Breast Invasive Carcinoma: Association of mutation, copy number alteration, and subtype markers with pathways
(primary solid tumor cohort)
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 43 genes with significant mutation (Q value <= 0.1) and 195 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 :

12 pathways significantly enriched with genes with copy number alteration or mutation.

4 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 7 4.6 0 0
BIOCARTA_TNFR1_PATHWAY 29 6 4.2 0 0.0001
BIOCARTA_FAS_PATHWAY 30 5 3.9 0 0.0022
BIOCARTA_CDC42RAC_PATHWAY 16 4 4.5 0 0.0022
BIOCARTA_PTEN_PATHWAY 18 4 4.3 0 0.0029
List of CNV_Mut genes in this pathway

PIK3CA,PAK1,PIK3R1,TFDP1,RB1,CDKN1B,IKBKB

List of CNV_Mut genes in this pathway

MAP3K7,CASP8,PAK1,MAP2K4,RB1,RIPK1

List of CNV_Mut genes in this pathway

MAP3K7,CASP8,PAK1,MAP2K4,RB1

List of CNV_Mut genes in this pathway

ARPC3,PIK3CA,PAK1,PIK3R1

List of CNV_Mut genes in this pathway

FOXO3,CDKN1B,PIK3CA,PIK3R1

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_VASCULAR_SMOOTH_MUSCLE_CONTRACTION 115 24 1.3 0 0.003
KEGG_WNT_SIGNALING_PATHWAY 151 29 1.1 0 0.003
KEGG_MELANOGENESIS 102 22 1.3 0 0.003
KEGG_SYSTEMIC_LUPUS_ERYTHEMATOSUS 140 25 1.2 0.0001 0.0036
KEGG_RIBOSOME 87 18 1.2 0.0003 0.014
List of marker genes for gene expression subtype 1 in this pathway

ADCY2,ADCY8,PRKX,PTGIR,PRKACB,ROCK2,MAPK1,PPP1CA,PLA2G2E,PLA2G2F,MYL6,KCNMB2,CACNA1S,AVPR1B,RHOA,GUCY1A3,KCNMA1,PRKCG,PRKCQ,GNAS,GUCY1B3,CALML6,CALML5,RAF1

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

PRKX,CTNNB1,WNT2,MAP3K7,PRKACB,WNT6,CUL1,ROCK2,RBX1,AXIN1,DVL3,SMAD3,RHOA,PRKCG,SUMO1,CCND3,NKD2,PPP3R2,TCF7L2,PPP2CA,WNT8B,APC,NFATC1,CSNK1A1,FZD1,FZD5,FZD7,TBL1X,TBL1Y

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

ADCY2,ADCY8,PRKX,CTNNB1,WNT2,CREB3L2,CREB3L1,PRKACB,WNT6,MAPK1,DVL3,PRKCG,GNAS,TCF7L2,CALML6,CALML5,WNT8B,CREB1,FZD1,RAF1,FZD5,FZD7

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

HIST1H2BO,HIST1H2BM,HIST1H2BK,HIST1H2BL,HIST1H2BG,H2AFY,CD40LG,HLA-DRB5,HLA-DOA,HIST1H4G,HIST1H4H,HIST1H3A,HIST1H3E,HIST3H2A,HIST3H2BB,CD86,CD80,HIST2H2BE,TNF,HIST1H2BD,HIST1H2BE,HIST1H2BH,TRIM21,HIST1H2AH,HIST1H2AK

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

RPL18,RPL14,RPL13,RPL26L1,FAU,RPS17,RPS13,RPS11,RPL27A,RPL10L,RPS27,RPL30,RPL32,RPL8,RPS21,RPL23A,RPS5,RPL21

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_PARKINSONS_DISEASE 130 19 0.98 0.0025 0.41
KEGG_HUNTINGTONS_DISEASE 183 27 0.86 0.0013 0.41
KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION 272 36 0.61 0.0053 0.44
KEGG_VIRAL_MYOCARDITIS 73 13 1.2 0.0041 0.44
BIOCARTA_NKT_PATHWAY 28 7 1.5 0.008 0.44
List of marker genes for gene expression subtype 2 in this pathway

NDUFAB1,COX7B,COX6B1,UBE2L3,ATP5B,UBE2G2,UQCRFS1,NDUFS7,CASP3,CASP9,ATP5H,CYCS,UBB,NDUFB9,ATP5G3,NDUFB1,NDUFA6,SDHD,SLC18A1

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

NDUFAB1,BDNF,CREB3L3,POLR2J2,DCTN1,COX7B,COX6B1,CREBBP,NFE2L1,ATP5B,PPARG,UQCRFS1,NDUFS7,CASP3,CASP9,DLG4,ATP5H,CYCS,POLR2E,NDUFB9,ATP5G3,POLR2C,NDUFB1,CREB3,NDUFA6,SOD1,SDHD

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

S1PR1,LTB4R,S1PR5,CRHR1,SSTR1,F2,CHRNB4,CHRNB2,CHRNB1,GPR83,CSH1,MCHR1,TRPV1,EDNRB,NMUR1,RXFP2,GRM1,GRM8,GRM7,GRM6,PARD3,NPY2R,FPR1,GHRHR,CYSLTR1,DRD3,ADORA2A,DRD5,P2RY1,GABRQ,GABRD,GABRA3,P2RX3,CALCRL,PTGER2,PTAFR

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

CASP3,CASP9,MYH1,CYCS,HLA-A,EIF4G3,SGCG,CD40LG,SGCA,CAV1,RAC3,CD28,MYH11

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

CCL3,TGFB2,CD4,IFNGR2,CD28,CCR7,CD40LG

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 0.011
KEGG_OLFACTORY_TRANSDUCTION 389 57 0.72 0.0001 0.011
KEGG_LYSINE_DEGRADATION 44 11 1.5 0.0009 0.097
KEGG_ADHERENS_JUNCTION 75 15 1.2 0.0013 0.11
KEGG_TGF_BETA_SIGNALING_PATHWAY 86 16 1.1 0.0024 0.16
List of marker genes for gene expression subtype 3 in this pathway

SP100,TNF,CREBBP,SIRT1,DAXX,TNFRSF1A,SUMO1,PRAM1

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

OR6S1,OR51L1,OR2S2,OR1S1,OR52K2,OR2T2,GUCY2D,OR7E24,OR2W1,OR10AD1,OR5V1,OR4N4,OR4N2,OR6Y1,OR10R2,OR52R1,OR2A12,OR4P4,OR51D1,OR10S1,OR52E6,OR52E8,OR51A4,OR10V1,OR52J3,OR1L6,OR51F2,OR1L3,CALML6,OR8H2,OR1E1,OR4D1,OR13F1,OR7G2,OR13H1,OR4B1,OR8D2,OR8D4,OR10A4,OR52B4,OR2H2,OR2G2,OR13D1,OR4D10,PRKACA,OR4M2,OR5M9,OR5AS1,OR11H4,OR4K1,OR52W1,OR4C15,OR10J5,OR10J1,OR10G2,OR10H1,OR3A3

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

EHHADH,AASS,PLOD2,PLOD3,AASDH,DLST,EHMT2,DOT1L,ASH1L,SETD7,NSD1

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

WASF1,VCL,ACTG1,CSNK2A2,RHOA,PTPRM,PTPRF,ACTN3,WASL,PTPRB,PTPN6,TGFBR1,CREBBP,CSNK2B,FYN

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

FST,RHOA,RBL2,AMH,ACVR1,TNF,DCN,THBS3,TFDP1,TGFBR1,CREBBP,ID2,BMP7,BMP5,BMP8B,BMP8A

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)
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