Ovarian Serous Cystadenocarcinoma: Association of mutation, copy number alteration, and subtype markers with pathways
Maintained by Spring Yingchun Liu (Broad 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 9 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
--- | --- | --- | --- | --- | ---
KEGG_UBIQUITIN_MEDIATED_PROTEOLYSIS | 137 | 8 | 2.4 | 0.0001 | 0.047
KEGG_RNA_DEGRADATION | 55 | 5 | 3 | 0.0004 | 0.066
BIOCARTA_CHREBP2_PATHWAY | 44 | 4 | 3.1 | 0.0013 | 0.086
BIOCARTA_TEL_PATHWAY | 18 | 3 | 3.9 | 0.001 | 0.086
BIOCARTA_TOLL_PATHWAY | 37 | 4 | 3.2 | 0.0008 | 0.086

List of CNV_Mut genes in this pathway

BTRC,CUL1,UBE2D3,UBOX5,BRCA1,UBE2G2,UBE3C,UBE4A

List of CNV_Mut genes in this pathway

DCPS,EXOSC2,EXOSC1,DCP1B,DCP1A

List of CNV_Mut genes in this pathway

PRKAG2,PPP2R2D,PPP2R5E,PPP2R2A

List of CNV_Mut genes in this pathway

RB1,KRAS,PTEN

List of CNV_Mut genes in this pathway

CHUK,MAP2K4,IKBKB,EIF2AK2

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_MAPK_PATHWAY | 87 | 17 | 1.2 | 0.001 | 0.18
KEGG_ADHERENS_JUNCTION | 75 | 15 | 1.2 | 0.0011 | 0.18
KEGG_FRUCTOSE_AND_MANNOSE_METABOLISM | 34 | 9 | 1.6 | 0.0017 | 0.19
BIOCARTA_ETS_PATHWAY | 18 | 6 | 1.9 | 0.0029 | 0.24
BIOCARTA_CARM_ER_PATHWAY | 35 | 8 | 1.4 | 0.0067 | 0.25

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

MEF2A,TGFB2,FOS,MAP3K8,MAP4K3,RIPK1,MAPK7,MAP3K13,MAP3K12,TRAF2,MAP3K2,RAC1,MAP2K1,MAPK10,MEF2D,RPS6KA3,RPS6KA4

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

WASF3,CTNNB1,RHOA,ACTN1,PARD3,ERBB2,PVRL1,SORBS1,RAC1,YES1,MLLT4,PTPRB,PTPN6,TCF7,SNAI1

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

ALDOA,SORD,PFKFB4,HK2,MTMR2,MTMR6,KHSRP,AKR1B1,FPGT

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

RBL1,HDAC5,FOS,SIN3A,ETS2,DDX20

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

ERCC3,NR0B1,PPARGC1A,HDAC5,HDAC4,PHB2,CARM1,HDAC6

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_RIBOSOME | 87 | 19 | 1.3 | 0.0001 | 0.032
KEGG_MAPK_SIGNALING_PATHWAY | 267 | 39 | 0.75 | 0.0006 | 0.095
KEGG_ADHERENS_JUNCTION | 75 | 15 | 1.2 | 0.0011 | 0.095
KEGG_T_CELL_RECEPTOR_SIGNALING_PATHWAY | 108 | 19 | 1 | 0.0017 | 0.095
KEGG_ALZHEIMERS_DISEASE | 167 | 25 | 0.88 | 0.0015 | 0.095

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

RPL36AL,RPL14,RPL13,RPS27L,FAU,RPS18,RPS13,RPS10,RPL35,RPL27A,RPL10L,RPS27,RPS28,RPL10A,RPSA,RPL24,RPS6,MRPL23,RPL18A

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

MEF2C,JUN,PLA2G2E,HSPA1A,DUSP14,TGFBR1,TAOK3,MAP2K4,FGF6,NFKB1,NFKB2,MYC,CACNG4,FLNB,GADD45G,MAP3K12,MKNK2,PPP3CB,RPS6KA4,TGFB1,RELA,STK4,ARRB2,ARRB1,TRAF2,ELK1,CACNA2D1,NR4A1,CACNA2D4,ATF4,CACNA1F,CACNA1D,CHUK,AKT2,PPM1B,RASGRP4,RASGRP1,MAPK8IP2,MAPK8IP3

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

LMO7,FER,VCL,CSNK2A2,CSNK2A1,RHOA,ACTN4,CTNNA3,EP300,PARD3,CTNND1,PVRL4,IGF1R,TGFBR1,PTPN1

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

BCL10,RELA,JUN,VAV3,CBLC,NFKB1,PDCD1,PAK6,PAK4,RHOA,CHUK,AKT2,DLG1,RASGRP1,PPP3CB,PIK3R3,CD28,NFATC1,IL4

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

SNCA,RYR3,EIF2AK3,NDUFA4L2,NDUFV3,NDUFV2,CACNA1F,CACNA1D,UQCRC1,UQCRFS1,NDUFB10,CYCS,NDUFC2,COX4I1,NDUFB4,NDUFB7,NDUFB9,ATP5G1,PPP3CB,CALML6,NDUFA3,CAPN1,NCSTN,SDHD,APBB1

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 | 38 | 0.7 | 0.0012 | 0.4
KEGG_PYRIMIDINE_METABOLISM | 98 | 17 | 1 | 0.0029 | 0.48
KEGG_PURINE_METABOLISM | 158 | 23 | 0.75 | 0.0069 | 0.6
KEGG_TYROSINE_METABOLISM | 42 | 9 | 1.3 | 0.0073 | 0.6
BIOCARTA_GH_PATHWAY | 28 | 6 | 1.3 | 0.027 | 0.78

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

GRIN3B,LTB4R,GRIN2C,CHRNA4,CHRNA2,HTR6,GH1,CHRNB2,CHRNE,CHRNG,CCKAR,MCHR2,NMUR1,GRM3,NPY2R,NPFFR2,MAS1,PLG,P2RY10,HTR2C,F2RL2,GRIK5,VIPR1,GHRHR,SCTR,GALR3,GALR2,NTSR1,NTSR2,CYSLTR1,DRD3,DRD4,GABRE,GRIN1,ADRA1B,CHRM5,OXTR,CHRNA10

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

NP,NME4,NME5,POLE4,POLE2,ENTPD8,ENTPD6,UPB1,POLD1,TXNRD2,POLR2K,UPP1,POLR2B,TYMS,DCTD,POLR3G,POLR3B

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

ADCY8,NP,NME4,NME5,PDE5A,PDE6A,POLE4,POLE2,ENTPD8,ENTPD6,ENTPD2,GUCY2C,POLD1,GUK1,IMPDH1,PDE9A,POLR2K,POLR2B,PDE1B,POLR3G,NPR2,POLR3B,PDE2A

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

TH,ADH1C,ADH6,COMT,THPO,GSTZ1,HEMK1,METTL2B,AOC2

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

HNF1A,PIK3CA,PRKCA,MAPK1,GH1,JAK2

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.

- 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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