Ovarian Serous Cystadenocarcinoma: Association of mutation, copy number alteration, and subtype markers with pathways
Maintained by Spring Yingchun Liu (Dana-Farber Cancer Institute)
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 20 genes with significant mutation (Q value <= 0.1) and 187 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.

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

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

18 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 0.038
BIOCARTA_CHREBP2_PATHWAY 44 4 3.3 0.0008 0.042
BIOCARTA_TEL_PATHWAY 18 3 4.1 0.0007 0.042
BIOCARTA_ARF_PATHWAY 17 3 4.2 0.0006 0.042
KEGG_PANCREATIC_CANCER 70 5 2.8 0.0006 0.042
List of CNV_Mut genes in this pathway

AKT1,CCNE1,RAC1,RB1

List of CNV_Mut genes in this pathway

PPP2R5D,YWHAQ,PPP2R5E,PPP2R2A

List of CNV_Mut genes in this pathway

RB1,AKT1,KRAS

List of CNV_Mut genes in this pathway

POLR1C,RB1,RAC1

List of CNV_Mut genes in this pathway

AKT1,RB1,KRAS,RAC1,BRCA2

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 56 1.2 0 0
BIOCARTA_MAPK_PATHWAY 87 20 1.3 0.0001 0.004
KEGG_MAPK_SIGNALING_PATHWAY 267 44 0.87 0 0.004
KEGG_WNT_SIGNALING_PATHWAY 151 28 1 0.0001 0.0065
KEGG_ENDOCYTOSIS 183 31 0.94 0.0002 0.0077
List of marker genes for gene expression subtype 1 in this pathway

ADORA3,S1PR2,HTR1A,CHRNA9,GRIN2D,HTR1D,CHRNA2,SSTR4,HTR7,MC2R,PPYR1,HCRTR1,ADRB3,PTH2R,GH2,GLRA1,GLRA2,HTR5A,GRM1,GRM4,GRM8,NPFFR1,MC3R,OPRL1,GRIA4,PLG,GRIA2,HTR2C,F2RL3,GRIK1,GRIK3,GABRB1,GHRHR,GALR2,GLP1R,ADCYAP1R1,DRD5,P2RY6,GABRA2,GABRA1,GABRA4,GABRA3,GRIN1,GPR35,P2RX6,P2RX2,ADRA1B,ADRA1D,GABRG2,FSHR,CHRM5,FSHB,TSHB,PRLR,MLNR,OPRD1

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

MEF2A,DAXX,PAK1,RAPGEF2,MAP2K7,MAP2K6,MAP2K5,BRAF,MAP4K3,MAPK1,MAPK6,MAPK4,MAP3K10,MAP3K13,MKNK2,MAPKAPK3,ELK1,MAP4K1,MAP3K3,PSG1

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

MOS,RAPGEF2,MAP2K7,MAP2K6,MAP2K5,BRAF,MAPK1,PLA2G2A,CACNB1,HSPA1A,HSPA1L,RAC3,TAOK2,FGF5,DAXX,MAPT,MAP3K13,GADD45A,MKNK2,CHP,RASA1,DUSP4,FGF14,FGF12,RRAS,FGF22,DDIT3,MAP4K3,STMN1,MAPKAPK3,MAP4K1,ELK1,CACNA2D1,CACNA1I,NR4A1,CACNA2D2,RAP1A,CACNA1A,PAK1,AKT2,TNFRSF1A,HSPA2,MAP3K3,HSPA6

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

PPP2R5B,PPP2R5A,WNT2,WNT1,WNT3,WNT10B,RAC3,DVL2,SFRP1,RHOA,FRAT2,PLCB1,CTBP2,SUMO1,WNT16,APC2,CHP,NFATC3,CAMK2A,APC,CSNK1A1,FZD9,FZD3,FZD7,DKK4,DKK1,LRP6,LRP5

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

HLA-C,HLA-F,ERBB4,HSPA1A,CHMP2B,HSPA1L,ADRB3,IQSEC1,AP2M1,IQSEC2,PARD6A,GRK4,SMURF2,CLTA,LDLR,RAB5C,IL8RA,PIP5K1C,PIP5K1A,RAB5A,EPN1,HSPA2,HSPA6,IL2RG,EHD1,DNM3,IL2RA,DNM1L,ARAP2,DNM1,RNF41

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_OXIDATIVE_PHOSPHORYLATION 133 28 1.5 0 0
KEGG_ENDOCYTOSIS 183 39 1.3 0 0
KEGG_ALZHEIMERS_DISEASE 167 32 1.2 0 0.0002
KEGG_SPLICEOSOME 126 25 1.3 0 0.0004
KEGG_LYSOSOME 121 26 1.3 0 0.0004
List of marker genes for gene expression subtype 2 in this pathway

ATP6AP1,NDUFAB1,ATP6V1B1,COX8A,PPA1,NDUFV2,COX11,UQCRC1,UQCRFS1,UQCRQ,NDUFS3,NDUFS2,ATP5H,COX17,NDUFC2,COX4I1,ATP6V1F,NDUFB3,NDUFB5,NDUFB6,NDUFB7,ATP5G3,NDUFB1,ATP5F1,SDHA,SDHB,ATP6V0A1,ATP5A1

