Rectum Adenocarcinoma: 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 9 genes with significant mutation (Q value <= 0.1) and 508 genes with significant copy number alteration (Q value <= 0.25). The identified marker genes (Q value <= 0.01 or within top 2000) are 1088 for subtype 1, 1088 for subtype 2, 1088 for subtype 3. Pathways significantly enriched with these genes (Q value <= 0.01) are identified :

5 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

15 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
--- | --- | --- | --- | --- | ---
KEGG_PARKINSONS_DISEASE | 130 | 13 | 2.3 | 0 | 0.0011
BIOCARTA_CHREBP2_PATHWAY | 44 | 7 | 2.8 | 0.0001 | 0.0056
KEGG_RNA_DEGRADATION | 55 | 8 | 2.6 | 0.0001 | 0.0056
KEGG_NEUROTROPHIN_SIGNALING_PATHWAY | 126 | 12 | 2 | 0.0001 | 0.0056
KEGG_SPLICEOSOME | 126 | 11 | 2 | 0.0001 | 0.0074

List of CNV_Mut genes in this pathway

COX5A,VDAC2,VDAC3,ATP5E,UBE2G1,CASP9,NDUFS2,ATP5H,UBB,NDUFB8,ATP5F1,PARK7,SDHD

List of CNV_Mut genes in this pathway

PPP2R5D,PPP2CB,PPP2R2D,YWHAB,YWHAE,PPP2R5E,PPP2R2A

List of CNV_Mut genes in this pathway

LSM7,CNOT2,CNOT7,LSM1,EXOSC1,XRN2,WDR61,DCP1B

List of CNV_Mut genes in this pathway

PIK3CA,RIPK2,MAPK7,KRAS,RAP1A,IKBKB,CDC42,CAMK2G,YWHAB,YWHAE,NRAS,CALM1

List of CNV_Mut genes in this pathway

LSM7,CTNNBL1,HNRNPC,SNRPB2,SNW1,CRNKL1,MAGOHB,CDC5L,WBP11,PRPF8,BCAS2

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_ECM_RECEPTOR_INTERACTION | 84 | 14 | 1.8 | 0 | 0.014
KEGG_FOCAL_ADHESION | 201 | 21 | 1.1 | 0.0006 | 0.095
KEGG_CELL_ADHESION_MOLECULES_CAMS | 134 | 15 | 1.2 | 0.0014 | 0.15
KEGG_TIGHT_JUNCTION | 134 | 14 | 1.1 | 0.004 | 0.24
KEGG_PATHWAYS_IN_CANCER | 328 | 27 | 0.77 | 0.0039 | 0.24

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

SV2B,SV2A,COL11A1,COL1A2,LAMC1,ITGA11,ITGB3,COMP,ITGB7,ITGB6,THBS2,THBS4,COL4A4,HSPG2

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

CTNNB1,PPP1CA,LAMC1,ITGA11,RAC1,KDR,COL11A1,THBS2,THBS4,PDGFC,COL1A2,ITGB3,DOCK1,ITGB7,ITGB6,MYLK,AKT3,SHC4,VASP,COMP,COL4A4

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

NCAM1,PHOX2A,CD226,ITGB7,HLA-DOA,CLDN6,NRXN1,SIGLEC1,CD80,CNTN1,CLDN2,CLDN19,CDH5,NLGN2,NLGN3

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

AMOTL1,CTNNB1,MPDZ,MYH4,MYH7B,PPP2R2B,PARD6B,MYH13,MYH10,CLDN6,AKT3,EPB41L1,CLDN2,CLDN19

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

SHH,CTNNB1,CUL2,RARB,LAMC1,RAC1,FGF5,MITF,SPI1,GLI2,GLI3,GLI1,NOS2,AKR1B1,FZD8,FOXO1,FGF12,WNT4,RALA,FGFR1,AKT3,RUNX1T1,CDK2,NCOA4,TCF7L1,COL4A4,KLK3

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_VIRAL_MYOCARDITIS | 73 | 13 | 2 | 0 | 0.0045
KEGG_FOCAL_ADHESION | 201 | 23 | 1.3 | 0.0001 | 0.013
KEGG_ECM_RECEPTOR_INTERACTION | 84 | 13 | 1.7 | 0.0002 | 0.013
KEGG_LEUKOCYTE_TRANSENDOTHELIAL_MIGRATION | 118 | 16 | 1.5 | 0.0001 | 0.013
BIOCARTA_EIF_PATHWAY | 16 | 5 | 2.8 | 0.0005 | 0.02

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

HLA-DMB,HLA-DMA,ACTG1,CASP8,MYH4,EIF4G2,CD86,SGCD,HLA-DPA1,MYH7B,SGCA,ITGB2,MYH13

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

ACTG1,ROCK2,ITGA11,SPP1,LAMA1,PTEN,COL11A1,PARVG,COL6A2,THBS2,IGF1,PDGFC,MYL9,ITGAV,ITGA4,MYLK,AKT3,SHC4,PRKCB,TNC,COMP,COL4A4,BAD

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

SDC2,SV2B,COL11A1,TNC,ITGA11,COMP,ITGAV,COL6A2,THBS2,SPP1,COL4A4,ITGA4,LAMA1

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

MMP9,MMP2,ACTG1,NCF2,NCF1,ROCK2,CTNNA1,THY1,ITGB2,MYL9,ITGA4,MSN,PRKCB,VCAM1,MLLT4,CYBB

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

EIF6,EEF2,EIF4G2,EIF4A1,EEF2K

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_CTL_PATHWAY | 15 | 8 | 4 | 0 | 0
BIOCARTA_CTLA4_PATHWAY | 21 | 8 | 3.5 | 0 | 0
KEGG_CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION | 267 | 30 | 1.6 | 0 | 0
KEGG_ANTIGEN_PROCESSING_AND_PRESENTATION | 89 | 16 | 2.4 | 0 | 0
KEGG_NATURAL_KILLER_CELL_MEDIATED_CYTOTOXICITY | 137 | 22 | 2.1 | 0 | 0

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

PRF1,CD3D,CD247,HLA-A,FASLG,ITGB2,TRA@,B2M

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

CD3D,CD247,CTLA4,TRA@,PTPN11,CD86,CD80,CD28

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

IFNG,CCR2,CX3CR1,VEGFA,FLT3LG,CXCL9,CXCL6,ENC1,IL10RA,CD27,IL7,CCL19,CCL15,CCL13,CXCL11,IL15RA,CCL3,CCL8,TNFSF10,IL21R,FASLG,IL8RB,CXCR6,TNFRSF9,ACVR2B,TNFSF13B,TNF,TNFRSF4,TNFRSF18,IL2RB

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

KLRC3,CD8A,B2M,CIITA,HLA-A,HLA-C,HLA-DQA2,HLA-G,HLA-F,KLRC1,KIR3DL1,KIR2DL4,CTSL1,TAP1,HLA-DPB1,KIR2DS4

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

KLRC3,IFNG,HLA-A,HLA-C,HLA-G,KLRC1,KIR3DL1,KIR2DL4,ITGB2,ZAP70,FCER1G,KIR2DS4,PTPN11,TNFSF10,FASLG,SH2D1A,NCR3,PRKCB,LCP2,PRF1,TNF,CD247

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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