Lung Squamous 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 115 genes with significant mutation (Q value <= 0.1) and 290 genes with significant copy number alteration (Q value <= 0.25). The identified marker genes (Q value <= 0.01 or within top 2000) are 1163 for subtype 1, 1163 for subtype 2, 1163 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.

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

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

6 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 24 1.7 0 0.0002
KEGG_UBIQUITIN_MEDIATED_PROTEOLYSIS 137 11 2.1 0.0001 0.0089
KEGG_SPLICEOSOME 126 9 2 0.0003 0.037
KEGG_MTOR_SIGNALING_PATHWAY 52 6 2.6 0.0005 0.039
KEGG_PROTEIN_EXPORT 24 4 3.2 0.0009 0.059
List of CNV_Mut genes in this pathway

OR2T2,OR2T5,OR2T8,OR2AK2,OR8K5,OR8K3,OR51B2,OR2T33,OR5AC2,OR2T29,OR2T12,OR52J3,OR8H2,OR2A5,OR10A4,OR6F1,OR2G6,OR5L2,OR4M2,OR4M1,OR5M9,OR5AS1,OR6K3,OR10G8

List of CNV_Mut genes in this pathway

CUL5,CUL1,ANAPC4,SKP2,FBXO4,UBE2F,UBE2K,UBE3C,UBE4A,PARK2,BIRC2

List of CNV_Mut genes in this pathway

SNRPA1,AQR,HNRNPC,SNRPF,PPIE,CDC5L,DHX16,BCAS2,TXNL4A

List of CNV_Mut genes in this pathway

BRAF,MAPK1,STK11,PRKAA1,RHEBP1,EIF4E2

List of CNV_Mut genes in this pathway

SRP14,OXA1L,SRPR,SEC61G

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_GLUTATHIONE_METABOLISM 50 12 2.2 0 0.0017
KEGG_DRUG_METABOLISM_CYTOCHROME_P450 72 14 1.9 0 0.0022
KEGG_METABOLISM_OF_XENOBIOTICS_BY_CYTOCHROME_P450 70 13 1.8 0 0.005
KEGG_AXON_GUIDANCE 129 15 1.2 0.0023 0.15
KEGG_DILATED_CARDIOMYOPATHY 92 12 1.4 0.0022 0.15
List of marker genes for gene expression subtype 1 in this pathway

GSTM5,GSTM1,GPX2,GSTM2,GSR,GSTM3,GCLC,GSTO1,GSTA3,GSTA4,GSTA5,GGT7

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

CYP2C19,GSTM5,GSTM1,GSTM2,GSTM3,ALDH3B2,ALDH3B1,ADH5,ALDH3A1,FMO3,GSTO1,GSTA3,GSTA4,GSTA5

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

CYP2C19,GSTM5,GSTM1,GSTM2,GSTM3,ALDH3B2,ALDH3B1,ADH5,ALDH3A1,GSTO1,GSTA3,GSTA4,GSTA5

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

PLXNA1,PLXNB1,EFNB2,MAPK1,EPHB3,EPHA1,RGS3,SEMA3F,PAK1,SEMA4G,NCK1,SEMA4B,CHP,FYN,GSK3B

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

ADCY8,ADCY6,PRKX,SGCG,MYL3,CACNB2,ITGB5,TPM4,SLC8A1,ITGA2,ATP2A2,ITGA7

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
BIOCARTA_AGR_PATHWAY 36 12 1.9 0 0.0043
KEGG_ENDOCYTOSIS 183 33 1.1 0 0.0043
KEGG_ARRHYTHMOGENIC_RIGHT_VENTRICULAR_CARDIOMYOPATHY_ARVC 76 18 1.5 0 0.0044
KEGG_FOCAL_ADHESION 201 34 0.95 0.0001 0.0072
BIOCARTA_INTRINSIC_PATHWAY 23 8 2 0.0005 0.02
List of marker genes for gene expression subtype 2 in this pathway

ITGB1,PXN,CDC42,PAK1,NRG2,ITGA1,DVL1,LAMA2,MAPK1,LAMA4,PSG1,MAPK8

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

PSD3,HLA-C,HLA-G,HLA-F,ARRB2,ERBB3,ASAP2,ASAP1,ASAP3,SNF8,AP2M1,GIT1,PARD6B,KDR,RABEP1,PIP4K2B,VPS37A,IL8RB,VPS37C,CDC42,BRD8,UNC45A,CXCR4,ADRB1,CHMP1B,IGF1R,HSPA2,SH3GLB1,IL2RG,EHD2,STAMBP,FAM125B,DNM3

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

ACTG1,DES,ACTN1,CACNB2,ITGB3,TCF7L2,ITGB1,ITGB7,CACNA2D1,TCF7,ITGA1,ITGA3,LAMA2,ITGA6,DSG2,ITGA8,ITGA7,DSC2

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

ACTG1,ILK,RAPGEF1,PIK3CG,BRAF,MAPK1,MAPK8,PXN,LAMB4,KDR,LAMA2,LAMA1,LAMA4,PTEN,CCND1,CAPN2,BIRC2,FYN,ACTN1,CAV2,ITGB3,ITGB1,DOCK1,ITGB7,ITGA1,ITGA3,ITGA6,ITGA8,ITGA7,CDC42,PAK1,IGF1R,PIK3R3,COL4A6

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

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

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_BASAL_CELL_CARCINOMA 55 16 2 0 0.0004
KEGG_WNT_SIGNALING_PATHWAY 151 27 1.3 0 0.0021
KEGG_MELANOGENESIS 102 20 1.4 0 0.0045
KEGG_PATHWAYS_IN_CANCER 328 44 0.86 0.0001 0.0054
BIOCARTA_G1_PATHWAY 28 9 2.1 0.0001 0.0066
List of marker genes for gene expression subtype 3 in this pathway

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

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

PPP2R5A,WNT3A,MMP7,WNT3,CUL1,WNT10A,WNT5A,DAAM2,RAC1,SMAD4,SFRP2,LEF1,CTNNBIP1,SUMO1,CCND1,TCF7L1,NFAT5,CSNK1A1,FZD9,GPI,FZD4,FZD7,WNT2B,FZD6,FZD10,WNT7B,WNT7A

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

ADCY3,ADCY5,WNT3A,WNT3,CREB3L1,CREB3L4,WNT10A,WNT5A,LEF1,TCF7L1,CALML3,CALML5,FZD9,FZD4,FZD7,FZD6,WNT2B,WNT7B,FZD10,WNT7A

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

WNT10A,MECOM,LAMC2,RAC1,FH,SMAD4,LAMA4,LAMA3,FGF8,NFKB1,TGFA,CCND1,SUFU,FZD9,FZD4,FZD7,FZD6,WNT7B,WNT7A,FGF19,WNT3A,TGFB3,FGF13,MMP1,WNT3,CDKN2B,CSF3R,STK4,WNT5A,ITGB1,ITGA2,BRCA2,CDKN1A,CDKN1B,HDAC1,ABL1,AKT3,LEF1,SMO,NCOA4,TCF7L1,MSH6,WNT2B,FZD10

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

TGFB3,CDKN2B,SMAD4,CCND1,CDKN1A,CDKN1B,DHFR,HDAC1,ABL1

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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