Association of mutation, copy number alteration, and subtype markers with pathways
Brain Lower Grade Glioma (Primary solid tumor)
23 September 2013 | analyses__2013_09_23
Maintainer Information
Citation Information
doi:10.7908/C1NK3CCF
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/C1NK3CCF
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 19 genes with significant mutation (Q value <= 0.1) and 497 genes with significant copy number alteration (Q value <= 0.25). The identified marker genes (Q value <= 0.01 or within top 2000) are 713 for subtype 1, 713 for subtype 2, 713 for subtype 3. Pathways significantly enriched with these genes (Q value <= 0.01) are identified :

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

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

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

0 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_IGF1MTOR_PATHWAY | 20 | 6 | 3.6 | 0 | 0.001
BIOCARTA_VEGF_PATHWAY | 29 | 7 | 3.3 | 0 | 0.001
BIOCARTA_CTCF_PATHWAY | 23 | 6 | 3.4 | 0 | 0.0017
KEGG_ALZHEIMERS_DISEASE | 167 | 14 | 1.9 | 0 | 0.0025
KEGG_INOSITOL_PHOSPHATE_METABOLISM | 54 | 8 | 2.6 | 0 | 0.0033

List of CNV_Mut genes in this pathway

PTEN,EIF2S1,PPP2CA,PIK3CA,PIK3R1,EIF2B5

List of CNV_Mut genes in this pathway

HRAS,EIF1AX,PIK3CA,EIF2B2,PIK3R1,EIF2B5,EIF2S1

List of CNV_Mut genes in this pathway

SMAD4,TP53,PTEN,PPP2CA,PIK3CA,PIK3R1

List of CNV_Mut genes in this pathway

BACE1,NDUFA4L2,ATP2A2,UQCRC1,ATP5B,ATP5H,PSEN2,NDUFB9,NDUFB1,GAPDH,NDUFA2,NDUFA3,NDUFA9,CALM1

List of CNV_Mut genes in this pathway

PTEN,PIK3C3,PIK3CA,ITPK1,ALDH6A1,PIK3C2B,PIK3CD,TPI1

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_B_CELL_RECEPTOR_SIGNALING_PATHWAY | 75 | 10 | 2.1 | 0.0001 | 0.033
BIOCARTA_LAIR_PATHWAY | 17 | 4 | 2.9 | 0.0015 | 0.14
KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION | 44 | 6 | 2.2 | 0.0019 | 0.14
KEGG_GLYCOSAMINOGLYCAN_BIOSYNTHESIS_HEPARAN_SULFATE | 26 | 5 | 2.6 | 0.0011 | 0.14
KEGG_CHEMOKINE_SIGNALING_PATHWAY | 190 | 14 | 1.2 | 0.002 | 0.14

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

BTK,SYK,PIK3CG,BCL10,PIK3CD,CARD11,NFKBIB,NFATC1,BLNK,VAV1

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

C3,VCAM1,SELPLG,IL1A

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

HADHA,HMGCL,BCKDHA,ACADM,DBT,PCCB

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

NDST3,B3GALT6,EXTL2,HS2ST1,HS6ST1

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

ADCY2,PIK3CG,PIK3CD,CX3CR1,GNAI3,NFKBIB,VAV1,CDC42,SHC3,PLCB2,PRKCD,GNB1,CCR1,GSK3A

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 | 8 | 2.5 | 0.0001 | 0.015
KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION | 272 | 10 | 2.2 | 0.0001 | 0.015
BIOCARTA_PGC1A_PATHWAY | 24 | 2 | 3.4 | 0.014 | 0.93
BIOCARTA_CREB_PATHWAY | 27 | 2 | 3.2 | 0.02 | 0.93
KEGG_CARDIAC_MUSCLE_CONTRACTION | 78 | 3 | 2.4 | 0.019 | 0.93

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

ADRA1B,CACNA1A,HTR5A,CCKBR,PRKCB,CHRM3,CHRM2,CAMK2B

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

HTR5A,CCKBR,OPRK1,GABRA2,GABRA1,ADRA1B,CHRM3,CHRM2,PRSS1,PRSS3

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

CAMK1G,CAMK2B

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

CAMK2B,PRKCB

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

SLC9A6,CACNG3,CACNA2D3

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
--- | --- | --- | --- | --- | ---
BIOCARTA_DC_PATHWAY | 22 | 3 | 4.3 | 0.0004 | 0.08
KEGG_FC_GAMMA_R_MEDIATED_PHAGOCYTOSIS | 97 | 5 | 2.9 | 0.0005 | 0.08
BIOCARTA_CTCF_PATHWAY | 23 | 2 | 3.7 | 0.01 | 0.39
BIOCARTA_IL2_PATHWAY | 22 | 2 | 3.8 | 0.0095 | 0.39
BIOCARTA_NKCELLS_PATHWAY | 20 | 2 | 3.9 | 0.0079 | 0.39

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

TLR4,TLR7,CD33

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

SYK,ASAP3,DOCK2,VAV1,PIKFYVE

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

PTEN,TGFB1

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

STAT5A,SYK

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

VAV1,SYK

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.

- 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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