Association of mutation, copy number alteration, and subtype markers with pathways
Glioblastoma Multiforme (Primary solid tumor)
16 April 2014  |  analyses__2014_04_16
Maintainer Information
Citation Information
Maintained by Spring Yingchun Liu (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2014): Association of mutation, copy number alteration, and subtype markers with pathways. Broad Institute of MIT and Harvard. doi:10.7908/C1SX6BV4
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 10 genes with significant mutation (Q value <= 0.1) and 166 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 :

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

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

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

8 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_G1_PATHWAY 28 7 4.9 0 0
BIOCARTA_GCR_PATHWAY 20 5 5 0 0
BIOCARTA_CTCF_PATHWAY 23 7 5.2 0 0
BIOCARTA_CELLCYCLE_PATHWAY 23 6 5 0 0
BIOCARTA_RACCYCD_PATHWAY 26 8 5.2 0 0
List of CNV_Mut genes in this pathway

TGFB3,CDKN2A,TFDP1,TP53,CDK6,RB1,CDK4

List of CNV_Mut genes in this pathway

HSP90AA1,AKT1,PIK3CA,PIK3R1,CALM1

List of CNV_Mut genes in this pathway

TGFB3,TP53,PTEN,CDKN2A,MDM2,PIK3CA,PIK3R1

List of CNV_Mut genes in this pathway

CDK6,RB1,CDK4,CDKN2A,CDKN2C,TFDP1

List of CNV_Mut genes in this pathway

HRAS,AKT1,PIK3CA,PIK3R1,TFDP1,CDK6,RB1,CDK4

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_MAPK_SIGNALING_PATHWAY 267 53 1.1 0 0
KEGG_PATHWAYS_IN_CANCER 328 62 1.1 0 0
KEGG_VIRAL_MYOCARDITIS 73 19 1.6 0 0.0001
KEGG_INTESTINAL_IMMUNE_NETWORK_FOR_IGA_PRODUCTION 48 14 1.8 0 0.0003
KEGG_NEUROTROPHIN_SIGNALING_PATHWAY 126 27 1.2 0 0.0003
List of marker genes for gene expression subtype 1 in this pathway

HRAS,BDNF,PLA2G1B,MAP2K5,BRAF,MECOM,MAPK9,MAPK8,PLA2G2D,KRAS,RAC3,NTF3,TAOK2,MAP2K2,PLA2G4A,JMJD7-PLA2G4B,FGF5,FGF9,TP53,CACNG2,GADD45G,PLA2G3,GADD45B,MAP3K14,MAP3K12,MKNK2,PPP3CA,RASA1,GPI,RPS6KA6,DUSP1,RPS6KA2,FGF18,FGF17,TGFB3,PRKACB,RELB,RASGRF1,FGFR4,ELK4,PTPN7,NR4A1,CACNA1H,CACNA1F,CACNA1C,CDC42,CASP3,CHUK,PPM1B,MAP3K3,MAP3K1,NFATC4,NF1

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

HRAS,CUL2,BRAF,MECOM,CTNNA2,VEGFB,VEGFC,PIAS3,MAPK9,MAPK8,BCL2L1,KRAS,RAC3,DVL2,MAP2K2,CBLC,ETS1,FGF5,PPARD,FGF9,FLT3LG,AKR1B1,CTBP1,TP53,ZBTB16,FZD1,BIRC5,BIRC3,FZD4,PTCH2,FGF18,MMP9,FGF17,TGFB3,MMP2,WNT4,CDKN2B,TRAF1,RBX1,ITGAV,RUNX1,TRAF5,AXIN1,EPAS1,ITGA2,CDKN1A,CDKN1B,ABL1,E2F1,CDC42,CASP3,CHUK,CYCS,CDK6,DAPK3,DAPK1,EGLN2,EGLN1,TCF7L2,IGF1R,CEBPA,COL4A2

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

CXADR,CASP3,CYCS,HLA-A,HLA-DQA1,CD80,SGCG,HLA-DPA1,MYH7B,HLA-DRA,SGCB,CAV1,HLA-DRB1,RAC3,HLA-DPB1,CD28,MYH11,ABL1,MYH10

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

HLA-DRB1,ENC1,CXCR4,ITGB7,CTLA4,HLA-DPB1,CD28,PIGR,HLA-DQA1,CD80,HLA-DPA1,MAP3K14,HLA-DRA,IL2

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

HRAS,FOXO3,BDNF,NGFRAP1,MAP2K5,BRAF,IRS1,MAPK9,MAPK8,NFKBIB,KRAS,NTF3,MAP2K2,ABL1,CDC42,SHC3,TP53,PSEN1,NGFR,YWHAZ,MAP3K3,MAP3K1,CAMK2A,YWHAE,RPS6KA6,YWHAH,RPS6KA2

