Association of mutation, copy number alteration, and subtype markers with pathways
Ovarian Serous Cystadenocarcinoma (Primary solid tumor)
22 February 2013  |  analyses__2013_02_22
Maintainer Information
Citation Information
doi:10.7908/C1W09440
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/C1W09440
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 254 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

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_RACCYCD_PATHWAY 26 4 3.6 0.0003 0.044
KEGG_UBIQUITIN_MEDIATED_PROTEOLYSIS 137 8 2.3 0.0002 0.044
BIOCARTA_TOLL_PATHWAY 37 4 3.2 0.001 0.12
BIOCARTA_PYK2_PATHWAY 29 3 3.1 0.0047 0.17
BIOCARTA_MAPK_PATHWAY 87 5 2.2 0.0043 0.17
List of CNV_Mut genes in this pathway

CCNE1,CHUK,RB1,IKBKB

List of CNV_Mut genes in this pathway

BTRC,CUL1,UBE2D3,UBOX5,UBE2G2,UBE2M,UBE3C,UBE4A

List of CNV_Mut genes in this pathway

CHUK,MAP2K4,IKBKB,EIF2AK2

List of CNV_Mut genes in this pathway

SRC,MAP2K4,CALM3

List of CNV_Mut genes in this pathway

MAX,MAP3K4,CHUK,MAP2K4,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
KEGG_INSULIN_SIGNALING_PATHWAY 137 24 1 0.0005 0.17
BIOCARTA_RELA_PATHWAY 16 1 -0.49 0.76 1
BIOCARTA_NO1_PATHWAY 31 3 0.19 0.48 1
BIOCARTA_CSK_PATHWAY 24 2 0.05 0.57 1
BIOCARTA_AMI_PATHWAY 20 3 0.78 0.24 1
List of marker genes for gene expression subtype 1 in this pathway

PRKACG,RAPGEF1,BRAF,PTPRF,PIK3CB,SOCS3,KHSRP,PHKA1,G6PC2,MAP2K1,ACACB,RPS6,PTPN1,PRKAG3,SHC3,SHC2,PHKG1,FLOT1,EXOC7,SORBS1,CALML3,PDE3A,LIPE,PYGB

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

RIPK1

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

PRKACG,PDE3A,CHRM1

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

PRKACG,ZAP70

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

F7,PROC,F2

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_ARF_PATHWAY 17 7 2.2 0.0003 0.035
KEGG_MAPK_SIGNALING_PATHWAY 267 41 0.81 0.0002 0.035
KEGG_MELANOGENESIS 102 20 1.2 0.0003 0.035
KEGG_STEROID_BIOSYNTHESIS 17 6 2.1 0.0015 0.087
KEGG_OXIDATIVE_PHOSPHORYLATION 133 20 0.99 0.0016 0.087
List of marker genes for gene expression subtype 2 in this pathway

POLR1A,POLR1C,POLR1B,CDKN2A,RAC1,ABL1,TWIST1

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

MAP3K8,PTPRR,PLA2G2A,IL1R2,CACNB4,KRAS,RAC1,MAP2K1,MAP2K3,PLA2G4A,JMJD7-PLA2G4B,FGF5,FLNC,FLNB,FLNA,MAP3K13,MAP3K11,MKNK2,SOS1,RPS6KA3,DUSP7,FGF19,FGF11,PRKACA,RELA,STK4,STK3,MAP4K4,ARRB2,TRAF2,ATF2,PTPN5,ATF4,CACNA1D,CACNA1B,MAX,PAK1,PRKCA,MAP3K3,RASGRP4,MAPK8IP3

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

ADCY1,ADCY6,MC1R,PRKACA,CREB3L4,WNT5A,KRAS,MAP2K1,PLCB3,PRKCA,LEF1,KIT,TCF7L2,CALML6,GNAO1,CREB3,FZD5,WNT7B,FZD10,WNT7A

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

TM7SF2,GLB1,CEL,CYP51A1,LSS,SC4MOL

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

COX5A,NDUFA4L2,COX8A,PPA1,COX11,ATP6V0D1,ATP6V0D2,ATP5H,COX15,ATP6V1C1,ATP5G2,COX7A2L,NDUFB1,NDUFA8,NDUFA1,SDHA,SDHB,ATP6V1E2,SDHD,ATP6V0A1

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_BCR_PATHWAY 35 7 1.2 0.022 0.7
BIOCARTA_FMLP_PATHWAY 37 8 1.4 0.0094 0.7
BIOCARTA_EDG1_PATHWAY 27 6 1.4 0.023 0.7
BIOCARTA_GPCR_PATHWAY 35 7 1.2 0.022 0.7
BIOCARTA_IGF1MTOR_PATHWAY 20 5 1.5 0.023 0.7
List of marker genes for gene expression subtype 3 in this pathway

BTK,FOS,RAC1,PPP3CB,PPP3CC,SHC1,CALM2

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

GNA15,RAC1,PPP3CB,PPP3CC,PLCB1,NCF2,GNGT1,CALM2

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

PDGFA,GNAI1,AKT1,RAC1,PLCB1,GNGT1

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

GNAI1,FOS,PPP3CB,PPP3CC,GNGT1,GNAQ,CALM2

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

INPPL1,RPS6,PTEN,AKT1,EIF2B5

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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