Association of mutation, copy number alteration, and subtype markers with pathways
Kidney Renal Clear Cell Carcinoma (Primary solid tumor)
23 May 2013  |  analyses__2013_05_23
Maintainer Information
Citation Information
doi:10.7908/C1C8279X
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/C1C8279X
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 9 genes with significant mutation (Q value <= 0.1) and 503 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 :

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

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

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

6 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_ENDOMETRIAL_CANCER 52 8 2.6 0 0.012
BIOCARTA_CHEMICAL_PATHWAY 22 5 3.2 0.0002 0.013
BIOCARTA_IGF1MTOR_PATHWAY 20 5 3.4 0.0001 0.013
KEGG_NOTCH_SIGNALING_PATHWAY 47 7 2.6 0.0001 0.013
KEGG_SPLICEOSOME 126 10 1.8 0.0005 0.03
List of CNV_Mut genes in this pathway

MLH1,PTEN,AKT1,CASP9,PIK3CD,TP53,GRB2,GSK3B

List of CNV_Mut genes in this pathway

TP53,AKT1,CASP9,EIF2S1,PARP1

List of CNV_Mut genes in this pathway

RPS6KB1,PTEN,AKT1,GSK3B,EIF2S1

List of CNV_Mut genes in this pathway

NUMB,DLL1,SNW1,DVL1,NCSTN,NOTCH2,HDAC2

List of CNV_Mut genes in this pathway

RBM8A,SLU7,SNRPE,CCDC12,CDC40,DHX8,SNW1,DDX5,EIF4A3,SYF2

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_SPLICEOSOME 126 24 1.3 0 0.0029
KEGG_ENDOCYTOSIS 183 33 1.1 0 0.0029
KEGG_CHEMOKINE_SIGNALING_PATHWAY 190 33 0.99 0.0001 0.0042
KEGG_PATHWAYS_IN_CANCER 328 48 0.74 0.0002 0.0095
KEGG_B_CELL_RECEPTOR_SIGNALING_PATHWAY 75 16 1.3 0.0007 0.021
List of marker genes for gene expression subtype 1 in this pathway

NCBP2,NCBP1,SNRPD2,CTNNBL1,DDX23,DHX38,U2AF1,SNRPA1,HNRNPU,SNRPB,HNRNPM,PRPF40A,PPIE,BUD31,PRPF6,SNRNP200,THOC2,PRPF38B,TRA2B,SF3B5,SF3B3,PRPF19,SF3A3,RBM17

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

DAB2,ITCH,PLD2,PSD4,HLA-E,HLA-G,ACAP1,FGFR4,FGFR3,ERBB4,ASAP1,ADRBK1,EGF,IQSEC3,KDR,GRK7,PARD6G,PIP4K2B,CLTA,VPS37A,BRD8,CXCR4,AGAP1,RAB11FIP5,SH3KBP1,KIT,SH3GLB2,SH3GLB1,VPS36,DNM3,CBL,AP2A1,ARAP2

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

ADCY3,ADCY4,FOXO3,GNG7,BRAF,NCF1,ROCK2,PIK3CD,ADRBK1,CX3CL1,RAC2,VAV1,CXCL14,CXCL13,GRK7,XCL2,NFKB1,PLCB3,CXCR4,RHOA,PLCB2,AKT3,LYN,GNB1,GNB4,CXCL2,GNG12,ENC1,SOS2,PIK3R1,STAT3,CCL17,JAK3

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

BRAF,RXRA,PIK3CD,LAMC1,LAMB2,RAC2,RAC3,BMP2,HGF,DVL1,LAMA4,MITF,SPI1,NFKB1,GLI1,MYC,CTBP2,KIT,SOS2,FZD1,STAT3,FGF18,TGFB3,FGF13,CDKN2B,RALB,STK4,EP300,HIF1A,TRAF2,FGFR3,RBX1,EGF,HDAC1,PLCG1,RHOA,TPR,AKT3,CDK6,RB1,DAPK1,CKS1B,TCF7L2,TPM3,PIK3R1,MSH2,CBL,HSP90B1

