Association of mutation, copy number alteration, and subtype markers with pathways
Brain Lower Grade Glioma (Primary solid tumor)
22 February 2013  |  analyses__2013_02_22
Maintainer Information
Citation Information
doi:10.7908/C1DJ5CVZ
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/C1DJ5CVZ
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 470 genes with significant copy number alteration (Q value <= 0.25). The identified marker genes (Q value <= 0.01 or within top 2000) are 245 for subtype 1, 245 for subtype 2, 245 for subtype 3. Pathways significantly enriched with these genes (Q value <= 0.01) are identified :

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

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

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

5 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_SPLICEOSOME 126 10 1.9 0.0003 0.097
BIOCARTA_TEL_PATHWAY 18 4 3.3 0.0007 0.11
BIOCARTA_EIF_PATHWAY 16 3 3.1 0.0045 0.32
BIOCARTA_CARDIACEGF_PATHWAY 18 3 2.8 0.0077 0.32
KEGG_BASAL_TRANSCRIPTION_FACTORS 36 4 2.3 0.0084 0.32
List of CNV_Mut genes in this pathway

NCBP2,SNRPE,NHP2L1,CDC40,SNW1,PUF60,PLRG1,PRPF31,WBP11,SF3B5

List of CNV_Mut genes in this pathway

EGFR,XRCC6,KRAS,PPP2CA

List of CNV_Mut genes in this pathway

EIF6,EIF4G2,EIF2S1

List of CNV_Mut genes in this pathway

EGFR,HRAS,RHOA

List of CNV_Mut genes in this pathway

GTF2A2,TAF2,TAF10,GTF2F2

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_CHEMOKINE_SIGNALING_PATHWAY 190 15 2.9 0 0
KEGG_FC_GAMMA_R_MEDIATED_PHAGOCYTOSIS 97 12 3.5 0 0
KEGG_LEUKOCYTE_TRANSENDOTHELIAL_MIGRATION 118 11 3.1 0 0
BIOCARTA_FCER1_PATHWAY 39 6 3.8 0 0.0003
KEGG_NATURAL_KILLER_CELL_MEDIATED_CYTOTOXICITY 137 9 2.6 0 0.0007
List of marker genes for gene expression subtype 1 in this pathway

ADCY7,GNGT2,PIK3CG,NCF1,CCR5,ARRB2,CX3CR1,GNAI3,DOCK2,VAV1,SHC3,WAS,GNB1,CCR1,HCK

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

SYK,PIK3CG,NCF1,ASAP3,DOCK2,VAV1,PLCG2,FCGR3A,WAS,SCIN,PIKFYVE,HCK

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

PIK3CG,NCF1,NCF4,GNAI3,SIPA1,ITGB2,ITGAM,VAV1,PLCG2,VCAM1,CYBB

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

BTK,FCER1G,SYK,PIK3CG,MAP2K4,VAV1

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

SYK,PIK3CG,ITGB2,FCER1G,PTPN6,VAV1,PLCG2,SHC3,FCGR3A

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_CALCIUM_SIGNALING_PATHWAY 178 10 3 0 0.0001
KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION 272 12 2.6 0 0.0001
BIOCARTA_PGC1A_PATHWAY 24 3 4.2 0.0005 0.06
BIOCARTA_STATHMIN_PATHWAY 19 2 3.9 0.0077 0.6
BIOCARTA_CREB_PATHWAY 27 2 3.4 0.015 0.6
List of marker genes for gene expression subtype 2 in this pathway

ITPKA,RYR2,CACNA1A,HTR5A,CCKBR,CHRM3,CHRM2,CAMK2B,CAMK2A,ITPR1

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

LPAR1,HTR5A,CCKBR,OPRK1,GABRA2,GABRA1,GABRA5,CHRM3,CHRM2,PRSS1,PRSS2,PRSS3

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

CAMK1G,CAMK2B,CAMK2A

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

CAMK2B,CAMK2A

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

CAMK2B,CAMK2A

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_LEISHMANIA_INFECTION 72 10 3.1 0 0.0001
BIOCARTA_LAIR_PATHWAY 17 5 4.1 0 0.0006
KEGG_CHEMOKINE_SIGNALING_PATHWAY 190 14 2.1 0 0.0006
KEGG_FC_GAMMA_R_MEDIATED_PHAGOCYTOSIS 97 10 2.6 0 0.0006
KEGG_LEUKOCYTE_TRANSENDOTHELIAL_MIGRATION 118 10 2.3 0 0.002
List of marker genes for gene expression subtype 3 in this pathway

TLR4,TGFB1,FCGR3A,IL1A,NCF2,NCF1,NCF4,C3,ITGB2,ITGAM

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

C3,ITGB2,VCAM1,SELPLG,IL1A

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

ADCY2,GNG4,PIK3CG,NCF1,PIK3CD,CCR5,CX3CR1,VAV1,GNGT1,IL8RB,PRKCD,CCR1,HCK,GSK3B

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

PIK3CG,NCF1,PIK3CD,VAV1,ORC3L,FCGR3A,PRKCD,PIKFYVE,PTPRC,HCK

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

PIK3CG,NCF2,NCF1,NCF4,PIK3CD,ITGB2,ITGAM,VAV1,VCAM1,CYBB

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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