Breast Invasive Carcinoma: 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 32 genes with significant mutation (Q value <= 0.1) and 212 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

4 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_CELLCYCLE_PATHWAY | 23 | 5 | 4.2 | 0 | 0.0019
BIOCARTA_RACCYCD_PATHWAY | 26 | 4 | 3.7 | 0.0002 | 0.032
BIOCARTA_TNFR1_PATHWAY | 29 | 4 | 3.6 | 0.0003 | 0.032
KEGG_CITRATE_CYCLE_TCA_CYCLE | 32 | 4 | 3.5 | 0.0004 | 0.032
KEGG_CELL_CYCLE | 128 | 7 | 2.3 | 0.0006 | 0.034

List of CNV_Mut genes in this pathway

CCNH,CDK7,RB1,CDKN1B,TFDP1

List of CNV_Mut genes in this pathway

TFDP1,RB1,CDKN1B,IKBKB

List of CNV_Mut genes in this pathway

MAP3K7,MAP2K4,RB1,RIPK1

List of CNV_Mut genes in this pathway

PDHB,FH,DLAT,SDHD

List of CNV_Mut genes in this pathway

CDC16,TFDP1,CDKN1B,CCNH,CDK7,RB1,ORC3L

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_CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION | 267 | 41 | 0.83 | 0.0001 | 0.044
KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION | 272 | 38 | 0.68 | 0.0018 | 0.2
KEGG_VIRAL_MYOCARDITIS | 73 | 14 | 1.2 | 0.0015 | 0.2
KEGG_LYSOSOME | 121 | 20 | 0.92 | 0.0031 | 0.2
KEGG_HUNTINGTONS_DISEASE | 183 | 26 | 0.8 | 0.0029 | 0.2

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

CCR8,VEGFC,CCR7,IFNB1,CCR2,GH2,TNFRSF10A,IL12B,CXCL5,CXCL9,CCL27,CCL22,CCL23,CCL21,IL10RA,CCL15,IL28A,IL18,TNFSF15,TNFSF14,IL15,TGFB2,IL17RB,C19orf10,TNFRSF14,IL22RA1,BMPR2,CCL4,IL8RA,CXCR3,THPO,IFNGR2,EDAR,IFNAR1,AMH,TNFRSF1B,TNFRSF19,FIGF,TNFSF4,MPL,BMPR1A

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

ADORA3,LPAR4,S1PR1,GRIN2B,LTB4R,S1PR5,GRID1,CRHR1,CRHR2,SSTR1,F2,GPR156,GH2,CHRNB4,CHRNB2,CHRNB1,GPR83,TRPV1,EDNRB,NMUR1,GRM8,GRM7,GRM6,PARD3,NPY2R,FPR1,DRD3,ADORA2A,DRD5,GABRQ,GABRD,GABRA2,GABRA3,P2RX3,PTGER2,CHRM5,PTAFR,DHX8

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

CASP3,CASP9,MYH1,HLA-G,HLA-F,CD86,EIF4G3,SGCG,SGCA,CAV1,ITGB2,RAC3,ACTB,ABL2

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

HGSNAT,IDS,PPT2,ACP2,SLC11A1,GALNS,LAMP2,CLTCL1,AP3S1,AP1S3,AP1S1,CLN3,CTSZ,CTSS,GAA,CTSE,PSAPL1,AP3M2,AP4S1,SLC17A5

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

NDUFAB1,GRIN2B,CREB3L3,POLR2J2,DCTN1,COX7B,COX6B1,CREBBP,NFE2L1,CLTCL1,PPARG,UQCRFS1,NDUFS7,GPX1,CASP3,CASP9,DLG4,ATP5H,NDUFS1,UQCRB,POLR2E,NDUFB8,POLR2C,NDUFB1,CREB3,SOD1

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 | 35 | 1.2 | 0 | 0.0004
KEGG_RIBOSOME | 87 | 21 | 1.5 | 0 | 0.0017
KEGG_MELANOGENESIS | 102 | 22 | 1.3 | 0 | 0.0048
KEGG_ALZHEIMERS_DISEASE | 167 | 29 | 1.1 | 0.0001 | 0.0049
WNT_SIGNALING | 89 | 19 | 1.3 | 0.0002 | 0.012

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

TBP,CREB3L2,CREB3L1,TBPL1,RCOR1,APEX1,GRIN1,VDAC1,DNAL4,AP2S1,CLTC,UQCRFS1,NDUFS7,NDUFS4,CASP8,DLG4,NDUFB10,COX4I1,NDUFB3,NDUFB4,POLR2G,NDUFB7,POLR2J,POLR2C,NDUFB2,DNAI1,NDUFA4,NDUFA8,CREB1,NDUFA7,CREB5,NDUFA1,SOD2,SDHC,SDHD

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

RPL18,RPL36AL,RPL19,RPL14,RPL13,RPS2,RPS3,RPL26L1,FAU,RPS13,RPS11,RPL27A,RPS27,RPL30,RPL32,RPL8,RPS21,RPL23A,RPS5,RPL29,RPL21

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

ADCY8,CTNNB1,WNT2,CREB3L2,CREB3L1,PRKACB,WNT6,WNT10A,MAPK1,DVL3,PRKCG,GNAS,WNT11,WNT16,TCF7L2,CALML6,CALML5,CAMK2A,CREB1,FZD1,RAF1,FZD5

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

GRIN2C,MAPK1,RYR3,LCP1,GRIN1,CACNA1S,ATF6,ATP2A2,UQCRFS1,NDUFS7,NDUFS4,CASP8,NDUFB10,COX4I1,ERN1,NDUFB3,NDUFB4,TNF,NDUFB7,NDUFB2,TNFRSF1A,CALML6,CALML5,NDUFA4,NDUFA8,NDUFA7,NDUFA1,SDHC,SDHD

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

B2M,CTNNB1,WNT2,WNT6,PITX2,FGF4,WNT10A,FOXN1,SUMO1,CCND3,WNT11,WNT16,CXXC4,T,PPP2CA,AXIN1,CSNK1A1,FZD1,FZD5

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_ANTIGEN_PROCESSING_AND_PRESENTATION | 89 | 17 | 1.3 | 0.0004 | 0.12
KEGG_LYSINE_DEGRADATION | 44 | 11 | 1.5 | 0.0009 | 0.14
KEGG_TGF_BETA_SIGNALING_PATHWAY | 86 | 16 | 1.1 | 0.0024 | 0.26
BIOCARTA_EIF_PATHWAY | 16 | 5 | 1.9 | 0.007 | 0.3
BIOCARTA_PML_PATHWAY | 17 | 5 | 1.7 | 0.012 | 0.3

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

KLRC2,RFXAP,B2M,HLA-A,HLA-B,HLA-E,HLA-G,KIR3DL3,KIR3DL2,HLA-DQB1,CALR,CTSL1,TAP2,TAP1,HSPA4,HSPA5,IFNA14

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

EHHADH,SETD1A,OGDHL,AASS,PLOD2,PLOD3,AASDH,DLST,DOT1L,WHSC1L1,NSD1

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

RHOA,MYC,RBL2,LEFTY1,ACVR1,TNF,DCN,THBS3,TFDP1,BMP4,TGFBR1,CREBBP,ID2,BMP7,BMP5,BMP8B

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

EIF5,EEF2,EIF4G3,EIF2S1,EEF2K

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

SP100,TNF,CREBBP,TNFRSF1A,SUMO1

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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