Association of mutation, copy number alteration, and subtype markers with pathways
Lung Squamous Cell Carcinoma (Primary solid tumor)
16 April 2014  |  analyses__2014_04_16
Maintainer Information
Citation Information
Maintained by Spring Yingchun Liu (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2014): Association of mutation, copy number alteration, and subtype markers with pathways. Broad Institute of MIT and Harvard. doi:10.7908/C1FX783Q
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 14 genes with significant mutation (Q value <= 0.1) and 201 genes with significant copy number alteration (Q value <= 0.25). The identified marker genes (Q value <= 0.01 or within top 2000) are 1094 for subtype 1, 1094 for subtype 2, 1094 for subtype 3, 1094 for subtype 4. Pathways significantly enriched with these genes (Q value <= 0.01) are identified :

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

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

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

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

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

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_G1_PATHWAY 28 5 4.1 0 0.0028
BIOCARTA_TEL_PATHWAY 18 4 4.4 0 0.0031
BIOCARTA_ARF_PATHWAY 17 4 4.5 0 0.0031
BIOCARTA_CTCF_PATHWAY 23 4 4.1 0.0001 0.0065
KEGG_UBIQUITIN_MEDIATED_PROTEOLYSIS 137 7 2.4 0.0004 0.028
List of CNV_Mut genes in this pathway

CDKN2A,TFDP1,SKP2,TP53,RB1

List of CNV_Mut genes in this pathway

XRCC5,TP53,RB1,PTEN

List of CNV_Mut genes in this pathway

TP53,RB1,CDKN2A,PIK3CA

List of CNV_Mut genes in this pathway

TP53,PTEN,CDKN2A,PIK3CA

List of CNV_Mut genes in this pathway

SAE1,SKP2,KEAP1,FBXW7,UBE2L3,UBE2F,CUL4A

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_ENDOCYTOSIS 183 21 1.3 0.0001 0.032
KEGG_TIGHT_JUNCTION 134 17 1.4 0.0002 0.032
KEGG_ADHERENS_JUNCTION 75 10 1.5 0.0026 0.28
KEGG_GLYCOSAMINOGLYCAN_BIOSYNTHESIS_CHONDROITIN_SULFATE 22 5 2.2 0.0034 0.28
BIOCARTA_MPR_PATHWAY 34 6 1.9 0.0052 0.35
List of marker genes for gene expression subtype 1 in this pathway

HRAS,VPS4B,EGFR,ARRB1,SH3GL1,ERBB3,ASAP2,TRAF6,AP2M1,PARD6A,NEDD4,IL8RA,IL8RB,BRD8,LDLRAP1,ADRB2,EEA1,KIT,VPS36,TFRC,RNF41

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

HRAS,OCLN,AMOTL1,CSNK2A1,F11R,CSDA,CGN,MYL5,GNAI1,PPP2R2C,PARD6A,CLDN7,CLDN9,PPP2R2A,CLDN16,MLLT4,TJP3

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

IQGAP1,CSNK2A1,EGFR,MAPK1,TCF7L1,PVRL4,MLLT4,SMAD3,SNAI1,FYN

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

CHST3,XYLT2,CHST11,CHST14,CHSY1

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

HRAS,GNAI1,PAQR7,ACTR3,ACTR2,MAPK1

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 11 1.8 0.0002 0.023
KEGG_DRUG_METABOLISM_OTHER_ENZYMES 51 13 1.6 0.0002 0.023
BIOCARTA_INTRINSIC_PATHWAY 23 8 2 0.0005 0.034
KEGG_NEUROTROPHIN_SIGNALING_PATHWAY 126 23 1 0.0005 0.034
BIOCARTA_AMI_PATHWAY 20 7 2 0.001 0.049
List of marker genes for gene expression subtype 2 in this pathway

ITGB1,PXN,CDC42,DMD,PAK1,NRG2,DVL1,LAMA2,MAPK1,PSG1,MAPK3

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

CYP3A5,IMPDH1,UMPS,UGT2B10,UGT2B15,XDH,TK1,UCK1,UCK2,UGT2B28,UPB1,TPMT,DPYD

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

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

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

MAGED1,BRAF,IRS1,MAPK1,MAPK3,RIPK2,IRAK4,ARHGDIB,PLCG1,ABL1,CDC42,CRKL,ZNF274,CALML3,CAMK2B,CALML5,PIK3R3,YWHAB,RPS6KA3,MAPK12,RPS6KA1,RPS6KA2,YWHAQ

