Colon/Rectal Adenocarcinoma: 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 120 genes with significant mutation (Q value <= 0.1) and 550 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

1 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
BIOCARTA_MTOR_PATHWAY 23 6 3 0.0001 0.021
BIOCARTA_PYK2_PATHWAY 29 6 2.8 0.0002 0.024
BIOCARTA_PROTEASOME_PATHWAY 19 5 3 0.0003 0.024
BIOCARTA_IGF1MTOR_PATHWAY 20 5 3 0.0003 0.024
KEGG_RIBOSOME 87 10 1.9 0.0004 0.024
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_NO1_PATHWAY 31 9 1.8 0.0008 0.052
BIOCARTA_IL2RB_PATHWAY 38 11 1.7 0.0003 0.052
KEGG_AXON_GUIDANCE 129 23 1 0.0006 0.052
BIOCARTA_GCR_PATHWAY 20 6 1.8 0.0045 0.099
BIOCARTA_EIF4_PATHWAY 24 7 1.7 0.0036 0.099
List of marker genes for gene expression subtype 1 in this pathway

CAV1,PDE3B,AKT1,NOS3,PRKACB,FLT1,FLT4,CALM3,CALM2

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

E2F1,STAT5B,BCL2L1,AKT1,FOS,IL2RG,PIK3R1,SYK,PTPN6,SOCS1,MAPK1

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

PLXNA2,ROBO2,ROBO3,PLXNB1,CHP2,MAPK1,RND1,GNAI3,EPHB1,SEMA5B,KRAS,RAC2,SEMA6A,FES,CFL2,SRGAP3,SEMA4C,SEMA4B,ABLIM2,PPP3CA,NGEF,DPYSL2,FYN

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

AKT1,ADRB2,CALM3,NOS3,PIK3R1,CALM2

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

PDK2,AKT1,MAPK1,PDPK1,PABPC1,PIK3R1,GHR

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_PURINE_METABOLISM 158 32 1.2 0 0.0019
BIOCARTA_AMI_PATHWAY 20 7 2 0.0011 0.12
KEGG_SMALL_CELL_LUNG_CANCER 84 17 1.2 0.0009 0.12
BIOCARTA_G1_PATHWAY 28 8 1.7 0.0022 0.16
KEGG_FOCAL_ADHESION 201 30 0.75 0.0024 0.16
List of marker genes for gene expression subtype 2 in this pathway

ADCY5,PDE3B,PDE4D,POLR2J2,NME7,PDE5A,ADSS,ENPP3,PPAT,PDE6A,ADSSL1,AK7,PDE6H,PDE6G,PDE7A,GUK1,PDE11A,CANT1,NT5E,POLR1E,PDE10A,GMPR,PKM2,POLR2I,POLA2,AK3L1,PDE1A,PAPSS1,POLR3GL,POLR3A,AMPD3,PAICS

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

F10,COL4A6,PLG,PROC,FGA,FGB,ERAF

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

E2F1,CASP9,NOS2,PIK3CD,CYCS,SKP2,CDK6,CDK2,CCND1,PIAS2,LAMC1,PIK3R5,ITGA2,COL4A6,CDKN1B,ITGA6,LAMA5

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

E2F1,TGFB3,SMAD4,SKP2,CDK6,CDK2,CCND1,CDKN1B

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

PIK3CD,PPP1CA,LAMC1,PXN,LAMA5,PDPK1,FLNB,CCND1,COL3A1,COL6A2,THBS2,CAPN2,FYN,MYL7,MYL2,DOCK1,ITGA2,ITGA6,ITGA5,ITGA8,RAP1A,MYLK,PAK3,CRKL,TNC,IGF1R,PIK3R5,COL5A2,COL4A6,GRLF1

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_CELL_ADHESION_MOLECULES_CAMS 134 29 1.4 0 0.0004
KEGG_ALLOGRAFT_REJECTION 38 12 2 0 0.003
KEGG_TYPE_I_DIABETES_MELLITUS 44 12 1.7 0.0001 0.012
KEGG_GRAFT_VERSUS_HOST_DISEASE 42 11 1.8 0.0002 0.014
KEGG_INTESTINAL_IMMUNE_NETWORK_FOR_IGA_PRODUCTION 48 12 1.6 0.0003 0.018
List of marker genes for gene expression subtype 3 in this pathway

HLA-F,HLA-DPA1,MADCAM1,HLA-DRA,GLG1,PVRL2,HLA-DOA,ITGA4,ITGA6,CLDN8,CD8A,CLDN3,CLDN6,SDC4,HLA-DMA,ICAM3,NRXN1,CD86,CD80,CNTN1,JAM2,CLDN19,CDH4,VCAM1,CD4,CD28,NLGN1,NLGN2,NLGN3

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

TNF,FASLG,HLA-DMA,HLA-DOA,CD28,GZMB,HLA-F,CD86,CD80,IL12A,HLA-DPA1,HLA-DRA

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

TNF,FASLG,HLA-DMA,HLA-DOA,CD28,GZMB,HLA-F,CD86,CD80,IL12A,HLA-DPA1,HLA-DRA

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

TNF,FASLG,HLA-DMA,HLA-DOA,CD28,GZMB,HLA-F,CD86,CD80,HLA-DPA1,HLA-DRA

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

ENC1,HLA-DMA,HLA-DOA,CD28,TNFRSF17,ITGA4,CD86,CD80,MADCAM1,HLA-DPA1,MAP3K14,HLA-DRA

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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