Glioblastoma Multiforme: Association of mutation, copy number alteration, and subtype markers with pathways
Maintained by Spring Yingchun Liu (Dana-Farber Cancer Institute)
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 250 genes with significant mutation (Q value <= 0.1) and 156 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 :

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

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

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

17 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
--- | --- | --- | --- | --- | ---
BIOCARTA_CTCF_PATHWAY | 23 | 7 | 4 | 0 | 0
BIOCARTA_ARF_PATHWAY | 17 | 7 | 4.4 | 0 | 0
KEGG_PANCREATIC_CANCER | 70 | 10 | 2.9 | 0 | 0
KEGG_GLIOMA | 65 | 13 | 3.4 | 0 | 0
KEGG_PROSTATE_CANCER | 89 | 12 | 2.8 | 0 | 0

List of CNV_Mut genes in this pathway

PIK3CG,TP53,PTEN,CDKN2A,MDM2,PIK3CA,PIK3R1

List of CNV_Mut genes in this pathway

PIK3CG,TP53,RB1,CDKN2A,MDM2,PIK3CA,PIK3R1

List of CNV_Mut genes in this pathway

CDKN2A,PIK3CA,AKT3,PIK3CG,EGFR,BRAF,TP53,RB1,CDK4,PIK3R1

List of CNV_Mut genes in this pathway

PTEN,CDKN2A,PIK3CA,AKT3,PIK3CG,EGFR,BRAF,TP53,RB1,CDK4,PDGFRA,MDM2,PIK3R1

List of CNV_Mut genes in this pathway

PTEN,PIK3CA,AKT3,PIK3CG,EGFR,BRAF,TP53,RB1,PDGFRA,MDM2,FGFR1,PIK3R1

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_PATHWAYS_IN_CANCER | 328 | 61 | 1 | 0 | 0
KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION | 272 | 49 | 1 | 0 | 0.0001
KEGG_PARKINSONS_DISEASE | 130 | 26 | 1.4 | 0 | 0.0001
KEGG_TGF_BETA_SIGNALING_PATHWAY | 86 | 20 | 1.4 | 0 | 0.0014
KEGG_ALZHEIMERS_DISEASE | 167 | 29 | 1 | 0.0001 | 0.0025

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

HRAS,PGF,RXRA,CTNNA1,MECOM,CTNNA3,VEGFB,MAPK3,VEGFA,PDGFRB,BCL2L1,BMP4,BMP2,SMAD4,SMAD2,CBLC,LAMA4,ETS1,NTRK1,FGF5,CCNE2,CCNE1,CTBP2,FZD8,FZD2,STAT1,NRAS,RASSF1,PDGFB,PDGFA,WNT4,CDKN2B,FGFR2,WNT5A,GRB2,AXIN1,EPAS1,E2F1,E2F3,FASLG,AKT1,MAX,RHOA,CHUK,CYCS,CDK2,PRKCB,DAPK1,NCOA4,WNT11,GSTP1,CKS1B,WNT16,CDH1,TPM3,FIGF,COL4A2,COL4A1,FLT3,CBL,WNT2B

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

ADORA3,LPAR3,AGTR1,AGTR2,HTR1F,F2,PPYR1,GH1,CHRNB3,CHRNB2,CHRNG,TRPV1,EDNRA,NMUR1,PTGDR,AVPR2,MC3R,P2RY11,P2RY14,F2RL2,GRIK3,GALR3,GABRR2,GABRR1,GLP1R,ADORA2B,P2RY1,ADRA2A,GABRP,GABRD,GABRE,GABRA4,GABRA5,P2RX6,MTNR1B,ADRA1D,TACR1,CALCRL,PTGER1,PTGER3,FSHR,ADRB2,CHRM4,CALCR,PRSS1,TSHB,HRH4,PRLR,F2R

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

COX6C,COX7B,UBE2L3,VDAC1,UBA1,UQCRC2,ATP5E,UBE2G1,CYC1,UBE2G2,UCHL1,NDUFS6,NDUFS4,NDUFS2,CYCS,UBB,NDUFB7,ATP5G1,COX7A2L,ATP5G3,NDUFA8,NDUFA6,NDUFA7,NDUFA1,PARK7,SLC18A1

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

E2F4,ACVRL1,CDKN2B,RHOA,ROCK1,ACVR2A,AMH,MAPK3,TNF,COMP,PPP2CA,THBS2,BMP4,AMHR2,BMP2,SMAD7,SMAD4,SMAD2,PSG1,BMPR1A

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

PSENEN,COX6C,MAPK3,BACE1,COX7B,CACNA1F,UQCRC2,ATP5E,CYC1,NDUFS6,NDUFS4,PLCB4,NDUFS2,CYCS,PSEN2,ERN1,ADAM17,TNF,NDUFB7,PPP3R1,COX7A2L,ATP5G1,ATP5G3,CALML3,CHP,NDUFA8,NDUFA6,NDUFA7,NDUFA1

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_MAPK_SIGNALING_PATHWAY | 267 | 50 | 1 | 0 | 0
KEGG_PATHWAYS_IN_CANCER | 328 | 68 | 1.2 | 0 | 0
KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION | 272 | 47 | 0.92 | 0 | 0.0001
KEGG_CELL_CYCLE | 128 | 28 | 1.3 | 0 | 0.0001
KEGG_COMPLEMENT_AND_COAGULATION_CASCADES | 69 | 19 | 1.6 | 0 | 0.0001

