Association of mutation, copy number alteration, and subtype markers with pathways
Kidney Renal Clear Cell Carcinoma (Primary solid tumor)
22 February 2013  |  analyses__2013_02_22
Maintainer Information
Citation Information
doi:10.7908/C1DZ06HN
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/C1DZ06HN
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 11 genes with significant mutation (Q value <= 0.1) and 529 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 :

3 pathways significantly enriched with genes with copy number alteration or mutation.

0 pathways significantly enriched with marker genes of gene expression subtype 1

11 pathways significantly enriched with marker genes of gene expression subtype 2

1 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_IGF1MTOR_PATHWAY 20 6 3.5 0 0.0027
KEGG_SPLICEOSOME 126 12 2 0 0.0057
KEGG_ENDOMETRIAL_CANCER 52 8 2.6 0.0001 0.0057
BIOCARTA_TFF_PATHWAY 21 5 3.2 0.0002 0.012
KEGG_NOTCH_SIGNALING_PATHWAY 47 7 2.5 0.0002 0.012
List of CNV_Mut genes in this pathway

RPS6KB1,PTEN,AKT1,GSK3B,EIF2S1,PIK3CA

List of CNV_Mut genes in this pathway

RBM8A,HNRNPU,SLU7,SNRPE,CCDC12,CDC40,DHX8,SNW1,DDX5,EIF4A3,RBM25,SYF2

List of CNV_Mut genes in this pathway

MLH1,PTEN,AKT1,CASP9,PIK3CA,PIK3CD,GRB2,GSK3B

List of CNV_Mut genes in this pathway

GRB2,AKT1,CASP9,RHOA,PIK3CA

List of CNV_Mut genes in this pathway

NUMB,DLL1,SNW1,DVL1,NCSTN,NOTCH2,HDAC2

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_GSK3_PATHWAY 27 9 1.9 0.0003 0.025
KEGG_TRYPTOPHAN_METABOLISM 40 11 1.7 0.0003 0.025
KEGG_B_CELL_RECEPTOR_SIGNALING_PATHWAY 75 17 1.4 0.0002 0.025
BIOCARTA_G1_PATHWAY 28 8 1.7 0.0022 0.058
BIOCARTA_WNT_PATHWAY 26 8 1.8 0.0013 0.058
List of marker genes for gene expression subtype 1 in this pathway

TOLLIP,TIRAP,PPP2CA,EHHADH,PIK3R1,FZD1,DVL1,GSK3B,EIF2AK2

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

EHHADH,IL4I1,OGDH,ACAT1,HAAO,AANAT,CAT,MAOB,INMT,ABP1,AOX1

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

AKT3,LYN,PIK3CD,CARD11,NFKBIA,CD72,RAC2,DAPP1,RASGRP3,SOS2,CHP,PIK3R3,PIK3R1,CR2,MALT1,VAV1,GSK3B

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

TGFB3,CDK6,ATR,CDK4,CDC25A,ATM,HDAC1,GSK3B

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

PPP2CA,MYC,GPI,CREBBP,FZD1,DVL1,HDAC1,GSK3B

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_OXIDATIVE_PHOSPHORYLATION 133 31 1.6 0 0
KEGG_PATHOGENIC_ESCHERICHIA_COLI_INFECTION 59 16 1.8 0 0.0015
KEGG_CELL_CYCLE 128 26 1.2 0 0.0018
KEGG_PARKINSONS_DISEASE 130 24 1.3 0 0.0018
KEGG_PEROXISOME 78 19 1.5 0 0.002
List of marker genes for gene expression subtype 2 in this pathway

ATP6V1G3,ATP6V1B1,COX8A,PPA2,UQCRC2,COX11,UQCRFS1,ATP5L,NDUFS3,ATP5H,NDUFC2,ATP6V1H,NDUFA10,ATP6V1A,UQCRH,UQCRB,NDUFB5,NDUFB8,ATP6V1G2,NDUFB1,NDUFB2,TCIRG1,NDUFA5,COX7A2,NDUFA8,ATP5F1,NDUFA1,SDHB,SDHD,ATP5A1,ATP6V0A4

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

OCLN,TLR5,CTNNB1,RHOA,TUBB6,TUBA1A,TUBA1B,TUBB3,TUBA1C,LY96,ARPC1B,WASL,EZR,TUBA3C,TUBA3D,CD14

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

PTTG2,PTTG1,TGFB1,CCNA2,ESPL1,SKP1,ORC1L,ANAPC13,CHEK2,SMAD4,CDC20,CDC26,CDC14B,CDC45L,CDC7,CDC2,MCM4,MCM5,MCM6,BUB1B,BUB1,CDC25C,YWHAE,CDC25B,CCNB2,ORC3L

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

UBA7,COX8A,UQCRC2,UQCRFS1,NDUFS3,ATP5H,SLC25A4,NDUFC2,NDUFA10,UQCRH,UBB,UQCRB,NDUFB5,NDUFB8,NDUFB1,NDUFB2,NDUFA5,COX7A2,NDUFA8,ATP5F1,NDUFA1,SDHB,SDHD,ATP5A1

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

ACOX1,EHHADH,PRDX5,PEX3,ACOX3,PEX1,CAT,PECI,DHRS4,CROT,HACL1,ABCD1,ACSL1,PEX19,IDH1,PEX12,ACSL3,ACSL5,PHYH

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_SPLICEOSOME 126 30 1.6 0 0
BIOCARTA_PTEN_PATHWAY 18 6 1.9 0.0031 0.24
KEGG_PURINE_METABOLISM 158 25 0.85 0.0022 0.24
KEGG_TRYPTOPHAN_METABOLISM 40 9 1.4 0.0042 0.24
KEGG_ADHERENS_JUNCTION 75 14 1.1 0.0035 0.24
List of marker genes for gene expression subtype 3 in this pathway

SNRPD2,SMNDC1,SFRS4,RBM8A,LSM5,U2AF1,SNRPB,HNRNPC,BAT1,CCDC12,HSPA1L,HNRNPM,DDX46,HNRNPK,SNW1,DDX5,RBMX,SFRS2B,MAGOHB,PRPF3,SNRNP200,PRPF38B,TRA2B,SF3B3,PRPF19,SF3B1,DHX15,RBM25,SF3A1,RBM17

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

PDK2,FOXO3,PTEN,ITGB1,PTK2,ILK

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

ADCY4,SLC25A16,GMPR2,POLR2J2,NME7,NME4,ZNRD1,ENTPD5,ENTPD3,ENTPD2,AK1,GUCY2C,NT5M,GUCY1A3,PDE8A,NT5E,PDE10A,GMPS,GUCY1B3,POLR2J,POLA2,HPRT1,AK3L1,NPR2,APRT

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

EHHADH,WARS,HAAO,AANAT,MAOB,ACMSD,IDO1,ABP1,AOX1

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

WASF2,CTNNB1,CSNK2A2,PTPRM,ACTN4,CTNNA2,EP300,CTNND1,TCF7L2,PVRL4,YES1,CREBBP,CSNK2B,TJP1

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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