Association of mutation, copy number alteration, and subtype markers with pathways
Colon Adenocarcinoma (Primary solid tumor)
22 February 2013  |  analyses__2013_02_22
Maintainer Information
Citation Information
doi:10.7908/C13F4MSR
Maintained by Spring Yingchun Liu (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2013): Association of mutation, copy number alteration, and subtype markers with pathways. Broad Institute of MIT and Harvard. doi:10.7908/C13F4MSR
Overview
Introduction

This pipeline maps genes, with mutation or copy number alteration AND this alteration is highly correlated with mRNA expression, to pathways curated in the KEGG and BIOCARTA databases. It identifies pathways significantly enriched with these genes. The pipeline also identifies pathways significantly enriched with marker genes of each expression subtype of cancer.

genes with mutation: identified by the Mutation_Significance pipeline

genes with copy number alteration: identified by the CopyNumber_Gistic2 pipeline

correlation between copy number and mRNA expression: identified by the Correlate_CopyNumber_vs_mRNA pipeline

marker genes and expression subtypes: identified by the mRNAConsensusClustering pipeline

Summary

There are 61 genes with significant mutation (Q value <= 0.1) and 368 genes with significant copy number alteration (Q value <= 0.25). The identified marker genes (Q value <= 0.01 or within top 2000) are 2000 for subtype 1, 2000 for subtype 2, 2000 for subtype 3, 2000 for subtype 4. Pathways significantly enriched with these genes (Q value <= 0.01) are identified :

3 pathways significantly enriched with genes with copy number alteration or mutation.

2 pathways significantly enriched with marker genes of gene expression subtype 1

0 pathways significantly enriched with marker genes of gene expression subtype 2

1 pathways significantly enriched with marker genes of gene expression subtype 3

1 pathways significantly enriched with marker genes of gene expression subtype 4

Results
The top five pathways enriched with genes with copy number alteration or mutation

Table 1.  Get Full Table Top Pathways enriched with genes with copy number alteration or mutation. Nof Genes : No. of genes in this pathway. Nof CNV_Mut : No. of genes with copy number alteration or mutation in this pathway. Enrichment , P value and Q value : See Methods & Data below. CNV_Mut Genes in Pathway: genes with copy number alteration or mutation in this pathway.

Pathway Nof Genes Nof CNV_Mut Enrichment P value Q value
KEGG_PANCREATIC_CANCER 70 9 2.6 0 0.0022
KEGG_PROSTATE_CANCER 89 10 2.5 0 0.0022
BIOCARTA_TNFR1_PATHWAY 29 6 3.3 0 0.0024
BIOCARTA_HIVNEF_PATHWAY 56 7 2.6 0.0001 0.011
BIOCARTA_FAS_PATHWAY 30 5 3 0.0003 0.021
List of CNV_Mut genes in this pathway

CHUK,RB1,ERBB2,BCL2L1,TGFBR2,SMAD4,RAF1,SMAD2,IKBKB

List of CNV_Mut genes in this pathway

HSP90AB1,PTEN,CHUK,HSP90AA1,RB1,FGFR1,ERBB2,TCF7L2,RAF1,IKBKB

List of CNV_Mut genes in this pathway

PRKDC,BAG4,CASP3,CASP8,MAP2K4,RB1

List of CNV_Mut genes in this pathway

BAG4,CASP3,CASP8,CHUK,RB1,PSEN1,PRKDC

List of CNV_Mut genes in this pathway

PRKDC,CASP3,CASP8,MAP2K4,RB1

The top five pathways enriched with marker genes of gene expression subtype 1

Table 2.  Get Full Table Top Pathways enriched with marker genes of gene expression subtype 1 . Nof Genes : No. of genes in this pathway. Nof Marker : No. of marker genes of gene expression subtype 1 in this pathway. Enrichment , P value and Q value : See Methods & Data below. Marker Gene in Pathway: markers of gene expression subtype 1 in this pathway

Pathway Nof Genes Nof Marker Enrichment P value Q value
KEGG_LEUKOCYTE_TRANSENDOTHELIAL_MIGRATION 118 25 1.3 0 0.0038
KEGG_LYSOSOME 121 24 1.2 0.0001 0.0097
KEGG_GAP_JUNCTION 90 17 1.1 0.0014 0.097
KEGG_NOTCH_SIGNALING_PATHWAY 47 11 1.4 0.002 0.1
KEGG_MISMATCH_REPAIR 23 7 1.8 0.0027 0.11
List of marker genes for gene expression subtype 1 in this pathway

