Association of mutation, copy number alteration, and subtype markers with pathways
Colon/Rectal Adenocarcinoma (Primary solid tumor)
23 May 2013  |  analyses__2013_05_23
Maintainer Information
Citation Information
doi:10.7908/C1Q81B36
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/C1Q81B36
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 20 genes with significant mutation (Q value <= 0.1) and 555 genes with significant copy number alteration (Q value <= 0.25). The identified marker genes (Q value <= 0.01 or within top 2000) are 1960 for subtype 1, 1960 for subtype 2, 1960 for subtype 3, 1960 for subtype 4. Pathways significantly enriched with these genes (Q value <= 0.01) are identified :

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

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

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

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

3 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_COLORECTAL_CANCER 62 12 2.8 0 0
KEGG_PROTEASOME 48 9 2.9 0 0.0002
KEGG_PANCREATIC_CANCER 70 11 2.5 0 0.0002
KEGG_ENDOMETRIAL_CANCER 52 10 2.8 0 0.0002
BIOCARTA_PROTEASOME_PATHWAY 19 6 3.5 0 0.0005
List of CNV_Mut genes in this pathway

CASP3,PIK3CA,BRAF,TP53,TCF7L2,KRAS,RAC1,APC,SMAD4,SMAD3,RAF1,SMAD2

List of CNV_Mut genes in this pathway

PSMA7,PSMB5,PSMF1,PSMD4,PSMC6,PSMA6,PSMD12,PSMC1,PSMA3

List of CNV_Mut genes in this pathway

PIK3CA,BRAF,TP53,ERBB2,BCL2L1,KRAS,RAC1,SMAD4,RAF1,SMAD3,SMAD2

List of CNV_Mut genes in this pathway

PTEN,PIK3CA,BRAF,TP53,ERBB2,TCF7L2,KRAS,APC,RAF1,NRAS

List of CNV_Mut genes in this pathway

UBE3A,PSMA7,PSMB5,PSMA6,PSMA3,RPN2

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_CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION 267 49 1.1 0 0
KEGG_CELL_ADHESION_MOLECULES_CAMS 134 30 1.4 0 0
KEGG_ALLOGRAFT_REJECTION 38 12 2 0 0.0017
KEGG_TYPE_I_DIABETES_MELLITUS 44 12 1.8 0.0001 0.0077
KEGG_HEMATOPOIETIC_CELL_LINEAGE 88 18 1.3 0.0002 0.0096
List of marker genes for gene expression subtype 1 in this pathway

VEGFB,CCR7,CCR5,CCR3,CCR2,PDGFRA,PF4V1,LIF,IL17A,IFNA1,KDR,INHBB,TNFRSF10D,IL12A,CXCL9,CXCL6,ENC1,IL10RB,CCL21,IL7,CCL15,CCL17,CCL13,CXCL10,TNFRSF17,IL22,CCL2,IL22RA1,CCL8,CCL4,CXCL13,IL22RA2,FASLG,IL8RB,CXCR6,LTB,IL18RAP,EDAR,OSM,AMH,TNF,CTF1,KITLG,EPO,AMHR2,IL2RA,FLT3,PRLR,EPOR

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

NRCAM,HLA-F,MADCAM1,HLA-DRA,GLG1,CTLA4,PVRL2,HLA-DPB1,HLA-DOB,ITGA4,ITGA6,CLDN8,CD8A,CLDN5,SDC4,HLA-DMA,ICAM3,CD86,CD80,CLDN1,CNTN1,JAM2,CLDN19,CDH4,VCAM1,CD6,CD28,PTPRC,SELP,SELL

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

TNF,FASLG,HLA-DMA,HLA-DPB1,HLA-DOB,CD28,GZMB,HLA-F,CD86,CD80,IL12A,HLA-DRA

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

TNF,FASLG,HLA-DMA,HLA-DPB1,HLA-DOB,CD28,GZMB,HLA-F,CD86,CD80,IL12A,HLA-DRA

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

CD8A,CD3D,CD38,HLA-DRA,TNF,KITLG,CD9,FCGR1A,EPO,IL2RA,IL7,FLT3,CD1C,ITGA4,CD19,ITGA6,EPOR,CD14

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_PATHWAYS_IN_CANCER 328 60 1 0 0
BIOCARTA_PPARA_PATHWAY 58 14 1.5 0.0003 0.023
KEGG_CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION 267 40 0.77 0.0004 0.023
KEGG_CELL_ADHESION_MOLECULES_CAMS 134 24 1 0.0004 0.023
KEGG_LEISHMANIA_INFECTION 72 16 1.4 0.0003 0.023
List of marker genes for gene expression subtype 2 in this pathway

PTGS2,PGF,PIK3CG,WNT10B,CTNNA1,MECOM,VEGFB,BMP4,TCF7,HGF,LAMA1,LAMA4,NTRK1,FGF7,MLH1,NFKB1,NFKB2,GLI1,FLT3LG,NOS2,FGF1,AKR1B1,TP53,WNT9B,IL6,FZD2,STAT1,BIRC2,FZD7,WNT7B,RASSF5,TCEB1,PDGFB,PDGFA,MMP9,FOXO1,FGF12,MMP1,TGFB1,TGFB2,WNT4,CDKN2A,CDKN2B,CSF3R,FGF20,HIF1A,TRAF1,FGFR3,TRAF5,AXIN1,ITGA6,E2F3,CASP8,RUNX1T1,DAPK1,CKS1B,CEBPA,COL4A4,MSH3,COL4A6

