Lung Squamous 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 344 genes with significant mutation (Q value <= 0.1) and 504 genes with significant copy number alteration (Q value <= 0.25). The identified marker genes (Q value <= 0.01 or within top 2000) are 1580 for subtype 1, 1580 for subtype 2, 1580 for subtype 3. Pathways significantly enriched with these genes (Q value <= 0.01) are identified :

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

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

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

11 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_OLFACTORY_TRANSDUCTION | 389 | 48 | 1.6 | 0 | 0
KEGG_OXIDATIVE_PHOSPHORYLATION | 133 | 15 | 1.7 | 0.0001 | 0.0088
KEGG_RIBOSOME | 87 | 12 | 1.8 | 0.0002 | 0.014
KEGG_PARKINSONS_DISEASE | 130 | 14 | 1.6 | 0.0001 | 0.014
KEGG_PROTEASOME | 48 | 8 | 2.2 | 0.0003 | 0.022

List of CNV_Mut genes in this pathway

OR4S2,OR4N2,OR5D16,OR5D18,PDE1C,OR5B12,OR4Q3,OR10R2,OR5T3,OR10Q1,OR4P4,OR2J3,OR8J3,OR51B2,OR5M11,OR52E2,OR52J3,OR8H3,OR8I2,OR8H1,OR4C6,OR4D2,OR4D5,OR8B8,OR8B4,OR5F1,OR2A5,OR9A2,OR5B3,OR5L1,OR5L2,OR5M3,OR4M1,OR5M9,OR10AG1,OR4K5,OR4K1,OR4A15,OR4A16,OR6K3,OR4C13,OR4C16,OR4C15,OR4C12,OR4C11,OR5H6,OR5J2,OR10G9

List of CNV_Mut genes in this pathway

UQCRFS1,NDUFS6,ATP5I,NDUFS2,COX17,NDUFB10,COX4I1,ATP6V1F,ATP6V1A,NDUFB5,NDUFB2,NDUFA5,NDUFA7,ATP6V1E1,SDHC

List of CNV_Mut genes in this pathway

RPL18,RPL36AL,RPL35A,RPS19,RPS16,RPS15,MRPS12,RPS28,RPL24,RPS5,RPL28,MRPL23

List of CNV_Mut genes in this pathway

SLC6A3,LRRK2,UQCRFS1,NDUFS6,NDUFS2,NDUFB10,COX4I1,NDUFB5,NDUFB2,NDUFA5,NDUFA7,PARK2,PARK7,SDHC

List of CNV_Mut genes in this pathway

PSMB5,PSMB4,PSMD2,PSMD7,PSMD8,PSMC6,PSMA6,PSMC4

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_DRUG_METABOLISM_CYTOCHROME_P450 | 72 | 16 | 1.7 | 0 | 0.0038
KEGG_AXON_GUIDANCE | 129 | 23 | 1.4 | 0 | 0.0038
KEGG_GLYCOLYSIS_GLUCONEOGENESIS | 62 | 14 | 1.7 | 0.0001 | 0.008
KEGG_GLUTATHIONE_METABOLISM | 50 | 12 | 1.8 | 0.0001 | 0.0085
KEGG_METABOLISM_OF_XENOBIOTICS_BY_CYTOCHROME_P450 | 70 | 14 | 1.5 | 0.0002 | 0.014

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

CYP2C19,ADH1C,GSTM1,GSTM2,GSTM3,ALDH3B2,ALDH3B1,ADH5,FMO1,FMO2,FMO3,GSTO1,GSTA2,GSTA3,GSTA4,GSTA5

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

PLXNA1,ROBO2,PLXNB1,EFNB2,MAPK1,GNAI1,EPHB3,EPHB6,EPHA1,NTN1,RGS3,SEMA3F,SEMA3E,SEMA3B,PAK1,SLIT1,SEMA4G,NCK1,SEMA4A,ABLIM1,CHP,FYN,GSK3B

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

PGAM1,ADH1C,ACSS1,FBP1,ALDH3B2,ALDH3B1,ALDH7A1,DLD,ADH5,HK2,HK1,ENO3,BPGM,PCK1

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

GSTM1,GPX2,GSTM2,GSR,GSTM3,GCLC,GSTO1,GSTA2,GSTA3,GSTA4,GSTA5,GGT7

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

CYP2C19,ADH1C,GSTM1,GSTM2,GSTM3,AKR1C1,ALDH3B2,ALDH3B1,ADH5,GSTO1,GSTA2,GSTA3,GSTA4,GSTA5

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_ENDOCYTOSIS | 183 | 39 | 1.3 | 0 | 0
KEGG_ARRHYTHMOGENIC_RIGHT_VENTRICULAR_CARDIOMYOPATHY_ARVC | 76 | 18 | 1.5 | 0 | 0.0058
BIOCARTA_AGR_PATHWAY | 36 | 10 | 1.6 | 0.0007 | 0.022
BIOCARTA_INTRINSIC_PATHWAY | 23 | 8 | 2 | 0.0005 | 0.022
KEGG_PYRIMIDINE_METABOLISM | 98 | 19 | 1.2 | 0.0006 | 0.022