MMP9,VCL,RAPGEF4,PIK3CG,PIK3CD,ACTN1,CTNNA2,ITGAL,GNAI3,RAC2,VAV2,PLCG2,RAP1B,CLDN8,PRKCG,TXK,CLDN18,CLDN10,CDH5,VCAM1,EZR,MLLT4,CLDN23,MAPK13,MAPK14

List of marker genes for gene expression subtype 1 in this pathway

AP4M1,ACP5,PPT2,PPT1,SLC11A2,SCARB2,ENTPD4,LAPTM4B,LAMP2,ASAH1,GLB1,CLN3,ATP6V1H,SORT1,CTSC,CTSH,CLN5,TCIRG1,PSAP,AP4S1,MANBA,ARSA,CTNS,GGA3

List of marker genes for gene expression subtype 1 in this pathway

ADCY3,TUBB2A,GUCY1A3,PRKACB,RP11-631M21.2,TUBB1,PLCB1,TUBA1A,PLCB2,TUBA1C,PRKCG,ADRB1,GUCY1B3,GNAI3,MAP3K2,MAP2K1,HTR2B

List of marker genes for gene expression subtype 1 in this pathway

LFNG,PTCRA,KAT2A,KAT2B,DTX3L,DTX2,DLL3,NOTCH1,EP300,PSEN1,RBPJ

List of marker genes for gene expression subtype 1 in this pathway

EXO1,SSBP1,MLH3,POLD3,RPA1,RFC5,RPA2

The top five pathways enriched with marker genes of gene expression subtype 2

Table 3.  Get Full Table Top Pathways enriched with marker genes of gene expression subtype 2 . Nof Genes : No. of genes in this pathway. Nof Marker : No. of marker genes of gene expression subtype 2 in this pathway. Enrichment , P value and Q value : See Methods & Data below. Marker Gene in Pathway: markers of gene expression subtype 2 in this pathway

Pathway Nof Genes Nof Marker Enrichment P value Q value
KEGG_GLYCOSAMINOGLYCAN_BIOSYNTHESIS_HEPARAN_SULFATE 26 8 1.8 0.0012 0.095
KEGG_ENDOCYTOSIS 183 29 0.88 0.0007 0.095
KEGG_HEMATOPOIETIC_CELL_LINEAGE 88 17 1.2 0.0008 0.095
KEGG_LEUKOCYTE_TRANSENDOTHELIAL_MIGRATION 118 21 1 0.0009 0.095
BIOCARTA_LAIR_PATHWAY 17 6 2 0.0022 0.14
List of marker genes for gene expression subtype 2 in this pathway

NDST3,HS3ST6,NDST4,NDST2,HS3ST2,HS6ST3,GLCE,HS3ST3B1

List of marker genes for gene expression subtype 2 in this pathway

CHMP5,CHMP4A,VPS4B,DNAJC6,ITCH,PLD1,HLA-A,HLA-E,HLA-G,HLA-F,ACAP1,ARFGAP3,FGFR4,ADRBK1,ARF6,AP2M1,CSF1R,NEDD4,CLTA,ZFYVE20,CXCR4,RAB11FIP4,RAB11FIP2,ADRB2,CHMP1B,HSPA2,EHD1,CBL,RAB31

List of marker genes for gene expression subtype 2 in this pathway

CD8A,GYPA,GP5,CD44,MS4A1,THPO,CD3G,CD3D,CD7,CSF1R,IL7,CD1C,CD1B,ITGA2,CD55,CD19,IL5RA

List of marker genes for gene expression subtype 2 in this pathway

MMP9,RAPGEF4,PIK3CG,ROCK2,NCF4,MYL7,GNAI2,RAC2,VAV3,VAV2,VAV1,PLCG2,CLDN8,CLDN5,CXCR4,ICAM1,CLDN17,CLDN10,CDH5,VCAM1,RASSF5

List of marker genes for gene expression subtype 2 in this pathway

KNG1,C7,ICAM1,IL8,VCAM1,SELPLG

The top five pathways enriched with marker genes of gene expression subtype 3

Table 4.  Get Full Table Top Pathways enriched with marker genes of gene expression subtype 3 . Nof Genes : No. of genes in this pathway. Nof Marker : No. of marker genes of gene expression subtype 3 in this pathway. Enrichment , P value and Q value : See Methods & Data below. Marker Gene in Pathway: markers of gene expression subtype 3 in this pathway

