Glioblastoma Multiforme: Association of mutation, copy number alteration, and subtype markers with pathways
Maintained by Spring Yingchun Liu (Broad 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 184 genes with significant mutation (Q value <= 0.1) and 110 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 :

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

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

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

16 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_GLIOMA | 65 | 7 | 3 | 0 | 0.0095
KEGG_MELANOMA | 71 | 7 | 2.8 | 0.0001 | 0.0095
KEGG_NON_SMALL_CELL_LUNG_CANCER | 54 | 6 | 3 | 0.0001 | 0.011
KEGG_BLADDER_CANCER | 42 | 5 | 3.1 | 0.0003 | 0.023
KEGG_ENDOMETRIAL_CANCER | 52 | 5 | 2.8 | 0.0008 | 0.05

List of CNV_Mut genes in this pathway

HRAS,AKT1,CDKN2A,EGFR,BRAF,RB1,PDGFRA

List of CNV_Mut genes in this pathway

HRAS,AKT1,CDKN2A,EGFR,BRAF,RB1,PDGFRA

List of CNV_Mut genes in this pathway

HRAS,AKT1,CDKN2A,EGFR,BRAF,RB1

List of CNV_Mut genes in this pathway

HRAS,CDKN2A,EGFR,BRAF,RB1

List of CNV_Mut genes in this pathway

HRAS,AKT1,ILK,EGFR,BRAF

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 | 58 | 0.96 | 0 | 0
KEGG_TYROSINE_METABOLISM | 42 | 14 | 1.9 | 0 | 0.0003
KEGG_MAPK_SIGNALING_PATHWAY | 267 | 46 | 0.92 | 0 | 0.0003
KEGG_HISTIDINE_METABOLISM | 29 | 11 | 2 | 0 | 0.0005
KEGG_CHEMOKINE_SIGNALING_PATHWAY | 190 | 34 | 0.99 | 0.0001 | 0.0009

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

PGF,BRAF,RXRA,CTNNA1,MAPK3,RAC1,BMP4,SMAD4,SMAD3,SMAD2,CBLC,LAMA4,LAMA5,ETS1,FGF5,FGF7,PTEN,CCNE2,CCNE1,FZD2,STAT1,RASSF1,FGF18,PDGFA,TGFB2,WNT4,SLC2A1,RET,FGF23,FGF22,EP300,FGFR2,WNT5B,AXIN1,EPAS1,HDAC2,E2F1,E2F3,FASLG,AKT1,MAX,PAX8,RHOA,HSP90AA1,PRKCB,DAPK1,WNT11,GSTP1,CKS1B,WNT16,TPM3,FIGF,COL4A2,COL4A1,FLT3,CBL,WNT2B,FZD10

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

TYRP1,ADH1C,WBSCR22,ADH1B,ADH1A,ADH7,AMH,ALDH3A1,DCT,GOT2,HYAL1,HGD,ALDH3B2,TRMT11

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

PRKX,BRAF,MAPK3,CACNB2,RAC1,NTF3,TAOK2,MAP2K4,JMJD7-PLA2G4B,FGF5,FGF7,FLNC,PLA2G3,MAP3K11,GNG12,PPP3CB,CHP,RASA2,DUSP4,MAPK12,FGF18,PDGFA,GNA12,TGFB2,FGF23,FGF22,MAP4K4,ARRB2,NGF,FGFR2,FGFR4,MAP4K2,ELK4,CACNA2D1,CACNA2D2,RAP1A,CACNA1F,CACNA1C,CACNA1A,FASLG,AKT1,MAX,PRKCB,PPM1A,PPP3R1,MAP3K3

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

WBSCR22,ALDH3A1,ASPA,HNMT,HDC,ALDH3B2,ABP1,ALDH7A1,TRMT11,ALDH1B1,ALDH2

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

CXCL11,PRKX,TIAM1,GNG5,ROCK1,BRAF,CCR8,CCR6,ARRB2,CCR4,CCR3,MAPK3,CX3CR1,GNAI3,CCL4,RAC1,RAP1A,XCL1,CXCR3,AKT1,PLCB4,RHOA,PRKCB,GNB5,WASL,PF4,GNG11,GNG12,CCL21,CCL19,STAT1,CCL16,GSK3A,JAK2

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 | 53 | 1.1 | 0 | 0
KEGG_COMPLEMENT_AND_COAGULATION_CASCADES | 69 | 20 | 1.7 | 0 | 0
KEGG_PATHWAYS_IN_CANCER | 328 | 68 | 1.2 | 0 | 0
KEGG_NEUROTROPHIN_SIGNALING_PATHWAY | 126 | 28 | 1.3 | 0 | 0.0001
KEGG_CHRONIC_MYELOID_LEUKEMIA | 73 | 20 | 1.6 | 0 | 0.0001

