Association of mutation, copy number alteration, and subtype markers with pathways
Rectum Adenocarcinoma (Primary solid tumor)
23 September 2013 | analyses__2013_09_23
Maintainer Information
Citation Information
doi:10.7908/C10K26WT
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/C10K26WT
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 3 genes with significant mutation (Q value <= 0.1) and 658 genes with significant copy number alteration (Q value <= 0.25). The identified marker genes (Q value <= 0.01 or within top 2000) are 885 for subtype 1, 885 for subtype 2, 885 for subtype 3. Pathways significantly enriched with these genes (Q value <= 0.01) are identified :

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

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

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

1 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_PROTEASOME | 48 | 11 | 3 | 0 | 0
BIOCARTA_CHREBP2_PATHWAY | 44 | 9 | 2.8 | 0 | 0.0009
KEGG_WNT_SIGNALING_PATHWAY | 151 | 16 | 1.8 | 0 | 0.0024
BIOCARTA_MTOR_PATHWAY | 23 | 6 | 3 | 0.0001 | 0.0041
KEGG_OOCYTE_MEIOSIS | 114 | 13 | 1.9 | 0.0001 | 0.0041

List of CNV_Mut genes in this pathway

SHFM1,PSMA7,PSMF1,PSMB6,PSMB3,PSMD3,PSMD4,PSMD12,PSMD11,PSMC1,PSME3

List of CNV_Mut genes in this pathway

PPP2R5D,PPP2R5C,PPP2CB,PPP2R2D,YWHAB,YWHAE,MLX,PPP2R5E,PPP2R2A

List of CNV_Mut genes in this pathway

PPP2R5D,PPP2R5C,PRKX,CSNK2A1,PPP2R5E,DAAM1,DVL2,SMAD4,SMAD3,TP53,CAMK2G,PPP2CB,PPP3CB,PPP3CC,APC,FZD3

List of CNV_Mut genes in this pathway

RPS6KB1,FKBP1A,PTEN,EIF4EBP1,EIF6,EIF4A1

List of CNV_Mut genes in this pathway

PPP2R5D,PPP2R5C,AURKA,PRKX,PPP2R5E,CAMK2G,PPP2CB,PPP3CB,PPP3CC,YWHAB,YWHAE,SMC3,CALM1

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_CELL_ADHESION_MOLECULES_CAMS | 134 | 16 | 1.6 | 0 | 0.016
KEGG_CHEMOKINE_SIGNALING_PATHWAY | 190 | 18 | 1.3 | 0.0004 | 0.022
KEGG_FC_GAMMA_R_MEDIATED_PHAGOCYTOSIS | 97 | 12 | 1.7 | 0.0004 | 0.022
KEGG_LEISHMANIA_INFECTION | 72 | 10 | 1.8 | 0.0004 | 0.022
KEGG_DILATED_CARDIOMYOPATHY | 92 | 12 | 1.8 | 0.0002 | 0.022

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

PDCD1LG2,HLA-DPA1,ITGB2,PVRL1,ITGAV,HLA-DPB1,ITGA4,HLA-DMB,SDC2,ICAM3,CD86,CDH2,PTPRC,SELP,NLGN2,CLDN23

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

ADCY2,GNGT2,GNG7,NCF1,CCR6,CCR3,CCR2,CCL2,FGR,CCL7,DOCK2,AKT3,SHC4,PRKCB,GNB4,CCR1,GNG11,CCL21

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

NCF1,DOCK2,SPHK2,SPHK1,MYO10,AKT3,PRKCB,CFL2,FCGR1A,PTPRC,FCGR2B,FCGR2A

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

HLA-DMB,NCF2,NCF1,PRKCB,HLA-DPA1,ITGB2,FCGR1A,HLA-DPB1,ITGA4,FCGR2A

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

ADCY2,ACTG1,DES,SGCD,SGCA,CACNB1,ITGA11,TPM2,ITGAV,IGF1,ITGA4,PLN

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_FOCAL_ADHESION | 201 | 25 | 1.7 | 0 | 0.0001
KEGG_ECM_RECEPTOR_INTERACTION | 84 | 16 | 2.3 | 0 | 0.0001
KEGG_PATHWAYS_IN_CANCER | 328 | 26 | 1 | 0.0005 | 0.06
BIOCARTA_INTRINSIC_PATHWAY | 23 | 5 | 2.4 | 0.0018 | 0.088
KEGG_NICOTINATE_AND_NICOTINAMIDE_METABOLISM | 23 | 5 | 2.4 | 0.0018 | 0.088

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

VEGFB,PDGFRA,PDGFRB,HGF,LAMA4,PARVA,COL6A3,COL6A2,COL6A1,THBS1,THBS4,IGF1,RELN,COL1A1,CAV1,ITGB3,MYL9,ITGAV,ITGA5,AKT3,SHC4,TNC,COL4A4,COL4A2,COL5A1

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

SDC2,RELN,COL1A1,TNC,ITGB3,ITGAV,COL6A3,COL6A2,COL6A1,THBS1,THBS4,COL4A4,COL4A2,COL5A1,LAMA4,ITGA5

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

RARA,CCNA1,VEGFB,PDGFRA,PDGFRB,TGFBR1,HGF,LAMA4,NOS2,FGF2,AKR1B1,FZD8,FZD1,IGF1,FOXO1,FGF12,TGFB2,RALA,STK4,FGFR1,ITGAV,TRAF6,E2F2,AKT3,COL4A4,COL4A2

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

COL4A4,COL4A3,COL4A2,SERPING1,F2R

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

NMNAT3,ENPP1,NADK,AOX1,NNMT

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_ANTIGEN_PROCESSING_AND_PRESENTATION | 89 | 6 | 3.4 | 0 | 0.0063
BIOCARTA_NKCELLS_PATHWAY | 20 | 3 | 4.4 | 0.0003 | 0.057
KEGG_CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION | 267 | 7 | 1.9 | 0.0025 | 0.16
KEGG_NATURAL_KILLER_CELL_MEDIATED_CYTOTOXICITY | 137 | 5 | 2.4 | 0.0023 | 0.16
KEGG_GRAFT_VERSUS_HOST_DISEASE | 42 | 3 | 3.5 | 0.0022 | 0.16

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

KLRC2,KLRC3,CD8A,PSME1,KLRC1,HLA-DRA

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

KLRC2,KLRC3,KLRC1

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

FAS,ENC1,CD27,IL15,EDA,CCL4,CXCL13

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

KLRC2,KLRC3,CD48,FAS,KLRC1

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

FAS,KLRC1,HLA-DRA

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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