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

MAP3K4,PLA2G1B,MAP2K5,MECOM,MAPK8,PLA2G2D,NTF3,MAP2K2,FGF5,FGF7,NFKB1,CACNG2,GADD45G,PLA2G3,GADD45B,MAP3K14,MAP3K12,MKNK2,PPP3CA,RASA1,RASA2,MAPK11,RPS6KA5,NRAS,DUSP2,RPS6KA2,MAPK14,DUSP9,FGF18,FGF17,TGFB3,TGFB1,PRKACB,FGF22,FGF20,NGF,FGFR4,MAPKAPK2,ELK4,EGF,CACNA1I,NR4A1,RAP1A,CACNA1H,CACNA1F,CACNA1C,PRKCB,MAP3K1,CDC25B,CRK

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

STAT5B,CTNNB1,RARB,MECOM,CTNNA3,CTNNA2,VEGFB,JUP,PIAS3,VEGFA,MAPK8,BCL2L1,DVL2,MAP2K2,CREBBP,SMAD3,SMAD2,CBLC,ETS1,FGF5,FGF7,NFKB1,FLT3LG,CTBP1,CTBP2,ZBTB16,FZD1,BIRC5,FZD4,NRAS,ARAF,TCEB1,WNT7A,FGF18,MMP9,FGF17,TGFB3,MMP2,TGFB1,WNT4,CDKN2B,RALA,FGF22,FGF20,ARNT,ITGAV,EGF,RUNX1,TRAF4,ITGA2,CDKN1A,CDKN1B,MTOR,ABL1,E2F1,PAX8,RUNX1T1,DAPK2,DAPK3,PRKCB,WNT11,EGLN2,CDH1,TCF7L1,IGF1R,COL4A2,BAX,CRK

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

CGA,ADORA3,LPAR3,CHRNA9,MC1R,LTB4R,S1PR4,CHRNA6,CHRNA1,HTR1F,SSTR5,SSTR1,F2,CHRNB3,MCHR1,GLRA3,EDNRA,MC5R,GRM1,GRM8,NPY2R,GRIA2,P2RY14,MC4R,HTR2C,F2RL2,TSPO,THRA,GABRB1,PTGIR,NTSR1,GABRR1,DRD1,DRD5,CNR1,P2RY2,GABRP,GRIN1,P2RX4,GPR35,PTGER2,PTGER3,CHRM4,CTSG,PRSS1,NR3C1,HRH3

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

TGFB3,PKMYT1,TTK,TGFB1,CDKN2B,CCNA2,ANAPC1,ANAPC2,CHEK1,CREBBP,SMAD3,SMAD2,CDKN1A,CDKN1B,ABL1,E2F1,CDC2,MCM5,MCM6,GADD45G,BUB1B,GADD45B,BUB1,CDC25C,YWHAE,CDC25A,CDC25B,ORC3L

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

MASP1,SERPINA5,CFI,F12,F10,F8,F7,C8G,SERPINF2,CNTN1,F2,TFPI,C3,C1S,FGA,FGB,CR2,C4BPB,SERPIND1

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_PURINE_METABOLISM | 158 | 35 | 1.3 | 0 | 0.0001
KEGG_CELL_CYCLE | 128 | 27 | 1.2 | 0 | 0.0012
KEGG_CITRATE_CYCLE_TCA_CYCLE | 32 | 11 | 2 | 0 | 0.0015
KEGG_PYRIMIDINE_METABOLISM | 98 | 22 | 1.3 | 0 | 0.0015
KEGG_CALCIUM_SIGNALING_PATHWAY | 178 | 33 | 1 | 0 | 0.0015

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

SLC25A16,ADCY8,NT5C2,POLE,NME5,PDE5A,ADSS,PPAT,POLE3,ENTPD5,ENTPD4,ENTPD1,ALLC,AK1,POLDIP2,PDE7B,PDE11A,GUCY1A3,IMPDH1,NT5C,POLR1D,POLR1B,ADK,POLR2K,POLA1,DCK,POLA2,POLR2D,PFAS,POLR3F,NPR2,PDE3A,AMPD3,POLR3D,ITPA

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

DBF4,CDKN2A,CDKN2D,CCNA1,CCNA2,STAG2,CUL1,ANAPC1,ANAPC2,RBL2,ESPL1,ORC1L,EP300,RBX1,TFDP2,TFDP1,CREBBP,E2F1,MAD1L1,CDC45L,CDK6,CCND2,BUB1B,ORC2L,YWHAB,CDC25C,YWHAH

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

PDHB,IDH3G,IDH1,PDHA1,SUCLA2,FH,IDH3A,SDHC,SDHD,KRT17,MDH1

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

NT5C2,POLE,NME5,CTPS2,CMPK1,POLE3,ENTPD5,CDA,ENTPD4,ENTPD1,POLDIP2,NT5C,POLR1D,POLR1B,POLR2K,POLA1,DCK,POLA2,POLR2D,POLR3F,POLR3D,ITPA

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

ADCY8,ITPKB,ATP2B1,AGTR1,ATP2B3,GRIN2C,PRKACA,BST1,NTSR1,PHKA2,ADORA2B,BDKRB1,SPHK1,VDAC2,VDAC3,VDAC1,ATP2A2,ATP2A3,TBXA2R,CACNA1G,ADRA1D,EDNRB,PLCB3,PLCB2,PRKCA,GRM1,PTAFR,PPP3R1,PTK2B,CHP,CAMK2A,PTGFR,HTR2C

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.

- Analysis Results (MD5 checksum)

- Auxiliary Data (MD5 checksum)

- MAGE-TAB File (MD5 checksum)

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)
Meta

- Maintainer = Spring Yingchun Liu

Copyright © 2011 Broad Institute TCGA GDAC as part of the TCGA Research Network. All rights reserved.
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