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

NFKB1,AKT3,LYN,PIK3CD,CARD11,CD72,RAC2,DAPP1,RASGRP3,RAC3,SOS2,CHP,PIK3R1,CR2,MALT1,VAV1

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_SPLICEOSOME 126 24 1.3 0 0.0089
KEGG_GLYOXYLATE_AND_DICARBOXYLATE_METABOLISM 16 6 2.1 0.0015 0.12
KEGG_ADHERENS_JUNCTION 75 15 1.2 0.0012 0.12
KEGG_HUNTINGTONS_DISEASE 183 27 0.86 0.0013 0.12
KEGG_LEUKOCYTE_TRANSENDOTHELIAL_MIGRATION 118 20 0.98 0.002 0.13
List of marker genes for gene expression subtype 2 in this pathway

LSM7,SNRPD2,SMNDC1,RBM8A,LSM5,U2AF1,SNRPB,HNRNPC,CCDC12,HSPA1L,HNRNPM,HNRNPK,DDX5,MAGOHB,PRPF3,SNRNP200,PRPF38B,TRA2B,SF3B3,PRPF19,SF3B1,DHX15,RBM25,RBM17

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

CS,MTHFD1L,HYI,GLYCTK,MTHFD1,PGPEP1

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

WASF2,CSNK2A2,EGFR,PTPRM,ACTN4,CTNNA2,EP300,CTNND1,ACP1,TCF7L2,PVRL4,YES1,CREBBP,CSNK2B,TJP1

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

TBP,COX5A,COX5B,CREB3L3,TAF4B,POLR2J2,EP300,COX6B2,HIP1,NDUFA4L2,CREBBP,COX8A,HDAC1,CLTB,UQCRC1,UQCRQ,SLC25A5,CYCS,COX4I2,COX4I1,POLR2J,ATP5G1,DNAH2,NDUFA9,CREB1,SOD1,AP2A2

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

ACTN4,ROCK2,CTNNA2,MYL5,GNAI2,ITGB1,PTK2,ITGA4,CLDN7,CXCR4,ESAM,MSN,CLDN2,CTNND1,CLDN10,CLDN11,VCAM1,EZR,PTK2B,MAPK14

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_HEMATOPOIETIC_CELL_LINEAGE 88 24 1.7 0 0
KEGG_CELL_CYCLE 128 28 1.3 0 0.0003
KEGG_PATHOGENIC_ESCHERICHIA_COLI_INFECTION 59 17 1.8 0 0.0003
BIOCARTA_MCM_PATHWAY 18 9 2.5 0 0.0005
KEGG_NOD_LIKE_RECEPTOR_SIGNALING_PATHWAY 62 16 1.5 0.0001 0.0039
List of marker genes for gene expression subtype 3 in this pathway

GYPA,CD44,IL4R,CSF3R,CD3G,IL11RA,CD36,IL1R2,CSF2,CSF1,KIT,ITGAM,CD9,FCGR1A,CD2,CD4,CD5,CD7,IL6,IL2RA,ITGA3,CD19,ITGA5,CD14

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

PTTG2,TGFB1,CCNA2,ESPL1,SKP1,ORC1L,ANAPC13,SMAD4,CDC20,CDC26,MAD1L1,CDC14A,CDC14B,CCNE1,CDC45L,CDC7,CDC6,CDC2,MCM2,MCM4,MCM5,MCM6,CDC25C,YWHAE,CDC25B,CCNB1,CCNB2,ORC3L

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

OCLN,TLR5,CTNNB1,RHOA,TUBB6,TUBA1A,TUBA1B,TUBB3,LY96,WAS,ARPC1B,WASL,ARPC5,ARPC2,TUBA3C,TUBA3D,CD14

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

CDC6,MCM2,MCM4,MCM5,ORC1L,MCM6,CDT1,CCNE1,ORC3L

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

CASP5,NLRC4,NOD2,CASP8,HSP90AA1,MAPK8,CCL5,PYDC1,PYCARD,PSTPIP1,TRAF6,IL6,CARD9,BIRC3,HSP90B1,TRIP6

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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