Lung Adenocarcinoma: 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 161 genes with significant mutation (Q value <= 0.1) and 448 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 :

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

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

2 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_PARKINSONS_DISEASE | 130 | 13 | 2 | 0 | 0.0059
KEGG_RIBOSOME | 87 | 11 | 2.1 | 0 | 0.0061
KEGG_WNT_SIGNALING_PATHWAY | 151 | 14 | 1.7 | 0.0001 | 0.0099
KEGG_ENDOMETRIAL_CANCER | 52 | 8 | 2.4 | 0.0001 | 0.0099
KEGG_ALZHEIMERS_DISEASE | 167 | 14 | 1.6 | 0.0002 | 0.011

List of CNV_Mut genes in this pathway

VDAC3,COX6A1,UQCRC1,PINK1,NDUFS5,CASP3,NDUFS4,CASP9,ATP5H,PARK7,SDHB,SDHD,SLC18A1

List of CNV_Mut genes in this pathway

RPL18,RPL14,RPL15,RPS13,RPS11,RPL37,RPL38,RPL10L,RPL32,RPL29,MRPL23

List of CNV_Mut genes in this pathway

PPP2R5E,DVL2,DVL3,RHOA,PPP2R1B,SUMO1,PSEN1,PPP2CA,PPP2CB,PPP3CC,CHP,PPP3CA,APC,FZD5

List of CNV_Mut genes in this pathway

CASP9,ILK,EGFR,BRAF,CTNNA2,APC,RAF1,NRAS

List of CNV_Mut genes in this pathway

COX6A1,UQCRC1,NDUFS5,CASP3,NDUFS4,CASP9,ATP5H,PSEN1,PPP3CC,CHP,PPP3CA,SDHB,SDHD,APBB1

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_SYSTEMIC_LUPUS_ERYTHEMATOSUS | 140 | 11 | 2.1 | 0 | 0.0066
KEGG_HOMOLOGOUS_RECOMBINATION | 28 | 5 | 3.2 | 0.0002 | 0.021
BIOCARTA_MCM_PATHWAY | 18 | 4 | 3.5 | 0.0004 | 0.025
KEGG_OOCYTE_MEIOSIS | 114 | 9 | 2 | 0.0004 | 0.025

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

DBF4,TTK,CCNA2,MAD2L1,ORC6L,CDC20,CDC27,CDC45L,CDC6,CDC2,MCM4,CCND3,BUB1B,ORC2L,BUB3,CDC25C,CDC25A,CCNB2

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

H2AFZ,H2AFX,HIST1H2AD,HIST2H2AB,C7,C3,HIST1H2AG,HIST1H2AE,HIST1H2AI,HIST1H2AH,HIST1H2AL

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

CDC6,MCM4,ORC2L,ORC6L

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

AURKA,SGOL1,MAD2L1,FBXO5,CDC20,CDC27,CDC2,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_FOCAL_ADHESION | 201 | 10 | 2.2 | 0.0001 | 0.014
KEGG_ECM_RECEPTOR_INTERACTION | 84 | 7 | 2.9 | 0 | 0.014
KEGG_PATHOGENIC_ESCHERICHIA_COLI_INFECTION | 59 | 5 | 3 | 0.0003 | 0.037
KEGG_TRYPTOPHAN_METABOLISM | 40 | 4 | 3.2 | 0.0008 | 0.069
KEGG_HYPERTROPHIC_CARDIOMYOPATHY_HCM | 85 | 5 | 2.4 | 0.0024 | 0.16

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

LAMC2,RAC2,SPP1,COL11A1,PARVB,COL6A3,COL6A1,COL1A1,ITGA2,ACTB

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

COL11A1,LAMC2,COL1A1,COL6A3,COL6A1,SPP1,ITGA2

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

TUBB6,NCK1,TUBA3C,TUBA3D,ACTB

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

TPM2,TPM4,ACTB,ITGA2,CACNA2D4

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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