Association of mutation, copy number alteration, and subtype markers with pathways
Colon Adenocarcinoma (Primary solid tumor)
21 April 2013  |  analyses__2013_04_21
Maintainer Information
Citation Information
doi:10.7908/C19021P0
Maintained by Spring Yingchun Liu (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2013): Colon Adenocarcinoma (Primary solid tumor cohort) - 21 April 2013: Association of mutation, copy number alteration, and subtype markers with pathways. Broad Institute of MIT and Harvard. doi:10.7908/C19021P0
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 360 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. Pathways significantly enriched with these genes (Q value <= 0.01) are identified :

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

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

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

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

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 2.7 0 0.0019
KEGG_PROSTATE_CANCER 89 10 2.5 0 0.0019
BIOCARTA_TNFR1_PATHWAY 29 6 3.4 0 0.0022
BIOCARTA_HIVNEF_PATHWAY 56 7 2.6 0.0001 0.01
BIOCARTA_FAS_PATHWAY 30 5 3.1 0.0003 0.02
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_T_CELL_RECEPTOR_SIGNALING_PATHWAY 108 23 1.3 0 0.0031
KEGG_VIRAL_MYOCARDITIS 73 17 1.5 0 0.0031
BIOCARTA_ALK_PATHWAY 37 11 1.7 0.0002 0.0065
BIOCARTA_IL7_PATHWAY 17 7 2.2 0.0003 0.0065
KEGG_ABC_TRANSPORTERS 44 12 1.6 0.0003 0.0065
List of marker genes for gene expression subtype 1 in this pathway

MAP2K7,PIK3CG,CD3G,CD3D,MAPK1,NFKBIA,ZAP70,PTPN6,VAV3,VAV1,ORC3L,PLCG1,CD8A,CDC42,NCK1,CSF2,PPP3R1,RASGRP1,NFAT5,PIK3R1,NRAS,MAPK12,FYN

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

CASP8,CYCS,MYH2,HLA-C,HLA-E,HLA-G,HLA-F,SGCG,SGCD,MYH7B,SGCA,RAC2,HLA-DOB,LAMA2,CD55,FYN,ABL2

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

MEF2C,HNF1A,MYL2,TGFB3,AXIN1,TGFBR1,SMAD6,SMAD5,SMAD4,GARS,NPPB

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

PIK3CG,MYO1C,IL7,STAT5B,EP300,FYN,PIK3R1

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

ABCA1,ABCA3,TAP1,ABCB9,ABCB1,CFTR,ABCB7,ABCB4,ABCC9,ABCC2,ABCC5,ABCC6

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_LEUKOCYTE_TRANSENDOTHELIAL_MIGRATION 118 24 1.2 0.0001 0.014
BIOCARTA_STATHMIN_PATHWAY 19 6 1.8 0.0044 0.15
KEGG_MISMATCH_REPAIR 23 7 1.8 0.0027 0.15
KEGG_AXON_GUIDANCE 129 22 0.96 0.0015 0.15
KEGG_CELL_ADHESION_MOLECULES_CAMS 134 22 0.93 0.002 0.15
List of marker genes for gene expression subtype 2 in this pathway

MMP2,VCL,RAPGEF4,PIK3CG,PIK3CD,ACTN1,ITGAL,RAC2,MYLPF,ITGA4,PLCG2,RAP1B,CLDN8,CLDN4,ARHGAP5,MSN,TXK,CLDN18,CLDN10,VCAM1,EZR,MLLT4,CLDN23,MAPK13

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

PRKAR2B,PRKAR2A,MAPK13,CAMK2D,CD2,PRKACB

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

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

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

PLXNA2,EFNA1,ROBO2,PLXNB1,EFNB1,RND1,PLXNC1,EPHB1,EPHB2,KRAS,RAC2,EPHA4,SEMA6B,SEMA6D,EPHA8,SEMA4B,SRGAP1,ABLIM2,PPP3R1,NFAT5,PPP3CA,FYN

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

PVR,PTPRM,HLA-DQA1,CD34,GLG1,ITGAL,ALCAM,CTLA4,PVRL2,ITGA4,CLDN8,CLDN4,NRXN3,VCAN,CLDN18,CLDN10,VCAM1,CD2,CD28,SELP,MAG,CLDN23

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_HEDGEHOG_SIGNALING_PATHWAY 56 12 1.4 0.0011 0.19
KEGG_AXON_GUIDANCE 129 21 1 0.0009 0.19
BIOCARTA_IGF1MTOR_PATHWAY 20 6 1.9 0.0034 0.23
KEGG_AMINOACYL_TRNA_BIOSYNTHESIS 41 9 1.5 0.0027 0.23
KEGG_WNT_SIGNALING_PATHWAY 151 22 0.87 0.0032 0.23
List of marker genes for gene expression subtype 3 in this pathway

ZIC2,GLI1,WNT2,WNT4,HHIP,PRKACB,WNT10A,CSNK1G1,SMO,WNT11,CSNK1A1L,BMP5

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

EFNA2,UNC5C,EFNB3,PLXNB3,RND1,EFNA5,SEMA5A,KRAS,EPHA4,SEMA6D,NELL1,SEMA3C,ARHGEF12,SEMA4B,ABLIM2,CHP,PPP3CA,NFATC1,NTNG1,DPYSL2,NRAS

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

PDK2,EIF2S3,IGF1,PTEN,EIF2S1,EIF2S2

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

EPRS,IARS2,IARS,WARS,NARS2,MARS,DARS,SARS2,HARS

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

PPP2R5C,WNT2,WNT4,PRKACB,WNT10A,AXIN2,WIF1,PLCB4,MYC,PRKCG,WNT11,SIAH1,NKD2,TCF7L2,CHD8,CHP,PPP3CA,NFATC1,GPI,CSNK1A1L,DKK4,LRP6

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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