Association of mutation, copy number alteration, and subtype markers with pathways
Uterine Corpus Endometrioid Carcinoma (Primary solid tumor)
23 May 2013  |  analyses__2013_05_23
Maintainer Information
Citation Information
doi:10.7908/C1BR8Q82
Maintained by Spring Yingchun Liu (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2013): Association of mutation, copy number alteration, and subtype markers with pathways. Broad Institute of MIT and Harvard. doi:10.7908/C1BR8Q82
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 29 genes with significant mutation (Q value <= 0.1) and 395 genes with significant copy number alteration (Q value <= 0.25). The identified marker genes (Q value <= 0.01 or within top 2000) are 238 for subtype 1, 238 for subtype 2, 238 for subtype 3. Pathways significantly enriched with these genes (Q value <= 0.01) are identified :

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

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

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

1 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_ENDOMETRIAL_CANCER 52 13 3.6 0 0
KEGG_PROSTATE_CANCER 89 13 2.8 0 0
KEGG_THYROID_CANCER 29 8 3.8 0 0
BIOCARTA_TNFR1_PATHWAY 29 7 3.6 0 0.0001
KEGG_PATHWAYS_IN_CANCER 328 22 1.7 0 0.0001
List of CNV_Mut genes in this pathway

HRAS,PTEN,CTNNB1,CASP9,PIK3CA,MYC,TP53,CCND1,ERBB2,CDH1,KRAS,PIK3R1,NRAS

List of CNV_Mut genes in this pathway

HRAS,PTEN,CTNNB1,CCNE1,CASP9,PIK3CA,TP53,CCND1,FGFR2,ERBB2,KRAS,PIK3R1,NRAS

List of CNV_Mut genes in this pathway

HRAS,CDH1,CTNNB1,KRAS,MYC,TP53,NRAS,CCND1

List of CNV_Mut genes in this pathway

TRAF2,CASP8,CASP2,ETFA,MAP2K4,TRADD,PARP1

List of CNV_Mut genes in this pathway

HRAS,CTNNB1,PIK3CA,ERBB2,KRAS,FH,PTEN,CCNE1,MYC,CTBP1,TP53,CCND1,NRAS,FGFR2,TRAF2,ARNT,TRAF4,CASP9,CASP8,EGLN1,CDH1,PIK3R1

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_AMINO_SUGAR_AND_NUCLEOTIDE_SUGAR_METABOLISM 44 4 3.1 0.0011 0.38
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
List of marker genes for gene expression subtype 1 in this pathway

GNE,GNPNAT1,GALK2,FUK

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 25 2.7 0 0
KEGG_RIBOSOME 87 13 2.2 0 0.0002
KEGG_SPLICEOSOME 126 15 2.1 0 0.0002
KEGG_OOCYTE_MEIOSIS 114 15 2.1 0 0.0002
KEGG_P53_SIGNALING_PATHWAY 69 11 2.3 0 0.0005
List of marker genes for gene expression subtype 2 in this pathway

DBF4,TTK,PTTG1,CCNA2,RBL1,ANAPC4,SKP2,ESPL1,ORC1L,CHEK1,CDC20,PLK1,E2F1,CCNE1,CDC45L,MCM2,MCM4,CDK2,BUB1B,GADD45B,GADD45A,BUB1,CDC25C,CCNB1,CCNB2

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

RPL19,RPL15,RPLP0,RPS4X,RPS15A,RPL9,RPL3,RPL7A,RPL26,RPS9,RPS6,RPL13A,RPL22

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

CHERP,CTNNBL1,RBM8A,LSM3,HNRNPC,SNRPB2,HNRNPA1,PPIH,PRPF3,SNRNP200,THOC4,PRPF38A,SR140,SF3B4,USP39

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

PTTG1,PGR,SGOL1,ANAPC4,ESPL1,CDC20,PLK1,CCNE1,CDK2,CALML3,BUB1,CDC25C,CCNB1,RPS6KA6,CCNB2

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

PMAIP1,GTSE1,CCNE1,TP53I3,CDK2,RRM2,GADD45B,GADD45A,CHEK1,CCNB1,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_CELL_CYCLE 128 19 2 0 0.0001
BIOCARTA_G2_PATHWAY 24 6 2.7 0.0002 0.041
KEGG_OOCYTE_MEIOSIS 114 13 1.6 0.0004 0.045
KEGG_GLUTATHIONE_METABOLISM 50 7 1.9 0.0027 0.22
BIOCARTA_MCM_PATHWAY 18 4 2.5 0.0045 0.23
List of marker genes for gene expression subtype 3 in this pathway

TTK,PTTG1,CDKN2A,ANAPC4,CHEK1,CHEK2,CDC20,E2F1,CCNE1,MCM2,MCM4,MDM2,BUB1B,GADD45B,ORC2L,BUB1,CDC25C,CDC25B,CCNB2

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

CHEK1,CHEK2,CDC25C,CDC25B,RPS6KA1,MDM2

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

PTTG1,MOS,ANAPC4,CDC20,CCNE1,CALML3,BUB1,CALML6,CDC25C,RPS6KA6,CCNB2,ADCY9,RPS6KA1

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

GGT1,GSTM4,GSTZ1,GSTK1,ODC1,GGT7,MGST2

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

MCM2,MCM4,CCNE1,ORC2L

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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