Association of mutation, copy number alteration, and subtype markers with pathways
Breast Invasive Carcinoma (Primary solid tumor)
23 May 2013  |  analyses__2013_05_23
Maintainer Information
Citation Information
doi:10.7908/C1WM1BHK
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/C1WM1BHK
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 70 genes with significant mutation (Q value <= 0.1) and 213 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 :

41 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 7 4.3 0 0
BIOCARTA_PTEN_PATHWAY 18 6 4.6 0 0
KEGG_ENDOMETRIAL_CANCER 52 8 3.5 0 0
KEGG_PROSTATE_CANCER 89 10 3.1 0 0
KEGG_CHRONIC_MYELOID_LEUKEMIA 73 9 3.2 0 0
List of CNV_Mut genes in this pathway

AKT1,PIK3CA,PIK3R1,TFDP1,RB1,CDKN1B,IKBKB

List of CNV_Mut genes in this pathway

FOXO3,PTEN,AKT1,CDKN1B,PIK3CA,PIK3R1

List of CNV_Mut genes in this pathway

FOXO3,PTEN,AKT1,PIK3CA,TP53,ERBB2,CDH1,PIK3R1

List of CNV_Mut genes in this pathway

PTEN,AKT1,PIK3CA,TP53,RB1,FGFR2,ERBB2,PIK3R1,CDKN1B,IKBKB

List of CNV_Mut genes in this pathway

AKT1,GAB2,PIK3CA,TP53,RB1,RUNX1,PIK3R1,CDKN1B,IKBKB

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
BIOCARTA_CYTOKINE_PATHWAY 21 6 1.7 0.0076 0.2
BIOCARTA_HIVNEF_PATHWAY 56 11 1.1 0.0083 0.2
BIOCARTA_MAPK_PATHWAY 87 15 0.94 0.0081 0.2
BIOCARTA_TALL1_PATHWAY 15 5 1.9 0.0072 0.2
KEGG_GLYCEROLIPID_METABOLISM 49 11 1.3 0.0029 0.2
List of marker genes for gene expression subtype 1 in this pathway

IL3,IL8,IL15,IL17A,IFNB1,LTA

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

NFKB1,MAP3K5,CASP9,DFFB,CYCS,MAP3K14,TRAF1,TRAF2,NUMA1,RASA1,PARP1

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

NFKB1,MAX,MAP3K5,MAP4K5,MAPK4,MAP3K14,MAP3K12,TRAF2,GRB2,ELK1,MAP4K1,CEBPA,TGFBR1,MEF2D,MAPK13

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

TRAF2,TNFRSF13B,NFKB1,MAP3K14,TRAF5

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

AGPAT6,AGPAT3,AGPAT1,PPAP2C,GALK2,DGKA,AGK,LCP1,DGKQ,DGKH,DGKZ

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_PURINE_METABOLISM 158 26 0.91 0.001 0.33
KEGG_LYSOSOME 121 20 0.93 0.0031 0.34
KEGG_ENDOCYTOSIS 183 27 0.79 0.0027 0.34
KEGG_SPLICEOSOME 126 19 0.94 0.0043 0.36
KEGG_HUNTINGTONS_DISEASE 183 25 0.75 0.0058 0.38
List of marker genes for gene expression subtype 2 in this pathway

ADCY4,SLC25A16,ADCY2,PDE3B,POLE,PDE4D,PRPS1,POLE2,ENTPD3,ENTPD2,GUCY2F,AK1,AK2,GUCY2C,PDE6G,NT5M,ADCY10,NT5E,IMPDH1,PDE10A,GUCY1B3,POLR2C,POLR3A,POLR3C,APRT,AMPD1

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

HGSNAT,AP4M1,NPC2,ACP5,CTSL1,SLC11A1,LAPTM5,CLTCL1,CLTA,AP1S3,AP1S1,CD164,DNASE2B,CTSE,AP1M1,PSAPL1,NAGPA,AP3M2,AP4S1,GGA1

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

STAM,HLA-A,FGFR4,STAM2,ADRBK2,ADRBK1,CHMP2B,EGF,IQSEC2,GIT1,PARD6A,EPS15,CBLC,HGS,CLTCL1,CLTA,IL8RA,IL8RB,AGAP2,RAB11FIP4,EPN2,EHD3,DNM3,VTA1,ARAP3,DNM1,ARAP1

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

CHERP,SNRPD2,SFRS7,PQBP1,LSM4,SFRS2,AQR,SNRPB2,ISY1,DHX8,DDX5,PLRG1,PRPF4,THOC2,THOC1,TRA2A,SF3B4,SF3B3,SYF2

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

TBP,COX5B,BDNF,CREB3L3,DCTN1,COX6B1,CREBBP,NDUFV3,NFE2L1,CLTCL1,CLTA,PPARG,UQCRFS1,CASP3,CASP9,ATP5H,NDUFS1,UQCRB,NDUFB8,NDUFB9,DNAH1,POLR2C,NDUFB1,SOD1,SDHD

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_WNT_SIGNALING_PATHWAY 151 29 1.1 0 0.0095
KEGG_MISMATCH_REPAIR 23 9 2.2 0.0001 0.011
KEGG_ENDOCYTOSIS 183 31 0.98 0.0001 0.014
KEGG_ADHERENS_JUNCTION 75 16 1.3 0.0004 0.032
KEGG_VEGF_SIGNALING_PATHWAY 76 16 1.3 0.0006 0.035
List of marker genes for gene expression subtype 3 in this pathway

PPP2R5C,CTNNB1,MAP3K7,WNT4,PRKACB,CUL1,WNT10B,CHP2,WNT5A,DAAM1,CACYBP,AXIN1,SMAD4,PLCB1,PPP2R1A,SIAH1,RUVBL1,NKD1,WNT16,APC2,NFAT5,PPP3CC,PPP3CA,NFATC2,CAMK2A,FZD8,GPI,FZD5,TBL1Y

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

SSBP1,LIG1,POLD3,RFC5,RFC4,RFC1,POLD1,POLD2,PMS2

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

CHMP4A,CHMP6,HLA-C,ARFGAP3,ARFGAP2,STAM2,ASAP3,SRC,CHMP2B,ADRB3,SNF8,TRAF6,IQSEC1,KDR,CBLC,NEDD4,SMURF2,PARD6G,SMURF1,PIP4K2B,LDLR,CDC42,UNC45A,CXCR4,EPN2,FLT1,AP2A2,RAB31,VPS24,DNM2,F2R

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

WASF2,LMO7,VCL,CTNNB1,MAP3K7,CDC42,INSR,PTPRJ,PTPRM,ACTN4,ACTN3,ERBB2,SRC,GPI,SMAD4,TJP1

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

CDC42,AKT2,CHP2,SH2D2A,PLA2G6,PLA2G5,SRC,PXN,JMJD7-PLA2G4B,NFAT5,PPP3CC,PPP3CA,NFATC2,PIK3R2,KDR,MAPK13

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)
Copyright © 2013 Broad Institute TCGA GDAC as part of the TCGA Research Network. All rights reserved.
Made with Nozzle