Association of mutation, copy number alteration, and subtype markers with pathways
Ovarian Serous Cystadenocarcinoma (Primary solid tumor)
16 April 2014 | analyses__2014_04_16
Maintainer Information
Citation Information
doi:10.7908/C1TX3D2T
Maintained by Spring Yingchun Liu (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2014): Association of mutation, copy number alteration, and subtype markers with pathways. Broad Institute of MIT and Harvard. doi:10.7908/C1TX3D2T
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 231 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 | 3.8 | 0.0002 | 0.042
KEGG_OOCYTE_MEIOSIS | 114 | 7 | 2.5 | 0.0003 | 0.042
KEGG_MAPK_SIGNALING_PATHWAY | 267 | 10 | 1.8 | 0.0008 | 0.043
KEGG_UBIQUITIN_MEDIATED_PROTEOLYSIS | 137 | 7 | 2.2 | 0.0007 | 0.043
KEGG_NEUROTROPHIN_SIGNALING_PATHWAY | 126 | 7 | 2.3 | 0.0005 | 0.043

List of CNV_Mut genes in this pathway

AKT1,CCNE1,RAC1,CHUK

List of CNV_Mut genes in this pathway

BTRC,CUL1,ANAPC2,PPP2R5E,CCNE1,YWHAQ,CALM3

List of CNV_Mut genes in this pathway

MAP3K4,KRAS,RAC1,MAP2K4,TP53,GNA12,PPP5C,AKT1,MAX,CHUK

List of CNV_Mut genes in this pathway

BTRC,CUL1,ANAPC2,UBOX5,UBE2G2,UBE2M,UBE3C

List of CNV_Mut genes in this pathway

NFKBIB,KRAS,RAC1,AKT1,TP53,YWHAQ,CALM3

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_AMI_PATHWAY | 20 | 6 | 1.8 | 0.0047 | 0.52
BIOCARTA_INTRINSIC_PATHWAY | 23 | 7 | 1.8 | 0.0021 | 0.52
KEGG_COMPLEMENT_AND_COAGULATION_CASCADES | 69 | 13 | 1.1 | 0.0043 | 0.52
KEGG_RIBOSOME | 87 | 14 | 0.91 | 0.012 | 0.97
BIOCARTA_RELA_PATHWAY | 16 | 0 | 0 | 1 | 1

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

F7,PROC,FGG,FGA,F2,SERPINC1

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

F11,KNG1,PROC,FGG,FGA,F2,SERPINC1

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

CD46,CFD,KNG1,F11,F7,PROC,SERPINF2,F2,MBL2,FGG,FGA,SERPINC1,VWF

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

RPL14,RPS27A,RPS16,RPS17,RPL3L,RPL27A,RPL30,RPS28,RPL6,RPL5,RPL26,RPL23A,RPS7,RPL29

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

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_ADHERENS_JUNCTION | 75 | 17 | 1.4 | 0.0001 | 0.037
KEGG_RIBOFLAVIN_METABOLISM | 16 | 6 | 2.1 | 0.0015 | 0.17
KEGG_ALZHEIMERS_DISEASE | 167 | 25 | 0.89 | 0.0015 | 0.17
BIOCARTA_MAPK_PATHWAY | 87 | 16 | 1.1 | 0.0027 | 0.22
BIOCARTA_CARM_ER_PATHWAY | 35 | 8 | 1.4 | 0.0068 | 0.32

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

WASF3,VCL,CTNNB1,CTNNA3,PARD3,ERBB2,CDH1,ACP1,TCF7L2,PVRL1,SORBS1,RAC1,YES1,MLLT4,PTPRB,GPI,SNAI1

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

ENPP3,ACP1,ACPP,MTMR2,MTMR6,PHPT1

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

COX5A,EIF2AK3,NDUFA4L2,ATP2A3,NDUFV1,CACNA1D,ATP5D,UQCRQ,NDUFS6,CASP9,ADAM10,ERN1,NDUFB9,PPP3R1,ATP5G2,NDUFB1,NDUFB2,NOS1,NDUFA3,NDUFA8,CAPN2,NDUFA1,SDHA,LRP1,SDHD

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

MEF2A,TGFB2,MAX,MAP3K8,MAP4K3,MAPK4,RIPK1,MAP3K13,MAP3K12,MAP3K3,MAP3K2,RAC1,MAP2K4,RPS6KA3,RPS6KA4,MAPK13

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

TBP,GTF2A1,NR0B1,HIST2H3C,HDAC4,PHB2,CARM1,HDAC6

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_MATURITY_ONSET_DIABETES_OF_THE_YOUNG | 25 | 9 | 2 | 0.0001 | 0.029
KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION | 272 | 40 | 0.77 | 0.0003 | 0.04
KEGG_GLYCEROLIPID_METABOLISM | 49 | 12 | 1.5 | 0.0006 | 0.047
BIOCARTA_CERAMIDE_PATHWAY | 22 | 7 | 1.9 | 0.0017 | 0.093
KEGG_PRION_DISEASES | 35 | 9 | 1.6 | 0.002 | 0.093

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

ONECUT1,PAX4,BHLHA15,SLC2A2,HES1,HHEX,GCK,HNF4A,PKLR

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

GRIN2D,HTR4,LPAR6,HTR6,PTH2R,GH2,CHRNB4,UTS2R,GLRA3,KISS1R,NMUR1,GHR,GRM5,GRIA3,GRIA1,GABRB2,GRIK3,GABRB1,GHRHR,GALR1,GALR3,NTSR2,DRD1,CNR1,GABRP,GABRD,GRIN1,P2RX4,P2RX1,P2RX2,TACR1,GABBR1,CALCRL,PTGER1,PTGER2,PTGER4,FSHR,CHRM3,CTSG,CALCR

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

DAK,LCLAT1,GALK2,DGKB,DGKQ,AWAT2,GLA,MBOAT1,MBOAT2,DGKZ,GCK,LIPC

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

MAP2K1,MAP2K4,NFKB1,FADD,BAD,TNFRSF1A,BAX

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

ELK1,HSPA1A,IL1A,MAP2K1,SOD1,C8B,NOTCH1,FYN,BAX

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

In addition to the links below, the full results of the analysis summarized in this report can also be downloaded programmatically using firehose_get, or interactively from either the Broad GDAC website or TCGA Data Coordination Center Portal.

- Analysis Results (MD5 checksum)

- Auxiliary Data (MD5 checksum)

- MAGE-TAB File (MD5 checksum)

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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