Association of mutation, copy number alteration, and subtype markers with pathways
Colon Adenocarcinoma (Primary solid tumor)
23 May 2013  |  analyses__2013_05_23
Maintainer Information
Citation Information
doi:10.7908/C1RB72MW
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/C1RB72MW
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 14 genes with significant mutation (Q value <= 0.1) and 372 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 :

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

17 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 11 3.1 0 0
KEGG_ENDOMETRIAL_CANCER 52 9 3.2 0 0
KEGG_PROSTATE_CANCER 89 13 3 0 0
KEGG_COLORECTAL_CANCER 62 9 3 0 0.0001
KEGG_CHRONIC_MYELOID_LEUKEMIA 73 10 2.9 0 0.0001
List of CNV_Mut genes in this pathway

PIK3CA,CHUK,BRAF,TP53,RB1,ERBB2,KRAS,SMAD4,RAF1,SMAD2,IKBKB

List of CNV_Mut genes in this pathway

PTEN,PIK3CA,BRAF,TP53,ERBB2,KRAS,APC,RAF1,NRAS

List of CNV_Mut genes in this pathway

HSP90AB1,PTEN,PIK3CA,CHUK,HSP90AA1,BRAF,TP53,RB1,ERBB2,KRAS,RAF1,NRAS,IKBKB

List of CNV_Mut genes in this pathway

CASP3,PIK3CA,BRAF,TP53,KRAS,APC,SMAD4,RAF1,SMAD2

List of CNV_Mut genes in this pathway

PIK3CA,CHUK,BRAF,TP53,RB1,KRAS,SMAD4,RAF1,NRAS,IKBKB

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 28 1.5 0 0
KEGG_FOCAL_ADHESION 201 40 1.2 0 0.0001
KEGG_SMALL_CELL_LUNG_CANCER 84 21 1.5 0 0.0007
KEGG_NATURAL_KILLER_CELL_MEDIATED_CYTOTOXICITY 137 27 1.2 0 0.0015
KEGG_VEGF_SIGNALING_PATHWAY 76 18 1.4 0.0001 0.0032
List of marker genes for gene expression subtype 1 in this pathway

PIK3CG,BCL10,CD3G,RELA,PIK3CD,NFKBIA,ZAP70,PTPN6,ITK,VAV3,VAV1,ORC3L,PLCG1,PAK6,PAK3,CHUK,AKT2,MAP3K14,CSF2,PPP3R1,RASGRP1,NFAT5,PPP3CB,PIK3R1,PDK1,NRAS,MAPK12,FYN

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

PIK3CG,PIK3CD,PPP1CA,PDGFRB,LAMB2,RAC2,KDR,LAMA2,COL11A1,FLNC,COL2A1,COL6A6,COL6A3,THBS2,THBS3,IGF1,CAPN2,BIRC2,FYN,MYL10,PPP1CC,PPP1CB,COL1A2,RELN,MYL2,MYL9,ITGAV,VAV3,ITGA2,VAV1,ITGA5,MYLK,PAK6,PAK3,AKT2,TNC,PIK3R1,TNXB,BAD,COL5A2

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

E2F1,PTGS2,CCNE2,MAX,CDKN2B,CHUK,AKT2,PIK3CG,RELA,PIK3CD,CYCS,CDK2,TRAF1,NFKBIA,LAMB2,ITGAV,TRAF5,PIK3R1,ITGA2,BIRC2,LAMA2

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

MICB,KLRC2,PIK3CG,PIK3CD,HLA-C,HLA-E,KIR2DL1,RAC2,ZAP70,PTPN6,VAV3,KIR2DS4,VAV1,ORC3L,PLCG1,PLCG2,IFNGR1,GZMB,NCR1,CSF2,PPP3R1,PPP3CB,NFAT5,PIK3R1,NRAS,FYN,SH3BP2

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

PTGS2,AKT2,PIK3CG,PIK3CD,SH2D2A,PPP3R1,MAPKAPK2,RAC2,PPP3CB,NFAT5,PIK3R1,SPHK2,BAD,KDR,NRAS,PLCG1,MAPK12,PLCG2

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_LYSOSOME 121 24 1.2 0.0001 0.019
KEGG_APOPTOSIS 88 18 1.2 0.0005 0.023
KEGG_ADHERENS_JUNCTION 75 16 1.3 0.0005 0.023
KEGG_MELANOGENESIS 102 20 1.2 0.0004 0.023
KEGG_FOCAL_ADHESION 201 31 0.81 0.0011 0.028
List of marker genes for gene expression subtype 2 in this pathway

AP1G1,AP4M1,ACP5,PPT2,CTSA,SLC11A2,SCARB2,ENTPD4,LAPTM4B,LAMP3,HEXA,ASAH1,GLB1,AP1S2,CLN3,HYAL1,SORT1,CTSC,CTSH,TCIRG1,CEL,AP4S1,CTNS,GGA3

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

AKT1,PRKAR2B,PRKAR2A,CASP3,MYD88,IL1RAP,CSF2RB,PRKACB,PIK3CG,AIFM1,TNFRSF10B,IL1R1,TNF,PPP3R1,IRAK4,PPP3CA,BIRC2,TNFSF10

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

FER,VCL,PTPRM,ACTN1,CTNNA2,EP300,PARD3,SRC,RAC2,SORBS1,PVRL3,MLLT4,PTPRB,SNAI2,TJP1,PTPN1

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

ADCY3,ADCY4,HRAS,ADCY7,ADCY5,EDN1,PRKACB,CREB3L3,WNT10B,EP300,WNT5B,KRAS,MITF,PLCB2,PRKCG,WNT11,TYRP1,CALML3,FZD3,FZD4

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

HRAS,PIK3CG,IBSP,LAMB2,RAC2,PDPK1,FLNA,COL6A6,COL6A2,COL6A1,THBS2,THBS3,BIRC2,VCL,ACTN1,PPP1CC,COL1A2,COL1A1,CAV1,SRC,MYLPF,ITGA4,RAP1B,AKT1,PAK7,SHC3,PRKCG,FIGF,FLT4,VWF,CRK

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 13 1.6 0.0003 0.095
KEGG_RNA_POLYMERASE 29 8 1.8 0.0013 0.11
KEGG_WNT_SIGNALING_PATHWAY 151 23 0.95 0.0013 0.11
WNT_SIGNALING 89 16 1.2 0.0013 0.11
KEGG_AMINOACYL_TRNA_BIOSYNTHESIS 41 9 1.5 0.0025 0.12
List of marker genes for gene expression subtype 3 in this pathway

ZIC2,GLI1,WNT2,WNT4,HHIP,PRKACB,WNT10A,WNT10B,CSNK1G1,SMO,WNT11,WNT5B,BMP5

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

POLR2F,POLR2J,ZNRD1,POLR2D,POLR2C,POLR2A,POLR3B,POLR3D

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

PPP2R5C,WNT2,WNT4,PRKACB,WNT10A,WNT10B,ROCK1,WNT5B,DAAM1,AXIN2,TCF7,WIF1,PLCB4,MYC,WNT11,NKD2,CHD8,CAMK2D,PPP3CA,NFATC1,GPI,DKK4,LRP6

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

WNT2,WNT4,MYC,WNT10A,CSNK1G1,TLE1,TLE2,WNT11,WNT5B,DAAM1,T,FBXW2,TCF7,GPI,LRP6,WIF1

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

NARS,EPRS,WARS,PARS2,NARS2,MARS2,MARS,DARS,HARS

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)
Copyright © 2013 Broad Institute TCGA GDAC as part of the TCGA Research Network. All rights reserved.
Made with Nozzle