Kidney Renal Clear Cell Carcinoma: 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 29 genes with significant mutation (Q value <= 0.1) and 411 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

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
--- | --- | --- | --- | --- | ---
KEGG_NOTCH_SIGNALING_PATHWAY | 47 | 6 | 2.6 | 0.0004 | 0.048
KEGG_ALZHEIMERS_DISEASE | 167 | 11 | 1.8 | 0.0004 | 0.048
KEGG_HUNTINGTONS_DISEASE | 183 | 12 | 1.8 | 0.0003 | 0.048
KEGG_OXIDATIVE_PHOSPHORYLATION | 133 | 9 | 1.9 | 0.0007 | 0.055
KEGG_VIBRIO_CHOLERAE_INFECTION | 56 | 6 | 2.4 | 0.0009 | 0.06

List of CNV_Mut genes in this pathway

NUMB,DLL1,SNW1,NCSTN,NOTCH2,HDAC2

List of CNV_Mut genes in this pathway

ATP5C1,ATF6,UQCRC1,UQCRFS1,CASP9,CDK5,NDUFB2,NDUFA5,NCSTN,GSK3B,CALM1

List of CNV_Mut genes in this pathway

TBP,CREB3L2,ATP5C1,NFE2L1,HDAC2,UQCRC1,UQCRFS1,GPX1,CASP9,SLC25A4,NDUFB2,NDUFA5

List of CNV_Mut genes in this pathway

ATP5C1,UQCRC1,UQCRFS1,COX17,ATP6V1F,ATP6V1A,NDUFB2,NDUFA5,ATP6V0A4

List of CNV_Mut genes in this pathway

ACTG1,CFTR,ATP6V1F,ATP6V1A,SEC61A1,ATP6V0A4

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.

- 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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