LUSC/00: Associate mutation, copy number alteration, and cancer subtype markers with pathways
Overview
Introduction

This pipeline maps genes with mutation, genes with copy number gain/loss AND this alteration is highly correlated with mRNA expression to pathways curated in the KEGG, BIOCARTA, and STKE databases. It identifies pathways significantly enriched with these genes.

This pipeline also maps marker genes of the identified subtypes of cancer to pathways and identifies pathways significantly enriched with markers genes of specific subtypes of cancer.

Summary

There are 5 pathways significantly enriched with genes with copy number gain/loss or mutation.

There are 5 pathways significantly enriched with marker genes of cancer subtype 1

There are 5 pathways significantly enriched with marker genes of cancer subtype 2

There are 5 pathways significantly enriched with marker genes of cancer subtype 3

Results
Top pathways enriched with genes with copy number gain/loss or mutation

Table 1.  Get Full Table Top Pathways enriched with genes with copy number gain/loss or mutation. Nof_Genes : No. of genes in this pathway. Nof_cnvOrMut_Genes : No. of genes with copy number gain/loss or mutation in this pathway. Enrichment , p_value and q_value : See Methods & Data below. cnvOrMut_Genes: genes with copy number gain/loss or mutation in this pathway.

Pathway Nof_Genes Nof_CnvOrMutGenes Enrichment p_value q_value CnvOrMut_Genes
REACTOME_LATE_PHASE_OF_HIV_LIFE_CYCLE 90 22 2.53781287660917 1.28696589994839e-11 9.0216309586382e-09 NCBP2,XPO1,RNGTT,GTF2E1,NUP37,NUP35,TAF4B,NUP85,GTF2H1,TAF11,TAF10,NUP205,RDBP,NUP43,NUP98,POLR2J,POLR2I,POLR2C,NUP54,WHSC2,NUP155,TCEB3
REACTOME_HIV_INFECTION 183 31 2.00873082640438 2.824603573634e-11 9.90023552558716e-09 NCBP2,XPO1,GTF2E1,NUP37,NUP35,TAF4B,PSMA1,RDBP,NUP43,DOCK2,PSMB1,NUP54,WHSC2,PSMC2,RNGTT,PAK2,PSMD8,NUP85,GTF2H1,TAF11,TAF10,NUP205,KPNA1,NUP98,POLR2J,POLR2I,POLR2C,NUP155,AP2A2,PSMD12,TCEB3
REACTOME_HIV_LIFE_CYCLE 103 22 2.34316544575562 2.1907456429679e-10 5.11904231906834e-08 NCBP2,XPO1,GTF2E1,NUP37,NUP35,TAF4B,RDBP,NUP43,NUP54,WHSC2,RNGTT,NUP85,GTF2H1,TAF11,TAF10,NUP205,NUP98,POLR2J,POLR2I,POLR2C,NUP155,TCEB3
REACTOME_GENE_EXPRESSION 425 45 1.37208947921177 4.70503783075543e-09 8.24557879839889e-07 RXRB,TAF4B,RPS19,EIF2S1,MRPS12,RDBP,GTF2H1,TAF11,TAF10,NUP205,RPL37,SF3B5,RPL28,MRPL23,TCEB3,TXNL4A,NCBP2,GTF2E1,DNAJC8,RPL35A,WHSC2,RBMX,NFX1,SARS,NUP85,NUP98,SLBP,NUP37,NUP35,EIF2B4,SF3B14,NUP43,CDC40,NUP54,CREBBP,NOTCH4,RNGTT,MED4,POLR2J,POLR2I,POLR2C,EEF1E1,CARS,TARS,NUP155
REACTOME_INFLUENZA_LIFE_CYCLE 137 21 1.87508893582996 2.26102803805277e-07 3.16996130934999e-05 XPO1,NUP37,NUP35,RPL35A,RPS19,MRPS12,NUP43,NUP54,CLTC,NUP85,NUP205,KPNA1,NUP98,POLR2J,POLR2I,RPL37,POLR2C,GRSF1,NUP155,RPL28,MRPL23
Top pathways enriched with marker genes of identified cancer subtype 1

Table 2.  Get Full Table Top Pathways enriched with marker genes of identified cancer subtype 1 . Nof_Genes : No. of genes in this pathway. Nof_MarkerGenes : No. of marker genes of cancer subtype 1 in this pathway. Enrichment , p_value and q_value : See Methods & Data below. Marker_Gene: markers of cancer subtype 1 in this pathway

Pathway Nof_Genes Nof_MarkerGenes Enrichment p_value q_value Marker_Genes
KEGG_DRUG_METABOLISM_OTHER_ENZYMES 51 17 2.01659161679319 2.19410992217475e-07 0.00015380710554445 CYP3A4,CYP3A5,CYP3A7,IMPDH1,GMPS,UMPS,UGT2B4,UGT2B10,UGT2B15,XDH,HPRT1,TK1,UCK1,UCK2,UGT2B28,NAT2,DPYD
REACTOME_SIGNALING_BY_TGF_BETA 15 7 2.4145556027131 0.000117016459031194 0.0410142688904333 SMAD7,SMAD6,TGFBR1,SMAD4,SMAD2,SKI,SMURF1
BIOCARTA_CASPASE_PATHWAY 23 8 1.990529320207 0.0004367433399092 0.0592283931538092 LMNB2,DFFA,DFFB,BIRC3,BIRC2,CASP4,CASP8,ARHGDIB
KEGG_HOMOLOGOUS_RECOMBINATION 28 9 1.87666135564872 0.000377284309843608 0.0592283931538092 RAD51C,NBN,XRCC2,BLM,RPA2,MUS81,BRCA2,RAD51,POLDIP2
KEGG_ENDOCYTOSIS 183 30 0.94524844090613 0.000262616375800706 0.0592283931538092 PSD3,ARRB2,ERBB3,ASAP2,ASAP3,SNF8,GIT1,PARD6B,KDR,EPS15,SMURF1,LDLR,VPS37A,IL8RA,IL8RB,PIP5K1A,AP2B1,AGAP1,LDLRAP1,RAB11FIP2,ADRB1,CHMP1B,SH3KBP1,SH3GLB1,EHD2,FAM125B,DNM3,DNM1L,RAB22A,ARAP1
Top pathways enriched with marker genes of identified cancer subtype 2

