Association of mutation, copy number alteration, and subtype markers with pathways
Colon/Rectal Adenocarcinoma (Primary solid tumor)
22 February 2013  |  analyses__2013_02_22
Maintainer Information
Citation Information
doi:10.7908/C1FJ2F0R
Maintained by Spring Yingchun Liu (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2013): Association of mutation, copy number alteration, and subtype markers with pathways. Broad Institute of MIT and Harvard. doi:10.7908/C1FJ2F0R
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 120 genes with significant mutation (Q value <= 0.1) and 555 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
BIOCARTA_MTOR_PATHWAY 23 6 3 0.0001 0.022
BIOCARTA_PYK2_PATHWAY 29 6 2.7 0.0002 0.025
BIOCARTA_PROTEASOME_PATHWAY 19 5 3 0.0003 0.025
BIOCARTA_IGF1MTOR_PATHWAY 20 5 3 0.0003 0.025
KEGG_RIBOSOME 87 10 1.8 0.0004 0.025
List of CNV_Mut genes in this pathway

FKBP1A,RPS6,PTEN,EIF6,EIF4A2,PIK3CA

List of CNV_Mut genes in this pathway

SRC,RAC1,MAP2K4,RAF1,PLCG1,CALM1

List of CNV_Mut genes in this pathway

UBE3A,PSMA7,PSMB5,PSMA6,RPN2

List of CNV_Mut genes in this pathway

RPS6,PTEN,EIF2S1,EIF2S2,PIK3CA

List of CNV_Mut genes in this pathway

RPL36AL,RPS17,RPS15,RPL37,RPS27,RPL32,RPS20,RPS21,RPS24,RPS6

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_CTLA4_PATHWAY 21 8 2.3 0.0001 0.029
KEGG_CELL_ADHESION_MOLECULES_CAMS 134 23 1 0.0007 0.1
KEGG_SYSTEMIC_LUPUS_ERYTHEMATOSUS 140 22 0.99 0.001 0.11
KEGG_PRIMARY_BILE_ACID_BIOSYNTHESIS 16 6 2.1 0.0015 0.12
KEGG_ALLOGRAFT_REJECTION 38 9 1.6 0.0022 0.14
List of marker genes for gene expression subtype 1 in this pathway

CD3D,CTLA4,TRA@,PTPN11,CD86,CD80,HLA-DRA,CD28

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

MADCAM1,HLA-DRA,GLG1,CTLA4,PVRL2,HLA-DPB1,ITGA6,CLDN8,CD8A,CLDN6,HLA-DMA,SDC2,NRXN2,ICAM3,NRXN1,CD86,CD80,CNTN1,CLDN18,CDH4,VCAM1,CD28,MAG

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

SNRPD3,SNRPD1,H2AFY,GRIN2A,ACTN1,SNRPB,HLA-DRA,HIST1H4A,HLA-DPB1,HIST1H3B,HLA-DMA,FCGR3A,C8A,CD86,CD80,C9,TNF,C1S,FCGR1A,C2,CD28,FCGR2B

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

AMACR,CYP39A1,CYP27A1,CH25H,HSD17B4,AKR1D1

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

TNF,HLA-DMA,HLA-DPB1,CD28,GZMB,CD86,CD80,IL12A,HLA-DRA

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_AXON_GUIDANCE 129 24 1.1 0.0002 0.043
BIOCARTA_NO1_PATHWAY 31 7 1.4 0.013 0.15
BIOCARTA_NDKDYNAMIN_PATHWAY 19 5 1.6 0.016 0.15
BIOCARTA_ECM_PATHWAY 24 6 1.5 0.015 0.15
BIOCARTA_IL2RB_PATHWAY 38 9 1.4 0.0045 0.15
List of marker genes for gene expression subtype 2 in this pathway

PLXNA2,EFNA1,ROBO3,PLXNB1,CHP2,MAPK1,RND1,GNAI3,EPHB1,SEMA5B,KRAS,RAC2,SEMA6A,EPHA8,FES,SEMA3A,CFL2,SRGAP3,SEMA4C,SEMA4B,SRGAP1,PPP3CA,NGEF,FYN

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

CAV1,PDE3B,AKT1,NOS3,FLT1,FLT4,CALM3

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

CALM3,SYNJ2,PPP3CA,EPN1,AP2M1

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

ITGA1,MAPK1,ARHGAP5,FYN,GSN,PIK3R1

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

E2F1,BCL2L1,AKT1,FOS,IL2RG,PIK3R1,SYK,SOCS1,MAPK1

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_PURINE_METABOLISM 158 29 1 0.0001 0.035
KEGG_STEROID_BIOSYNTHESIS 17 6 2.1 0.0017 0.22
KEGG_P53_SIGNALING_PATHWAY 69 14 1.2 0.002 0.22
BIOCARTA_ALK_PATHWAY 37 8 1.3 0.013 0.35
BIOCARTA_CARM_ER_PATHWAY 35 7 1.2 0.026 0.35
List of marker genes for gene expression subtype 3 in this pathway

ADCY5,PDE3B,POLR2J2,NME7,NME6,PDE5A,ADSS,PPAT,PDE6A,PDE6B,ENTPD5,ADSSL1,PDE6H,POLD3,PDE7B,GUK1,PDE11A,NT5E,POLR1E,PDE10A,GMPR,ADK,POLR2I,POLR2C,PDE1C,PAPSS1,POLR3GL,AMPD3,AMPD1

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

TM7SF2,SOAT1,GLB1,CEL,CYP27B1,DHCR7

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

LRDD,ZMAT3,RPRM,CASP9,CASP8,TP53AIP1,CDK2,RFWD2,TNFRSF10B,SERPINB5,CCNG2,BAI1,IGF1,TSC2

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

MYL2,AXIN1,TGFBR1,SMAD4,GARS,NPPB,BMP7,CHRD

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

CREBBP,ESR1,HIST2H3C,HDAC2,EP300,CARM1,MED1

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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