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 210 genes with significant mutation (Q value <= 0.1) and 490 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

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_PYK2_PATHWAY | 29 | 7 | 2.9 | 0 | 0.0094
BIOCARTA_ARAP_PATHWAY | 18 | 5 | 3.2 | 0.0001 | 0.022
KEGG_SPLICEOSOME | 126 | 12 | 1.7 | 0.0004 | 0.034
KEGG_EPITHELIAL_CELL_SIGNALING_IN_HELICOBACTER_PYLORI_INFECTION | 68 | 9 | 2 | 0.0004 | 0.034
KEGG_PROTEASOME | 48 | 7 | 2.2 | 0.0006 | 0.038

List of CNV_Mut genes in this pathway

SRC,RAC1,MAP2K3,MAP2K4,RAF1,PLCG1,CALM1

List of CNV_Mut genes in this pathway

ARFGAP3,KDELR2,COPA,ARFGEF2,ARFGEF1

List of CNV_Mut genes in this pathway

SMNDC1,CTNNBL1,LSM5,LSM3,SNRPB,HNRNPC,SNRPB2,SNW1,CRNKL1,PCBP1,WBP11,BCAS2

List of CNV_Mut genes in this pathway

CASP3,CHUK,ATP6V1H,ATP6V1D,SRC,RAC1,MAP2K4,MAPK10,PLCG1

List of CNV_Mut genes in this pathway

PSMA7,PSMB5,PSMF1,PSMC6,PSMA6,PSMD12,PSMC1

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.

- 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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