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

F10,F7,COL4A6,COL4A5,PROC,FGA,FGB

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_METABOLISM_OF_XENOBIOTICS_BY_CYTOCHROME_P450 70 8 2.2 0.0003 0.11
KEGG_DRUG_METABOLISM_CYTOCHROME_P450 72 7 2 0.002 0.13
KEGG_ECM_RECEPTOR_INTERACTION 84 8 1.9 0.0012 0.13
KEGG_ADHERENS_JUNCTION 75 7 1.9 0.0023 0.13
KEGG_HYPERTROPHIC_CARDIOMYOPATHY_HCM 85 8 1.9 0.0011 0.13
List of marker genes for gene expression subtype 3 in this pathway

CYP3A4,CYP3A5,CYP3A7,AKR1C3,GSTM4,AKR1C1,ALDH3B2,GSTO1

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

CYP3A4,CYP3A5,CYP3A7,GSTM4,ALDH3B2,FMO4,GSTO1

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

SDC2,ITGB3,ITGAV,THBS1,THBS2,COL4A2,COL4A1,ITGA1

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

ERBB2,PVRL1,RAC2,SORBS1,TGFBR1,SNAI1,FYN

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

SGCD,ITGB3,TPM1,ITGAV,IL6,ACTC1,ITGA1,CACNA1C

The top five pathways enriched with marker genes of gene expression subtype 4

Table 5.  Get Full Table Top Pathways enriched with marker genes of gene expression subtype 4 . Nof Genes : No. of genes in this pathway. Nof Marker : No. of marker genes of gene expression subtype 4 in this pathway. Enrichment , P value and Q value : See Methods & Data below. Marker Gene in Pathway: markers of gene expression subtype 4 in this pathway

Pathway Nof Genes Nof Marker Enrichment P value Q value
KEGG_CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION 267 48 1 0 0
KEGG_CELL_ADHESION_MOLECULES_CAMS 134 38 1.7 0 0
KEGG_TYPE_I_DIABETES_MELLITUS 44 15 2 0 0
KEGG_AUTOIMMUNE_THYROID_DISEASE 53 17 2 0 0
KEGG_ALLOGRAFT_REJECTION 38 15 2.3 0 0
List of marker genes for gene expression subtype 4 in this pathway

OSMR,IFNE,CD40,CCR6,CCR2,CX3CR1,PDGFRA,IL1R2,CD70,KDR,FLT3LG,IL20RB,CXCL5,CSF1,CCL21,IL8,CCL11,CCL13,PDGFB,IL15,TGFB1,IL11,TGFB2,CSF3R,IL15RA,PDGFC,C19orf10,IL24,BMPR2,CCL5,EGF,CXCL16,IL22RA2,CXCR4,IFNGR2,LTB,IL18RAP,IFNAR1,AMH,TNFSF13B,NGFR,ACVR1,TNFRSF8,PF4,TNFRSF1A,TNFRSF1B,FLT1,TNFSF4

List of marker genes for gene expression subtype 4 in this pathway

MPZL1,PTPRM,HLA-A,HLA-C,CD40,HLA-B,HLA-E,HLA-G,HLA-F,PHOX2A,CD34,HLA-DPA1,HLA-DRA,ITGAM,ALCAM,CTLA4,ITGA6,CLDN8,CLDN3,HLA-DMB,HLA-DMA,ESAM,NRXN3,ICAM3,CD86,CD80,CLDN1,CNTN1,VCAN,JAM3,HLA-DQB1,CDH1,CDH5,VCAM1,SELPLG,CD28,SELL,SELE

List of marker genes for gene expression subtype 4 in this pathway

HLA-DQB1,HLA-DMB,HLA-DMA,CD28,HLA-A,HLA-C,HLA-B,HLA-E,HLA-G,HLA-F,CD86,CD80,HLA-DPA1,HSPD1,HLA-DRA

List of marker genes for gene expression subtype 4 in this pathway

HLA-DMB,HLA-DMA,HLA-A,HLA-C,HLA-B,CD40,HLA-E,HLA-G,HLA-F,CD86,CD80,HLA-DPA1,HLA-DRA,HLA-DQB1,TSHB,CD28,CTLA4

List of marker genes for gene expression subtype 4 in this pathway

HLA-DQB1,HLA-DMB,HLA-DMA,CD28,HLA-A,HLA-C,HLA-B,CD40,HLA-E,HLA-G,HLA-F,CD86,CD80,HLA-DPA1,HLA-DRA

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

In addition to the links below, the full results of the analysis summarized in this report can also be downloaded programmatically using firehose_get, or interactively from either the Broad GDAC website or TCGA Data Coordination Center Portal.

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)