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

CHMP5,VPS4B,ITCH,ARRB2,PDCD6IP,CHMP2A,ARFGAP3,ARFGAP2,STAM2,ADRBK2,HSPA1A,ARF6,TRAF6,PARD6A,PARD6B,CBLC,CBLB,GRK6,SMURF1,CLTB,IL8RB,AP2B1,UNC45A,AGAP1,LDLRAP1,RAB11FIP5,RAB11FIP3,EPN2,PARD3,USP8,IGF1R,HSPA6,RAB11A,EHD3,EHD4,FAM125B,DNM1L,DNM1,RNF41

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

SNCA,NDUFAB1,FAS,HSD17B10,COX8A,NDUFV2,UQCRC1,UQCRFS1,UQCRQ,PLCB3,CASP7,CASP8,NDUFS3,NDUFS2,ATP5H,NDUFC2,COX4I1,NDUFB3,NDUFB5,NDUFB6,NDUFB7,ATP5G3,NDUFB1,TNFRSF1A,PPP3CA,ATP5F1,NAE1,SDHA,SDHB,GSK3B,ATP5A1,CALM1

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

NCBP1,SFRS6,SFRS7,RBM8A,SFRS9,SFRS3,HNRNPC,SNRPF,SNRPE,NHP2L1,HSPA1A,HNRNPM,HNRNPK,RBMX,HNRNPA1,PPIH,CRNKL1,PRPF31,SR140,SF3B5,SF3B3,PRPF8,USP39,HSPA6,RBM25

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

ATP6AP1,NPC1,ACP5,ACP2,CTSA,PPT1,CTSL1,ENTPD4,LAPTM4A,DNASE2,CLTB,ASAH1,TPP1,CTSK,CTSE,CTSC,CTSB,GNPTAB,AP3M2,GBA,CEL,PSAP,GLA,ARSA,ATP6V0A1,GGA2

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_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION 272 63 1.4 0 0
KEGG_PATHWAYS_IN_CANCER 328 57 0.94 0 0.0001
WNT_SIGNALING 89 22 1.4 0 0.0007
KEGG_MAPK_SIGNALING_PATHWAY 267 45 0.89 0 0.0009
KEGG_WNT_SIGNALING_PATHWAY 151 30 1.1 0 0.0009
List of marker genes for gene expression subtype 3 in this pathway

LHCGR,S1PR2,AGTR2,HTR1A,S1PR1,LTB4R,GRIN2C,CHRNA5,GRID2,CHRNA2,HTR1E,HTR4,SSTR5,CRHR2,F2,HCRTR2,CHRNB3,OPRM1,GLRA3,GHR,GRM1,GRM3,GRM2,GRM8,GRM7,NPY2R,NPFFR1,GRIA4,GRIA2,GRIA1,MC4R,THRA,GRIK1,GABRB2,GRIK3,GABRB1,SCTR,GALR3,GALR2,GABRR1,GLP1R,DRD1,DRD2,DRD5,ADRA2A,GABRA1,GABRA4,GABRA3,P2RX7,P2RX6,P2RX2,ADRA1B,ADRA1D,TACR2,GABBR1,PRL,FSHR,FSHB,TSHB,DHX15,GLRB,MLNR,CHRNA10

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

PTGS2,PGF,SHH,CTNNB1,CTNNA3,VEGFB,MAPK1,JUN,LAMC2,LAMB4,KRAS,DVL3,MAP2K1,SMAD2,CBLB,LAMA3,LAMA5,NTRK1,FGF5,MITF,PTEN,FGF3,CTBP1,TFG,FZD9,BIRC5,MAPK10,FZD6,RASSF1,FGF18,CDKN2A,WNT3,RET,FGF21,FGFR2,WNT5A,FGFR1,WNT5B,RBX1,TRAF4,AXIN1,EPAS1,ITGA3,IKBKG,MTOR,HSP90AB1,E2F2,MAX,PAX8,AKT2,PRKCB,CRKL,WNT11,GSTP1,EGLN3,CEBPA,COL4A1

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

CTNNB1,WNT3,AES,FOSL1,CTBP1,CSNK1G1,CTNNBIP1,CCND2,JUN,PYGO1,WNT11,FSHB,WNT5A,WNT5B,HPRT1,T,AXIN1,GPI,FZD6,CSNK1D,WIF1,LRP5

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

MOS,MAP2K7,MAPK1,JUN,PLA2G2A,MAPK7,PLA2G2E,PLA2G2D,CACNB2,KRAS,MAP2K1,TAOK2,PLA2G4A,NTRK1,FGF5,FGF3,ECSIT,FLNA,GADD45G,GADD45A,MAP3K12,MAP3K11,PLA2G12A,PPP3CC,GPI,MAPK10,MAPK13,RPS6KA2,DUSP8,FGF18,FGF21,MAP4K4,RASGRF1,PPP5C,FGFR2,FGFR1,MRAS,MAP4K1,ELK4,IKBKG,CACNA1A,MAX,AKT2,PRKCB,CRKL

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

PPP2R5B,PPP2R5A,CTNNB1,WNT3,JUN,WNT5A,WNT5B,RBX1,AXIN1,DVL3,SMAD2,SFRP5,WIF1,FOSL1,PLCB2,CTBP1,PRKCB,CTNNBIP1,CCND2,WNT11,CER1,PPP3CC,NFATC1,FZD9,GPI,MAPK10,DKK4,FZD6,LRP5,TBL1Y

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)
Meta

  • Maintainer = Spring Yingchun Liu

Copyright © 2011 Broad Institute TCGA GDAC as part of the TCGA Research Network. All rights reserved.
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