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

ACOX1,PPARA,PTGS2,PDGFA,EHHADH,CITED2,PRKAR2B,PRKAR2A,NOS2,PIK3CG,CD36,SOX9,FABP1,NCOR1

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

VEGFB,CCR2,IL1R1,IL17B,HGF,FLT3LG,TNFRSF10A,TNFRSF10B,CCL26,CCL23,CCL21,IL10RA,IL6,CCL13,CCL14,PDGFB,PDGFA,TNFSF15,TNFSF12,TGFB1,TGFB2,CSF3R,IL24,IL22,CCL3,CCL8,IL12RB2,XCL1,XCL2,IL21R,CXCR4,OSM,NGFR,TNFRSF8,TNFRSF18,EPO,FLT1,LEP,PRLR,EPOR

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

CADM1,F11R,PTPRM,PTPRF,PHOX2A,HLA-DPA1,HLA-DRA,ITGAM,ITGA6,ITGA8,NLGN4X,CLDN6,SDC4,HLA-DMB,HLA-DMA,CD86,SDC1,CLDN2,CLDN18,VCAM1,PTPRC,SELL,NLGN1,SELE

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

PTGS2,TLR2,NFKB1,HLA-DMB,HLA-DMA,TGFB1,TGFB2,NOS2,FCGR3A,NCF1,HLA-DPA1,HLA-DRA,C3,ITGAM,MAPK11,STAT1

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_GAP_JUNCTION 90 20 1.4 0.0001 0.015
KEGG_ANTIGEN_PROCESSING_AND_PRESENTATION 89 18 1.4 0.0001 0.02
KEGG_CELL_ADHESION_MOLECULES_CAMS 134 24 1.1 0.0003 0.03
BIOCARTA_NO2IL12_PATHWAY 17 6 2 0.0023 0.084
KEGG_LYSOSOME 121 21 0.98 0.0016 0.084
List of marker genes for gene expression subtype 3 in this pathway

ADCY3,ADCY4,PDGFB,ADCY7,ADCY5,GUCY1A3,PRKACB,RP11-631M21.2,PLCB1,PLCB2,TUBA1C,TUBB3,PRKCG,ADRB1,GUCY1B3,GNAI3,KRAS,ITPR1,TJP1,HTR2A

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

PDIA3,RFXANK,B2M,LTA,HLA-C,HLA-E,HLA-DQA1,HLA-G,HLA-F,KIR2DL1,KIR2DL2,HLA-DQB1,TAP1,HSPA4,CD4,HSPA5,HSPA8,KIR2DS4

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

PVR,HLA-C,CD40,HLA-E,HLA-G,HLA-DQA1,HLA-F,CD34,GLG1,ALCAM,PVRL3,CTLA4,ITGA4,ITGA9,JAM2,HLA-DQB1,CDH5,VCAM1,CD2,CD4,SELP,NLGN2,CLDN23,CDH15

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

CD247,IL12RB2,IL12RB1,IL12A,CD2,CD4

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

NPC2,PPT2,CTSA,SLC11A2,NAGA,SCARB2,LAPTM4B,CLTB,ASAH1,GLB1,ATP6V0D2,CLN3,HYAL1,CTSK,SORT1,CTSC,CTSG,AP4S1,MANBA,ARSA,GGA3

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_VASOPRESSIN_REGULATED_WATER_REABSORPTION 44 14 1.8 0 0.002
BIOCARTA_INTEGRIN_PATHWAY 38 12 1.8 0.0001 0.0045
KEGG_CALCIUM_SIGNALING_PATHWAY 178 31 0.98 0.0001 0.0066
BIOCARTA_ECM_PATHWAY 24 8 1.9 0.0007 0.02
BIOCARTA_MCALPAIN_PATHWAY 25 8 1.8 0.001 0.02
List of marker genes for gene expression subtype 4 in this pathway

ADCY3,RAB5B,AQP2,DYNLL1,DYNC2H1,RAB11B,RAB11A,CREB3L3,ARHGDIA,ARHGDIB,AVP,CREB1,DCTN2,GNAS

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

TLN1,ZYX,CSK,CAPNS1,MAP2K1,ITGA1,ACTN2,ACTN3,CAPN1,FYN,MAPK3,RAP1A

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

SLC8A3,ADCY3,ATP2B2,HTR4,RYR3,RYR1,RYR2,BDKRB2,ADRB3,GRIN1,SPHK1,P2RX1,PLCG1,LTB4R2,PLCG2,ADRA1B,MYLK,TACR3,PLCB2,PHKG1,GNAS,PPP3R1,DHX8,PDE1C,PPP3CB,PLCD4,CALML6,CAMK2B,SLC8A1,ITPR1,HTR2C

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

TLN1,MAP2K1,MYL2,ITGA1,ARHGAP5,FYN,MAPK3,MYLK

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

TLN1,MYL2,CAPNS1,ITGA1,CAPN2,CAPN1,MAPK3,MYLK

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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