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

PSD3,HLA-C,HLA-B,HLA-G,HLA-F,ARRB2,ARFGAP3,ERBB3,ASAP2,ASAP1,ASAP3,SNF8,AP2M1,GIT1,PARD6B,KDR,RABEP1,PIP4K2B,CLTA,VPS37A,IL8RB,VPS37C,CDC42,BRD8,UNC45A,CXCR4,LDLRAP1,RAB11FIP5,RAB11FIP2,ADRB1,CHMP1B,IGF1R,SH3GLB1,IL2RG,EHD2,STAMBP,FAM125B,DNM3,VPS28

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

GJA1,ACTG1,DES,ACTN1,CACNB2,ITGB3,TCF7L2,ITGB1,ITGB7,CACNA2D1,TCF7,ITGA1,ITGA3,LAMA2,ITGA9,DSG2,ITGA8,ITGA7

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

ITGB1,PXN,CDC42,NRG2,ITGA1,DVL1,LAMA2,MAPK1,PSG1,MAPK8

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

F12,F10,COL4A6,COL4A5,PROC,FGG,F5,FGA

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

NP,NME7,NME6,NME5,PNPT1,ZNRD1,TK1,DUT,NT5M,NT5E,POLR1D,POLR1B,UMPS,POLR2F,POLR2K,UCK2,POLR3H,POLR3A,POLR3B

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 | 35 | 1.4 | 0 | 0
KEGG_PATHWAYS_IN_CANCER | 328 | 58 | 1 | 0 | 0
KEGG_BASAL_CELL_CARCINOMA | 55 | 19 | 2 | 0 | 0
BIOCARTA_G1_PATHWAY | 28 | 12 | 2.3 | 0 | 0.0001
KEGG_MELANOGENESIS | 102 | 25 | 1.5 | 0 | 0.0001

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

PPP2R5A,BTRC,WNT3A,MMP7,PRKX,WNT3,CUL1,WNT10A,ROCK1,WNT5A,DAAM2,RAC1,AXIN1,SMAD4,SMAD3,SFRP2,PRICKLE2,LEF1,SUMO1,CCND1,TCF7L2,TCF7L1,NFAT5,CSNK1A1,FZD9,GPI,FZD4,FZD7,WNT2B,FZD6,FZD10,WNT7B,GSK3B,TBL1X,WNT7A

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

FAS,WNT10A,RXRG,MECOM,LAMC2,RAC1,FH,TGFBR2,SMAD4,SMAD3,LAMA4,LAMA3,FGF8,NFKB1,PTEN,TGFA,CCND1,SUFU,FZD9,FZD4,FZD7,FZD6,WNT7B,GSK3B,WNT7A,FGF19,WNT3A,TGFB3,FGF13,MMP2,MMP1,TGFB1,WNT3,CDKN2B,CSF3R,WNT5A,ITGB1,AXIN1,ITGA2,BRCA2,CDKN1B,HDAC1,ABL1,E2F1,HSP90AB1,AKT3,LEF1,CDK4,SMO,NCOA4,DCC,CKS1B,TCF7L2,TCF7L1,MSH6,WNT2B,FZD10,BAX

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

WNT3A,WNT3,WNT10A,LEF1,SMO,WNT5A,TCF7L2,TCF7L1,SUFU,AXIN1,FZD9,FZD4,FZD7,WNT2B,FZD6,WNT7B,FZD10,GSK3B,WNT7A

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

E2F1,TGFB3,TGFB1,CDKN2B,SMAD4,SMAD3,CDK4,CCND1,CDKN1B,HDAC1,GSK3B,ABL1

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

ADCY3,ADCY4,ADCY5,WNT3A,PRKX,WNT3,CREB3L1,CREB3L4,WNT10A,WNT5A,GNAI1,LEF1,TCF7L2,TCF7L1,CALML3,FZD9,FZD4,FZD7,FZD6,WNT2B,WNT7B,FZD10,GSK3B,WNT7A,CALM1

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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