Association of mutation, copy number alteration, and subtype markers with pathways
Ovarian Serous Cystadenocarcinoma (Primary solid tumor)
15 January 2014  |  analyses__2014_01_15
Maintainer Information
Citation Information
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/C1S46QDX
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_TEL_PATHWAY 18 4 4.3 0 0.013
BIOCARTA_MTOR_PATHWAY 23 4 4 0.0001 0.018
BIOCARTA_RACCYCD_PATHWAY 26 4 3.8 0.0002 0.02
KEGG_OOCYTE_MEIOSIS 114 7 2.5 0.0003 0.021
KEGG_SMALL_CELL_LUNG_CANCER 84 6 2.7 0.0003 0.023
List of CNV_Mut genes in this pathway

TP53,AKT1,KRAS,PTEN

List of CNV_Mut genes in this pathway

FKBP1A,PTEN,AKT1,TSC1

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

PTEN,AKT1,CCNE1,MAX,CHUK,TP53

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.

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)