Association of mutation, copy number alteration, and subtype markers with pathways
Breast Invasive Carcinoma (Primary solid tumor)
22 February 2013  |  analyses__2013_02_22
Maintainer Information
Citation Information
doi:10.7908/C13R0R14
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/C13R0R14
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 2 genes with significant mutation (Q value <= 0.1) and 196 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.

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

0 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
BIOCARTA_RACCYCD_PATHWAY 26 4 4 0.0001 0.019
BIOCARTA_TNFR1_PATHWAY 29 4 3.9 0.0001 0.019
KEGG_CITRATE_CYCLE_TCA_CYCLE 32 4 3.8 0.0002 0.019
BIOCARTA_CDC42RAC_PATHWAY 16 3 4.3 0.0004 0.032
KEGG_AMINOACYL_TRNA_BIOSYNTHESIS 41 4 3.4 0.0005 0.032
List of CNV_Mut genes in this pathway

PIK3CA,PAK1,TFDP1,IKBKB

List of CNV_Mut genes in this pathway

MAP3K7,PAK1,MAP2K4,RIPK1

List of CNV_Mut genes in this pathway

PDHB,FH,DLAT,SDHD

List of CNV_Mut genes in this pathway

ARPC3,PIK3CA,PAK1

List of CNV_Mut genes in this pathway

TARS2,NARS2,RARS2,CARS2

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_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION 272 40 0.75 0.0005 0.18
KEGG_VIRAL_MYOCARDITIS 73 13 1.1 0.0043 0.72
KEGG_PURINE_METABOLISM 158 22 0.66 0.017 0.79
KEGG_RIBOSOME 87 14 0.89 0.015 0.79
KEGG_SPLICEOSOME 126 18 0.86 0.0097 0.79
List of marker genes for gene expression subtype 1 in this pathway

ADORA3,S1PR1,GRIN2B,LTB4R,S1PR5,GRID1,CRHR1,CRHR2,SSTR1,F2,GPR156,GH2,CHRNB4,CHRNB2,CHRNB1,GPR83,TRPV1,EDNRB,NMUR1,RXFP2,GRM8,GRM7,GRM6,PARD3,NPY2R,FPR1,GHRHR,DRD3,ADORA2A,DRD5,GABRQ,GABRD,GABRA2,GABRA3,P2RX3,CALCRL,PTGER2,CHRM5,PTAFR,DHX8

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

CASP3,CASP9,MYH1,HLA-G,HLA-F,EIF4G3,SGCG,CD40LG,SGCA,CAV1,ITGB2,RAC3,ABL2

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

PDE3B,POLE,PDE4D,POLR2J2,POLE2,ENTPD3,PRPS1L1,ENTPD2,GUCY2C,NT5M,ADCY10,NT5E,IMPDH1,PDE10A,PKM2,GUCY1B3,POLR2E,POLR2C,PDE1B,ATIC,POLR3A,AMPD1

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

RPL18,RPL13,RPL22L1,RPS2,RPL26L1,RPL35A,RPS13,MRPL13,RPL30,RPL5,RPL10A,RPL26,RPS5,RPL22

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

SNRPD2,CTNNBL1,SFRS7,LSM4,SFRS2,AQR,SNRPE,SNRPB2,TCERG1,ISY1,DHX8,SNRNP27,BUD31,PLRG1,THOC2,THOC1,SF3B4,SF3B3

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
BIOCARTA_EIF_PATHWAY 16 6 2.2 0.0011 0.15
KEGG_LYSINE_DEGRADATION 44 11 1.5 0.0008 0.15
KEGG_PROTEASOME 48 10 1.4 0.0037 0.15
KEGG_TGF_BETA_SIGNALING_PATHWAY 86 16 1.1 0.0024 0.15
KEGG_ANTIGEN_PROCESSING_AND_PRESENTATION 89 15 1.1 0.0029 0.15
List of marker genes for gene expression subtype 2 in this pathway

EIF5,EIF4G3,EIF2S1,EIF4A1,EEF2K,EIF1

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

EHHADH,SETD1A,AASS,ACAT1,PLOD2,PLOD3,AASDH,DLST,EHMT2,SETD7,NSD1

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

SHFM1,PSMB11,PSMB5,PSMB3,PSMD3,PSMA1,PSMD13,PSMC4,PSMC1,POMP

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

FST,RHOA,MYC,LEFTY1,ACVR1,TNF,DCN,THBS3,TFDP1,TGFBR1,CREBBP,ID2,BMP7,BMP5,BMP8B,BMP8A

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

KLRC2,RFXAP,HLA-A,HLA-B,HLA-E,HLA-DQA2,HLA-G,HLA-F,KIR2DL4,KIR3DL2,HLA-DQB1,CALR,HSPA4,HSPA5,IFNA14

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_MAPK_SIGNALING_PATHWAY 267 44 0.9 0 0.0037
KEGG_RIBOSOME 87 19 1.3 0.0001 0.011
BIOCARTA_ERK_PATHWAY 28 9 1.9 0.0004 0.011
KEGG_VASCULAR_SMOOTH_MUSCLE_CONTRACTION 115 22 1.1 0.0002 0.011
KEGG_T_CELL_RECEPTOR_SIGNALING_PATHWAY 108 21 1.2 0.0003 0.011
List of marker genes for gene expression subtype 3 in this pathway

PRKX,MAP3K7,MAPKSP1,MAPK1,JUN,PLA2G2E,PLA2G2F,TAOK1,TGFBR1,NTRK1,FGF5,FGF4,CACNG7,CACNG6,MAP3K14,MAP3K12,MKNK2,RPS6KA5,RPS6KA3,MAPK12,ZAK,FGF11,TGFB2,PRKACB,STK3,RASGRF1,FGFR4,GRB2,JUND,PTPN5,NR4A1,CACNA1S,CACNA2D4,PAK2,AKT2,PRKCG,TNF,PPP3R2,TNFRSF1A,HSPA2,RASGRP4,RAF1,MAPK8IP2,MAPK8IP3

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

RPL18,RPL36AL,RPL14,RPL13,RPS3,RPL26L1,FAU,RPS13,RPS11,RPL27A,RPS27,RPL30,RPL32,RPL8,RPS21,RPL23A,RPS5,RPL29,RPL21

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

GRB2,MKNK2,IGF1R,PPP2CA,RAF1,RPS6KA5,MAPK1,GNGT1,GNAS

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

ADCY8,PRKG1,PRKX,PRKACB,ROCK2,MAPK1,PPP1CA,PLA2G2E,PLA2G2F,MYL6,CACNA1S,AVPR1B,AVPR1A,GUCY1A3,KCNMA1,PRKCG,PRKCQ,GNAS,CALML6,CALML5,RAF1,CALM3

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

MAP3K7,MAPK1,JUN,GRB2,NFKBIA,VAV1,CD8B,PAK6,PAK2,AKT2,CARD11,PRKCQ,MAP3K14,LCP2,CSF2,TNF,PPP3R2,NFATC1,CBL,RAF1,MAPK12

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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