Pathway Nof Genes Nof Marker Enrichment P value Q value
KEGG_DRUG_METABOLISM_CYTOCHROME_P450 72 7 3.2 0 0.0027
KEGG_METABOLISM_OF_XENOBIOTICS_BY_CYTOCHROME_P450 70 6 3.1 0.0001 0.012
KEGG_GLUTATHIONE_METABOLISM 50 4 3 0.0016 0.17
KEGG_O_GLYCAN_BIOSYNTHESIS 30 3 3.3 0.0035 0.29
KEGG_LEUKOCYTE_TRANSENDOTHELIAL_MIGRATION 118 5 2 0.0068 0.45
List of marker genes for gene expression subtype 3 in this pathway

ADH1C,ADH1A,CYP2A6,GSTA2,GSTA3,GSTA5,MGST1

List of marker genes for gene expression subtype 3 in this pathway

ADH1C,ADH1A,GSTA2,GSTA3,GSTA5,MGST1

List of marker genes for gene expression subtype 3 in this pathway

GSTA2,GSTA3,GSTA5,MGST1

List of marker genes for gene expression subtype 3 in this pathway

GALNT4,GALNTL2,ST6GALNAC1

List of marker genes for gene expression subtype 3 in this pathway

CLDN2,CLDN15,NOX1,MAPK12,MAPK14

The top five pathways enriched with marker genes of gene expression subtype 4

Table 5.  Get Full Table Top Pathways enriched with marker genes of gene expression subtype 4 . Nof Genes : No. of genes in this pathway. Nof Marker : No. of marker genes of gene expression subtype 4 in this pathway. Enrichment , P value and Q value : See Methods & Data below. Marker Gene in Pathway: markers of gene expression subtype 4 in this pathway

Pathway Nof Genes Nof Marker Enrichment P value Q value
KEGG_AXON_GUIDANCE 129 25 1.5 0 0.0006
KEGG_TGF_BETA_SIGNALING_PATHWAY 86 14 1.2 0.002 0.34
BIOCARTA_TEL_PATHWAY 18 5 2 0.0064 0.36
KEGG_PHENYLALANINE_METABOLISM 18 5 2 0.0064 0.36
KEGG_LYSOSOME 121 16 0.91 0.0087 0.36
List of marker genes for gene expression subtype 4 in this pathway

EFNA1,EFNA2,EFNA3,UNC5C,ROCK2,RND1,EFNA5,EPHB2,KRAS,EPHA5,EPHA4,SEMA6B,SEMA6D,NELL1,SEMA3E,SEMA3C,ABLIM1,ABLIM2,ABLIM3,CHP,PPP3CA,NFATC1,DPYSL2,NRAS,FYN

List of marker genes for gene expression subtype 4 in this pathway

E2F4,E2F5,ZFYVE9,RBL2,ROCK2,RBL1,LEFTY1,INHBB,AMH,TFDP1,SMAD7,SMAD5,ID3,BMP5

List of marker genes for gene expression subtype 4 in this pathway

XRCC5,HSP90AA1,POLR2A,KRAS,TNKS

List of marker genes for gene expression subtype 4 in this pathway

DDC,PAH,AMH,PRDX6,HPD

List of marker genes for gene expression subtype 4 in this pathway

GNPTG,GNS,CTSL2,NAGLU,ENTPD4,LAPTM4B,AP3S1,AP1S3,ATP6V0D1,CLN3,CLN5,CTSF,NAGPA,GNPTAB,CEL,MANBA

Methods & Data
Enrichment

Let genes with copy number alteration or mutation be query genes. Let marker genes of specific identified subtypes be query genes. The Enrichment is calculated as:

  • Enrichment = log2 (# of query genes in the pathway/# No of query genes) - log2 (# of genes in the pathway/# of human genes)

P value

The statistical signficance of the pathways that are enriched with genes with copy number alteration or mutation, and the pathways that are enriched with markers genes of specific identified subtypes is measured by P value.

  • P value = Fisher exact P value

Q value

The Q value is for adjusting P value for multiple testing. A public available R package is used to calculate the Q value.

Download Results

This is an experimental feature. The full results of the analysis summarized in this report can be downloaded from the TCGA Data Coordination Center.

References
[1] Qi Zheng, GOEAST: a web-based software toolkit for Gene Ontology enrichment analysis, Nucleic Acids Res. 36(issue suppl 2):W358-W363 (2008)
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