clinical data file = SKCM-TM.merged_data.txt

  • Number of patients = 285

  • Number of genes = 19738

  • Number of clinical features = 14

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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