Association of mutation, copy number alteration, and subtype markers with pathways
Lung Adenocarcinoma (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/C1RJ4H3G
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 93 genes with significant mutation (Q value <= 0.1) and 524 genes with significant copy number alteration (Q value <= 0.25). The identified marker genes (Q value <= 0.01 or within top 2000) are 19 for subtype 1, 19 for subtype 2, 19 for subtype 3. Pathways significantly enriched with these genes (Q value <= 0.01) are identified :

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

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

1 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_MELANOMA 71 13 2.6 0 0
KEGG_BLADDER_CANCER 42 10 3 0 0
KEGG_NON_SMALL_CELL_LUNG_CANCER 54 10 2.7 0 0.0004
KEGG_PANCREATIC_CANCER 70 11 2.4 0 0.0005
KEGG_PROSTATE_CANCER 89 12 2.2 0 0.0007
List of CNV_Mut genes in this pathway

PDGFA,FGF14,FGF12,CDKN2A,EGFR,BRAF,TP53,RB1,CDK4,FGFR1,KRAS,RAF1,NRAS

List of CNV_Mut genes in this pathway

ERBB2,KRAS,CDKN2A,EGFR,BRAF,TP53,RAF1,RB1,CDK4,NRAS

List of CNV_Mut genes in this pathway

CDKN2A,EGFR,BRAF,TP53,RB1,CDK4,ERBB2,KRAS,RAF1,NRAS

List of CNV_Mut genes in this pathway

CDKN2A,EGFR,BRAF,TP53,RB1,CDK4,ERBB2,KRAS,RAC1,SMAD4,RAF1

List of CNV_Mut genes in this pathway

PDGFA,CCNE1,EGFR,BRAF,TP53,RB1,FGFR1,ERBB2,KRAS,BCL2,RAF1,NRAS

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_RELA_PATHWAY 16 0 0 1 1
BIOCARTA_NO1_PATHWAY 31 0 0 1 1
BIOCARTA_CSK_PATHWAY 24 0 0 1 1
BIOCARTA_AMI_PATHWAY 20 0 0 1 1
BIOCARTA_ARAP_PATHWAY 18 0 0 1 1
List of marker genes for gene expression subtype 1 in this pathway

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

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

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

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

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_CELL_CYCLE 128 18 2.9 0 0
KEGG_HOMOLOGOUS_RECOMBINATION 28 5 3.2 0.0002 0.02
KEGG_SYSTEMIC_LUPUS_ERYTHEMATOSUS 140 10 2 0.0002 0.02
BIOCARTA_MCM_PATHWAY 18 4 3.5 0.0003 0.023
KEGG_OOCYTE_MEIOSIS 114 9 2 0.0003 0.023
List of marker genes for gene expression subtype 2 in this pathway

DBF4,TTK,CCNA2,MAD2L1,ORC6L,CDC20,CDC45L,CDC6,CDC2,MCM4,CCND3,BUB1B,ORC2L,BUB1,BUB3,CDC25C,CDC25A,CCNB2

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

BLM,SHFM1,ATRX,RAD51,RAD54B

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

H2AFZ,H2AFX,HIST2H2AB,C7,C3,HIST1H2AG,HIST1H2AE,HIST1H2AI,HIST1H2AH,HIST1H2AL

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

CDC6,MCM4,ORC2L,ORC6L

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

AURKA,SGOL1,MAD2L1,FBXO5,CDC20,CDC2,BUB1,CDC25C,CCNB2

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_ECM_RECEPTOR_INTERACTION 84 6 2.8 0.0003 0.085
KEGG_TRYPTOPHAN_METABOLISM 40 4 3.3 0.0007 0.11
KEGG_GLYCOLYSIS_GLUCONEOGENESIS 62 4 2.6 0.0041 0.43
KEGG_FOCAL_ADHESION 201 7 1.7 0.0052 0.43
KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION 44 3 2.7 0.01 0.57
List of marker genes for gene expression subtype 3 in this pathway

COL11A1,LAMC2,COL1A1,COL6A3,COL6A1,ITGA2

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

AADAT,MAOA,INMT,ALDH1B1

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

ACSS1,PFKP,ALDH1B1,PGK1

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

LAMC2,COL11A1,PARVB,COL6A3,COL6A1,COL1A1,ITGA2

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

BCAT2,BCKDHB,ALDH1B1

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)