Breast Invasive Carcinoma: 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 56 genes with significant mutation (Q value <= 0.1) and 299 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 :

1 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

2 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_SPLICEOSOME 126 13 2.8 0 0
BIOCARTA_RACCYCD_PATHWAY 26 5 3.5 0.0001 0.011
BIOCARTA_CELLCYCLE_PATHWAY 23 4 3.4 0.0005 0.045
KEGG_PROTEIN_EXPORT 24 4 3.4 0.0005 0.045
BIOCARTA_TNFR1_PATHWAY 29 4 3 0.0013 0.088
List of CNV_Mut genes in this pathway

DDX23,SFRS9,SF3B14,EFTUD2,AQR,SNRPE,CDC40,DHX8,SNW1,SF3B3,SF3B1,PRPF18,TXNL4A

List of CNV_Mut genes in this pathway

PIK3CA,TFDP1,RB1,CDKN1B,IKBKB

List of CNV_Mut genes in this pathway

CDK7,RB1,CDKN1B,TFDP1

List of CNV_Mut genes in this pathway

SRP14,SRP54,SEC63,SRPR

List of CNV_Mut genes in this pathway

MAP3K7,MAP2K4,RB1,RIPK1

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_HUNTINGTONS_DISEASE 183 30 1 0.0001 0.034
KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION 272 38 0.69 0.0015 0.17
KEGG_VIRAL_MYOCARDITIS 73 14 1.3 0.0013 0.17
KEGG_PARKINSONS_DISEASE 130 19 0.98 0.0023 0.19
BIOCARTA_MCALPAIN_PATHWAY 25 6 1.5 0.016 0.3
List of marker genes for gene expression subtype 1 in this pathway

NDUFAB1,TBP,COX5B,BDNF,CREB3L3,DCTN1,COX6B1,AP2M1,NDUFV3,NFE2L1,CLTCL1,CLTA,ATP5B,PPARG,UQCRFS1,NDUFS7,GPX1,CASP3,ATP5H,NDUFS1,UQCRB,POLR2E,POLR2C,NDUFB1,NDUFA3,CREB3,IFT57,SDHD,APAF1,ATP5A1

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

ADORA3,LPAR4,HTR1B,AGTR2,S1PR1,LTB4R,GRID1,CRHR1,CRHR2,SSTR3,SSTR1,GPR156,GH2,CHRNB4,CHRNB2,CHRNB1,CHRNE,NMUR1,RXFP2,GRM2,GRM7,GRM6,GIPR,NPY2R,GALR2,DRD3,ADORA2A,GABRQ,GABRD,GABRA2,P2RX3,CALCRL,PTGER2,PTGER4,CHRM5,PTAFR,OXTR,DHX8

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

MYH15,CASP3,MYH1,HLA-A,EIF4G3,SGCG,CD40LG,CAV1,DAG1,ITGB2,RAC3,CD28,MYH11,ABL2

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

NDUFAB1,COX5B,COX6B1,UBE2L3,NDUFV3,ATP5B,UBE2G2,UQCRFS1,NDUFS7,CASP3,ATP5H,NDUFS1,UQCRB,NDUFB1,NDUFA3,SDHD,ATP5A1,APAF1,SLC18A1

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

CXCR3,ITGB1,PRKACG,PRKAR2B,PTK2,EZR

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_HUNTINGTONS_DISEASE 183 31 1 0.0001 0.016
BIOCARTA_MAPK_PATHWAY 87 17 1.2 0.0011 0.058
KEGG_RIBOSOME 87 17 1.2 0.0009 0.058
KEGG_MAPK_SIGNALING_PATHWAY 267 39 0.74 0.0007 0.058
KEGG_PARKINSONS_DISEASE 130 20 1 0.0011 0.058
List of marker genes for gene expression subtype 2 in this pathway

TBP,CREB3L2,TBPL1,DCTN4,APEX1,AP2M1,GRIN1,VDAC3,DNAL1,AP2S1,ATP5B,CLTC,UQCRFS1,NDUFS7,NDUFS4,NDUFB10,NDUFB3,NDUFB4,POLR2G,NDUFB6,POLR2B,NDUFB2,DNAI1,NDUFA4,NDUFA8,CREB1,NDUFA7,ATP5F1,NDUFA1,SDHC,IFT57

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

MAP3K7,MAP3K5,PAK2,MYC,MAPK8,MAP3K14,MAP3K12,GRB2,MKNK2,MAPKAPK3,MAP3K3,TGFBR1,MAP2K3,CREB1,RPS6KA5,RPS6KA3,MAPK12

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

RPL36AL,RPL19,RPL14,RPL13,RPS3,RPL10,RPS13,UBA52,RPL27A,RPS27,RPL30,RPL32,RPL8,RPS21,RPL23A,RPL13A,RPL21

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

PRKX,MAP3K7,MAP3K5,MAPKSP1,MAPK8,PLA2G2E,CACNB3,TAOK1,MAP2K3,TGFBR1,FGF5,MYC,FGF4,CACNG6,CACNG1,MAP3K14,MAP3K12,MKNK2,RPS6KA5,RPS6KA3,MAPK12,ZAK,STK3,RASGRF1,FGFR4,GRB2,MAPKAPK3,CACNA1S,CACNA2D4,IKBKG,PAK2,AKT2,TNF,MAP3K3,RASGRP4,RASGRP1,NF1,MAPK8IP2,MAPK8IP1

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

VDAC3,GPR37,UBA1,ATP5B,UCHL1,UQCRFS1,NDUFS7,NDUFS4,NDUFB10,NDUFB3,NDUFB4,NDUFB6,NDUFB2,NDUFA4,NDUFA8,NDUFA7,ATP5F1,PARK2,NDUFA1,SDHC

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_PML_PATHWAY 17 8 2.4 0 0.0059
KEGG_ANTIGEN_PROCESSING_AND_PRESENTATION 89 19 1.4 0 0.0059
BIOCARTA_IL3_PATHWAY 15 6 2.2 0.001 0.11
KEGG_GLYOXYLATE_AND_DICARBOXYLATE_METABOLISM 16 6 2.1 0.0015 0.12
KEGG_RNA_DEGRADATION 55 12 1.3 0.0022 0.13
List of marker genes for gene expression subtype 3 in this pathway

SP100,TNF,CREBBP,PAX3,SIRT1,DAXX,SUMO1,PRAM1

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

KLRC2,RFXAP,B2M,HLA-A,HLA-B,HLA-E,HLA-DQA2,HLA-G,KIR3DL2,CALR,CTSL1,TAP2,IFNA5,TAP1,HLA-DRB5,HSPA4,HSPA5,HSPA8,KIR2DS1

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

IL3,MAP2K1,RAF1,FOS,SOS1,SHC1

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

ACO1,CS,AFMID,GLYCTK,MTHFD2,MDH1

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

CNOT8,EDC3,LSM5,EXOSC9,EXOSC1,XRN1,XRN2,PAPOLA,DCP1B,DCP2,DCP1A,HSPD1

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

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