Kidney Renal Clear Cell Carcinoma: Association of mutation, copy number alteration, and subtype markers with pathways
Maintained by Spring Yingchun Liu (Dana-Farber Cancer 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 23 genes with significant mutation (Q value <= 0.1) and 255 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.

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

6 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
--- | --- | --- | --- | --- | ---
KEGG_PROTEIN_EXPORT | 24 | 4 | 3.7 | 0.0002 | 0.072
BIOCARTA_AKT_PATHWAY | 22 | 3 | 3.4 | 0.0029 | 0.095
BIOCARTA_CHEMICAL_PATHWAY | 22 | 3 | 3.4 | 0.0029 | 0.095
BIOCARTA_RAS_PATHWAY | 23 | 3 | 3.3 | 0.0033 | 0.095
BIOCARTA_IGF1MTOR_PATHWAY | 20 | 3 | 3.5 | 0.0022 | 0.095

List of CNV_Mut genes in this pathway

SRP54,SEC63,SPCS1,SEC61A1

List of CNV_Mut genes in this pathway

NFKBIA,CASP9,PIK3CA

List of CNV_Mut genes in this pathway

CASP9,EIF2S1,PARP1

List of CNV_Mut genes in this pathway

CASP9,RHOA,PIK3CA

List of CNV_Mut genes in this pathway

GSK3B,EIF2S1,PIK3CA

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_WNT_PATHWAY | 26 | 10 | 2.1 | 0 | 0.0071
WNT_SIGNALING | 89 | 18 | 1.2 | 0.0006 | 0.059
BIOCARTA_G1_PATHWAY | 28 | 8 | 1.7 | 0.0021 | 0.079
BIOCARTA_P53HYPOXIA_PATHWAY | 22 | 7 | 1.8 | 0.002 | 0.079
KEGG_CELL_CYCLE | 128 | 21 | 0.93 | 0.0024 | 0.079

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

WNT1,CSNK2A1,PPP2CA,FRAT1,MYC,GPI,DVL1,CSNK1D,HDAC1,GSK3B

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

WNT1,WNT4,CSNK2A1,FRAT1,MYC,CTBP2,FOXN1,TLE2,EP300,WNT11,PPP2CA,GPI,DVL1,FZD6,CSNK1D,GSK3B,SFRP4,LRP5

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

TGFB3,CDK6,RB1,ATR,CDC25A,ATM,HDAC1,GSK3B

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

HSP90AA1,FHL2,ABCB1,ATM,RPA1,EP300,CSNK1D

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

DBF4,TGFB3,CDKN2C,EP300,ANAPC7,TFDP2,ATR,ATM,CDKN1C,HDAC1,MCM7,MYC,CDC7,CCNH,CDK6,RB1,ZBTB17,ORC2L,YWHAE,CDC25A,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_CELL_CYCLE | 128 | 25 | 1.2 | 0.0001 | 0.0049
KEGG_PARKINSONS_DISEASE | 130 | 23 | 1.2 | 0.0001 | 0.0049
KEGG_PATHOGENIC_ESCHERICHIA_COLI_INFECTION | 59 | 15 | 1.6 | 0 | 0.0049
KEGG_HEMATOPOIETIC_CELL_LINEAGE | 88 | 19 | 1.4 | 0.0001 | 0.0055

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

NDUFAB1,ATP6V1G3,ATP12A,ATP6V1B1,COX8A,PPA2,UQCRC2,COX11,UQCRFS1,ATP5L,NDUFS3,ATP5H,ATP6V1H,NDUFA10,ATP6V1A,UQCRH,UQCRB,NDUFB5,NDUFB8,ATP6V1G2,NDUFB1,NDUFB2,TCIRG1,NDUFA5,COX7A2,NDUFA8,ATP5F1,NDUFA1,SDHB,SDHD,ATP6V0A4

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

PTTG2,PTTG1,TGFB1,CCNA2,ESPL1,SKP1,ORC1L,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

NDUFAB1,UBA7,COX8A,UQCRC2,UQCRFS1,NDUFS3,ATP5H,SLC25A4,NDUFA10,UQCRH,UBB,UQCRB,NDUFB5,NDUFB8,NDUFB1,NDUFB2,NDUFA5,COX7A2,NDUFA8,ATP5F1,NDUFA1,SDHB,SDHD

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

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

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

GYPA,CD44,IL4R,CSF3R,CD3G,IL11RA,IL1R2,KIT,ITGAM,CD9,FCGR1A,CD2,CD5,IL6,IL2RA,ITGA3,CD19,ITGA5,CD14

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_WNT_SIGNALING_PATHWAY | 151 | 26 | 0.98 | 0.0004 | 0.039
KEGG_AXON_GUIDANCE | 129 | 23 | 1 | 0.0005 | 0.039
KEGG_COMPLEMENT_AND_COAGULATION_CASCADES | 69 | 16 | 1.4 | 0.0002 | 0.039
KEGG_PATHWAYS_IN_CANCER | 328 | 47 | 0.72 | 0.0003 | 0.039
KEGG_CELL_CYCLE | 128 | 22 | 1 | 0.0008 | 0.054

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

PPP2R5B,BTRC,WNT3A,MMP7,CSNK2A2,WNT1,WNT3,WNT6,ROCK2,EP300,RAC3,CREBBP,PORCN,PRICKLE2,MYC,CTBP2,PRKCG,APC2,TCF7L2,CAMK2B,NFATC3,CSNK2B,FZD6,GSK3B,LRP6,WNT7A

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

EFNA1,ROCK2,EFNA5,GNAI2,ITGB1,SEMA5B,PTK2,RAC3,MLF2,NTN1,NELL1,CXCR4,PAK4,SEMA3F,SEMA3E,LIMK2,LIMK1,CDK5,SLIT2,SRGAP3,SEMA4D,NFATC3,GSK3B

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

MASP2,F8,C8G,CNTN1,PROS1,C9,C6,FGA,CR1,CR2,C4BPB,C4BPA,PLG,CD55,SERPIND1,F2R

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

RARA,RARB,CCNA1,CTNNA2,LAMC3,LAMC1,ITGA2B,RAC3,BMP4,BMP2,MAP2K2,CREBBP,LAMA3,GLI2,NOS2,MYC,CTBP2,APC2,BIRC5,FZD6,RASSF5,GSK3B,WNT7A,PDGFA,WNT3A,WNT1,WNT3,CDKN2B,WNT6,EGFR,EP300,HIF1A,ITGB1,PTK2,EPAS1,E2F1,CYCS,PRKCG,CDK4,TCF7L2,TPM3,MSH6,COL4A2,COL4A1,VHL,MSH2,BAD

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

TTK,PTTG1,CDC16,CDKN2B,CCNA1,ANAPC5,WEE1,MAD2L1,EP300,ANAPC11,CREBBP,CDC20,CDC26,PLK1,E2F1,MYC,CDK4,MCM4,GADD45G,CDC25C,CCNB2,GSK3B

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)
Meta

- Maintainer = Spring Yingchun Liu

Copyright © 2011 Broad Institute TCGA GDAC as part of the TCGA Research Network. All rights reserved.
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