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_NUCLEOTIDE_EXCISION_REPAIR 44 14 1.8 0 0.0026
KEGG_PURINE_METABOLISM 158 30 1.1 0 0.0034
KEGG_CELL_ADHESION_MOLECULES_CAMS 134 26 1.2 0.0001 0.0034
BIOCARTA_RARRXR_PATHWAY 15 7 2.4 0.0001 0.0057
KEGG_CITRATE_CYCLE_TCA_CYCLE 32 10 1.9 0.0002 0.0057
List of marker genes for gene expression subtype 2 in this pathway

RBX1,ERCC8,ERCC6,POLE3,ERCC3,ERCC2,CCNH,DDB1,POLE,CDK7,RFC5,XPA,RFC4,CUL4A

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

ADCY8,POLE,PDE5A,ENPP1,PPAT,POLE3,ENTPD5,ENTPD4,ENTPD1,AK1,PDE6G,PDE11A,NT5M,GUCY1A3,ADCY10,IMPDH1,PDE10A,POLR1B,GMPS,ADK,POLA1,POLA2,PFAS,POLR2A,NUDT9,POLR3F,PDE3A,AMPD3,POLR3D,ITPA

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

OCLN,L1CAM,HLA-DQA1,CD40LG,CD34,HLA-DPA1,CD226,ITGAL,HLA-DRB1,ITGAV,CLDN8,CLDN3,CD8B,CLDN6,HLA-DMB,ICAM2,SIGLEC1,CLDN1,VCAN,ICOSLG,CLDN11,NEO1,CD4,CD6,CD28,MPZ

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

KAT2B,RXRA,TBP,POLR2A,GTF2E1,NCOA2,ERCC3

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

IDH3G,IDH1,PDHA1,DLST,CS,SDHC,SDHD,DLD,KRT17,MDH1

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_TGF_BETA_SIGNALING_PATHWAY 86 22 1.5 0 0.0007
KEGG_FATTY_ACID_METABOLISM 42 13 1.8 0 0.0031
BIOCARTA_VEGF_PATHWAY 29 10 1.9 0.0001 0.0045
KEGG_SPLICEOSOME 126 24 1.2 0.0001 0.0045
KEGG_PATHWAYS_IN_CANCER 328 50 0.75 0.0001 0.0045
List of marker genes for gene expression subtype 3 in this pathway

E2F5,GDF5,TGFB3,RPS6KB2,TGFB2,ZFYVE9,MYC,LEFTY1,ACVR2A,AMH,EP300,MAPK3,COMP,PPP2CA,AMHR2,SMAD4,PSG1,SMURF1,ID3,CHRD,BMP5,BMPR1A

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

ACADSB,ADH1C,ADH5,ADH1B,ADH1A,ADH7,ACOX3,ACSL3,ACADM,ACADS,PECI,CPT1A,ALDH2

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

HRAS,PXN,ARNT,EIF1,NOS3,FLT1,FLT4,EIF2S3,PRKCB,EIF2S1

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

SNRPD1,SFRS7,DDX23,DHX38,MAGOH,SFRS1,HNRNPU,HNRNPM,DDX46,DDX42,SNW1,SFRS2B,PRPF3,THOC2,PRPF38B,THOC1,TRA2B,SR140,SF3B4,PRPF19,PRPF8,USP39,DHX15,RBM25

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

HRAS,PGF,BRAF,VEGFB,MAPK3,RAC1,SMAD4,CBLC,LAMA5,FGF5,FGF7,PTEN,CCNE2,MYC,CTBP2,RAD51,FZD9,FZD8,STAT3,WNT7A,FGF18,PDGFA,TGFB3,TGFB2,WNT4,SLC2A1,EGFR,FGF23,EP300,FGFR2,WNT5B,ARNT,TRAF5,AXIN1,E2F1,E2F3,PAX8,TPR,AKT3,HSP90AA1,LEF1,PRKCB,DAPK1,CKS1B,WNT16,TPM3,COL4A1,MSH2,FZD10,BAX

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

In addition to the links below, the full results of the analysis summarized in this report can also be downloaded programmatically using firehose_get, or interactively from either the Broad GDAC website or TCGA Data Coordination Center Portal.

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)