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

MAP3K4,PLA2G1B,MAP2K5,MECOM,MAPK8,PLA2G2D,CACNB4,HSPA1L,NTF3,MAP2K2,FGF5,FGF7,FGF9,NFKB1,NFKB2,CACNG2,GADD45G,PLA2G3,GADD45B,MAP3K14,MKNK2,PPP3CA,RASA1,PLA2G10,GPI,MAPK11,RPS6KA5,NRAS,RPS6KA6,DUSP2,RPS6KA2,MAPK14,DUSP9,FGF18,FGF17,TGFB3,TGFB2,PRKACB,FGF20,NGF,FGFR4,MAPKAPK2,ELK4,EGF,NR4A1,RAP1A,CACNA1C,PRKCA,PPM1A,PPM1B,MAP3K1,NF1,CRK

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

MASP1,SERPINA5,CD46,CFI,F12,F10,F7,CNTN1,F2,C7,C6,BDKRB1,C1S,FGG,FGA,FGB,CR2,VWF,CPB2,PLAU

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

STAT5B,RARB,CTNNA1,MECOM,CTNNA3,CTNNA2,VEGFB,JUP,PIAS3,MAPK8,BCL2L1,DVL2,MAP2K2,CREBBP,SMAD3,DVL1,CBLC,FGF5,FGF7,FGF9,NFKB1,NFKB2,CTBP1,CTBP2,BIRC5,FZD4,NRAS,TCEB2,TCEB1,WNT7A,FGF18,MMP9,FGF17,TGFB3,MMP2,TGFB2,WNT4,CDKN2B,RALA,FGF20,RBX1,ARNT,ITGAV,EGF,RUNX1,TRAF4,AXIN1,EPAS1,ITGA2,CDKN1A,CDKN1B,ITGA6,ABL1,E2F1,PAX8,TPR,PRKCA,RUNX1T1,DAPK3,WNT11,EGLN2,EGLN1,CDH1,TCF7L1,PIK3R3,CEBPA,COL4A2,CRK

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

FOXO3,NGFRAP1,MAP2K5,RIPK2,MAPK8,NGF,MAPKAPK2,NTF3,MAP2K2,RAP1A,ABL1,NFKB1,CSK,SHC3,KIDINS220,PSEN1,NGFR,MAP3K1,CALML5,PIK3R3,MAPK11,YWHAE,RPS6KA5,RPS6KA6,NRAS,RPS6KA2,MAPK14,CRK

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

E2F1,STAT5B,TGFB3,NFKB1,TGFB2,SHC3,CTBP1,CTBP2,MECOM,BCL2L1,PIK3R3,RUNX1,MAP2K2,SMAD3,CBLC,NRAS,CDKN1A,CDKN1B,ABL1,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_CALCIUM_SIGNALING_PATHWAY | 178 | 31 | 1.1 | 0.0001 | 0.0022
KEGG_ENDOCYTOSIS | 183 | 31 | 1 | 0.0001 | 0.0022
KEGG_CELL_ADHESION_MOLECULES_CAMS | 134 | 25 | 1.2 | 0.0001 | 0.0022
KEGG_PATHWAYS_IN_CANCER | 328 | 50 | 0.86 | 0 | 0.0022
BIOCARTA_ACTINY_PATHWAY | 20 | 8 | 2.2 | 0.0001 | 0.0031

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

ADCY8,ITPKB,ITPKA,ATP2B1,ATP2B3,GRIN2C,BST1,NTSR1,PHKA2,ADORA2B,BDKRB1,SPHK1,VDAC2,VDAC3,VDAC1,ATP2A2,TBXA2R,CACNA1G,ADRA1D,EDNRB,PLCB3,PLCB2,PRKCA,GRM1,GNAL,PTAFR,PPP3R1,PTK2B,CHP,CAMK2A,HTR2B

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

CHMP5,CHMP6,DAB2,PLD1,SH3GL1,ASAP2,ADRBK2,SRC,HSPA1L,SNF8,MET,KDR,CBLB,RABEP1,GRK6,CLTB,RAB5B,VPS37A,VPS37B,VPS37C,PIP5K1A,LDLRAP1,RAB11FIP5,RAB11FIP2,RAB11FIP3,EEA1,PIKFYVE,EHD1,FLT1,VPS28,ARAP1

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

OCLN,HLA-DQA1,PHOX2A,HLA-DRA,HLA-DRB1,ITGAV,ITGB7,CTLA4,HLA-DOA,HLA-DOB,CLDN8,CLDN3,CLDN5,HLA-DMB,CD80,CLDN1,VCAN,JAM3,CLDN10,CLDN11,NEO1,CD4,SELPLG,MPZ,SELE

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

CUL2,RARB,CCNA1,PLD1,BCR,RXRA,RXRG,LAMC3,PIAS3,MAPK8,LAMC2,PIAS1,RAC3,DVL3,HGF,LAMA4,CBLB,FGF7,SPI1,MLH1,PTEN,AKR1B1,RAD51,BID,BIRC5,BIRC2,WNT7B,RASSF1,MMP9,CDKN2A,RALA,EP300,RBX1,ITGAV,TRAF4,TRAF3,MET,IKBKG,E2F1,AKT1,FOS,PAX8,PRKCA,NCOA4,WNT16,KITLG,EGLN1,TCF7L2,PIK3R5,RALGDS

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

ABI2,ARPC4,PSMA7,ACTR3,ACTR2,ARPC2,NCK1,PIR

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)
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