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 30 genes with significant mutation (Q value <= 0.1) and 242 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

2 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_CHREBP2_PATHWAY 44 5 3.2 0.0002 0.022
KEGG_PROTEIN_EXPORT 24 4 3.7 0.0002 0.022
KEGG_PROSTATE_CANCER 89 7 2.6 0.0002 0.022
BIOCARTA_RACCYCD_PATHWAY 26 4 3.6 0.0003 0.025
KEGG_CHRONIC_MYELOID_LEUKEMIA 73 6 2.7 0.0004 0.025
List of CNV_Mut genes in this pathway

PPP2CB,PPP2R2D,YWHAE,YWHAQ,PPP2R2A

List of CNV_Mut genes in this pathway

SRP54,SEC63,SRPR,SPCS1

List of CNV_Mut genes in this pathway

RB1,FGFR1,ERBB2,KRAS,CDKN1B,MTOR,IKBKB

List of CNV_Mut genes in this pathway

TFDP1,RB1,CDKN1B,IKBKB

List of CNV_Mut genes in this pathway

GAB2,RB1,KRAS,CDKN1B,IKBKB,CRK

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 40 0.79 0.0003 0.075
KEGG_LYSOSOME 121 22 1 0.0006 0.075
KEGG_HUNTINGTONS_DISEASE 183 28 0.9 0.0007 0.075
KEGG_VIRAL_MYOCARDITIS 73 14 1.2 0.0015 0.13
KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION 272 38 0.67 0.0019 0.13
List of marker genes for gene expression subtype 1 in this pathway

CCR8,VEGFC,CCR7,IFNB1,CCR2,GH2,TNFRSF10A,CXCL5,CXCL9,CCL27,CCL22,CCL23,IL10RA,CCL15,IL28A,IL18,TNFSF14,IL13,IL15,IL17RA,TGFB2,IL17RB,C19orf10,TNFRSF14,IL22RA1,CCL4,EGF,IL8RB,CXCR3,THPO,IFNGR2,EDAR,IFNAR1,AMH,TNFRSF1B,TNFRSF19,FIGF,TNFSF4,MPL,BMPR1A

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

HGSNAT,IDS,ACP5,PPT2,ACP2,CTSL1,SLC11A1,LAMP2,AP3S1,AP1S3,AP1S1,CLN3,CTSZ,CTSS,GAA,CTSE,PSAPL1,AP3M2,AP4S1,SLC17A5,GGA1,GGA2

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

NDUFAB1,GRIN2B,CREB3L3,POLR2J2,DCTN1,COX7B,COX6B1,CREBBP,NFE2L1,PPARG,UQCRFS1,NDUFS7,GPX1,CASP3,CASP9,DLG4,ATP5H,NDUFS1,CYCS,POLR2E,NDUFB8,ATP5G3,POLR2C,NDUFB1,CREB3,NDUFA6,SOD1,IFT57

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

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

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

ADORA3,S1PR1,GRIN2B,LTB4R,S1PR5,GRID1,CRHR1,SSTR1,F2,GPR156,GH2,CHRNB4,CHRNB2,CHRNB1,GPR83,CSH1,MCHR1,TRPV1,EDNRB,NMUR1,RXFP2,GRM2,GRM8,GRM7,GRM6,NPY2R,FPR1,DRD3,ADORA2A,DRD5,GABRQ,GABRD,GABRA3,P2RX3,PTGER2,CHRM5,PTAFR,DHX8

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 33 1.1 0 0.0018
KEGG_RIBOSOME 87 20 1.4 0 0.0036
KEGG_VASCULAR_SMOOTH_MUSCLE_CONTRACTION 115 22 1.1 0.0003 0.013
KEGG_NOD_LIKE_RECEPTOR_SIGNALING_PATHWAY 62 15 1.4 0.0002 0.013
KEGG_MELANOGENESIS 102 20 1.2 0.0004 0.015
List of marker genes for gene expression subtype 2 in this pathway

TBP,CREB3L2,CREB3L1,TBPL1,RCOR1,COX6B2,APEX1,AP2M1,HIP1,GRIN1,VDAC3,VDAC1,AP2S1,CLTC,UQCRFS1,NDUFS7,NDUFS4,CASP8,ATP5H,NDUFB10,NDUFB3,NDUFB4,POLR2G,NDUFB7,POLR2C,NDUFB2,NDUFA8,CREB1,CREB5,NDUFA1,SOD2,IFT57,SDHD

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

RPL18,RPL36AL,RPL19,RPL14,RPL13,RPS3,RPL26L1,FAU,RPS13,UBA52,RPL27A,RPL10L,RPS27,RPL30,RPL32,RPL8,RPL4,RPS21,RPS5,RPL21

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

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

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

CASP5,MAP3K7,NLRC4,CASP8,MAPK1,TNFAIP3,TNF,NFKBIA,PYDC1,PYCARD,PSTPIP1,IL8,SUGT1,CCL13,MAPK12

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

ADCY8,PRKX,CTNNB1,WNT2,CREB3L2,CREB3L1,PRKACB,WNT6,MAPK1,DVL3,PRKCG,GNAS,WNT11,CALML6,CALML5,CREB1,FZD1,RAF1,FZD5,FZD7

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 7 2.2 0.0003 0.054
KEGG_OLFACTORY_TRANSDUCTION 389 55 0.67 0.0002 0.054
KEGG_LYSINE_DEGRADATION 44 11 1.5 0.0009 0.074
KEGG_TGF_BETA_SIGNALING_PATHWAY 86 17 1.2 0.0009 0.074
BIOCARTA_EIF_PATHWAY 16 5 1.9 0.007 0.46
List of marker genes for gene expression subtype 3 in this pathway

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

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

OR51L1,OR2S2,OR52K2,OR2T2,GUCY2D,OR7E24,OR5V1,OR4N4,OR4N2,OR10R2,OR52R1,OR2A12,OR5T2,OR10S1,ARRB2,OR8J3,OR51B6,OR52E8,OR51A4,OR10V1,OR52J3,OR1L6,OR51F2,OR1L3,CALML6,OR7A5,OR8H2,OR1E1,OR4D1,OR13F1,OR8B4,OR7G2,OR13H1,OR4B1,OR8D2,OR8D4,OR10A4,OR52B4,OR2H2,OR2G2,OR5B3,OR4L1,OR4D10,OR4M2,OR5M9,OR5AS1,OR11H4,OR4K1,OR52W1,OR10J5,OR10J1,OR4K15,OR10G2,OR10H1,OR3A3

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

EHHADH,AASS,PLOD2,PLOD3,AASDH,DLST,EHMT2,WHSC1L1,ASH1L,SETD7,NSD1

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

FST,RHOA,MYC,RBL2,LEFTY1,ACVR1,TNF,DCN,THBS3,TFDP1,TGFBR1,CREBBP,ID2,BMP7,BMP5,BMP8B,BMP8A

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

EIF5,EIF4G3,EIF2S1,EEF2K,EIF1

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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