Table 3.  Get Full Table Top Pathways enriched with marker genes of identified cancer subtype 2 . Nof_Genes : No. of genes in this pathway. Nof_MarkerGenes : No. of marker genes of cancer subtype 2 in this pathway. Enrichment , p_value and q_value : See Methods & Data below. Marker_Gene: markers of cancer subtype 2 in this pathway

Pathway Nof_Genes Nof_MarkerGenes Enrichment p_value q_value Marker_Genes
KEGG_PATHWAYS_IN_CANCER 328 57 0.976957093881786 2.94443673895128e-07 0.000136794197334224 PTGS2,PGF,BCR,MECOM,JUP,MAPK8,RAC1,DVL2,TGFBR1,SMAD3,HGF,DVL1,LAMA3,LAMA5,PPARD,FGF8,FGF9,GLI3,GLI1,TGFA,HHIP,FGF2,SUFU,BCL2,IL6,IL8,FZD2,FZD7,FZD6,WNT7B,GSK3B,ARAF,FGF19,FGF18,FGF11,FGF13,WNT3,SLC2A1,RET,STK4,TRAF2,EGF,CSF1R,EPAS1,BRCA2,CDKN1A,AKT1,CDC42,DAPK2,DAPK1,SMO,NCOA4,TCF7L2,FIGF,COL4A4,WNT2B,FZD10
KEGG_CELL_ADHESION_MOLECULES_CAMS 134 29 1.32397616973198 2.04616480413573e-06 0.000475309026498188 SPN,PDCD1LG2,HLA-DPA1,CD226,ITGAL,HLA-DRB1,ITGB2,PVRL1,PVRL3,CTLA4,HLA-DPB1,ITGA9,NLGN4X,CD274,CLDN5,SDC4,PDCD1,SDC2,SDC3,NRXN2,SDC1,CD80,CNTN2,CLDN1,CNTN1,CLDN16,CDH3,VCAM1,CD2
KEGG_AXON_GUIDANCE 129 28 1.3070332229183 3.88721777559857e-06 0.000601981389107974 PLXNA2,PLXNB2,EFNB1,PLXNB3,GNAI3,GNAI1,EPHB4,RAC1,EPHA1,EPHA5,SEMA6C,NELL1,FES,PAK6,PAK7,CDC42,PAK3,SEMA3E,SEMA3C,LIMK2,SLIT1,SLIT2,NCK2,SEMA4B,NFAT5,CHP,DPYSL2,GSK3B
KEGG_MAPK_SIGNALING_PATHWAY 267 45 0.930367534511975 1.19339720980844e-05 0.00111851751968222 MAP3K6,MAP3K5,MECOM,MAPK8,PLA2G2D,CACNB1,DUSP14,RAC1,TGFBR1,FGF8,FGF9,FGF2,FLNB,MAP3K14,MKNK2,GNG12,CHP,GPI,DUSP5,RPS6KA5,RPS6KA6,RPS6KA4,MAPK13,DUSP8,DUSP7,FGF19,FGF18,FGF11,FGF13,IL1A,STK4,ARRB1,HSPB1,TRAF2,FGFR4,MAP4K1,JUND,EGF,CACNA2D1,CACNA2D4,AKT1,CDC42,PPM1A,HSPA2,RASGRP2
KEGG_BASAL_CELL_CARCINOMA 55 16 1.7070032741082 1.20378062165398e-05 0.00111851751968222 GLI3,GLI1,WNT3,HHIP,SMO,TCF7L2,SUFU,DVL2,FZD2,FZD7,WNT2B,DVL1,FZD6,WNT7B,FZD10,GSK3B
Top pathways enriched with marker genes of identified cancer subtype 3

Table 4.  Get Full Table Top Pathways enriched with marker genes of identified cancer subtype 3 . Nof_Genes : No. of genes in this pathway. Nof_MarkerGenes : No. of marker genes of cancer subtype 3 in this pathway. Enrichment , p_value and q_value : See Methods & Data below. Marker_Gene: markers of cancer subtype 3 in this pathway

Pathway Nof_Genes Nof_MarkerGenes Enrichment p_value q_value Marker_Genes
REACTOME_SIGNALING_IN_IMMUNE_SYSTEM 366 75 1.37567268159663 4.21645179364177e-15 2.95573270734288e-12 B2M,CD47,CD3G,CD3D,C1QA,LILRB1,LILRB2,C1QB,HLA-DRB5,HLA-DOA,TYROBP,CFB,CD58,ANGPT1,ICAM1,ICAM3,SLC3A2,ECSIT,SIGIRR,KLRG1,MAP3K14,HLA-DQB1,C7,CD177,C2,RPS6KA5,RPS6KA1,RPS6KA2,CD14,SLC7A8,TLR4,TLR7,SLC7A7,SPN,HLA-A,TNFRSF14,HLA-C,HLA-B,HLA-G,HLA-F,HCST,THBD,RIPK2,ITGAL,ITGB3,IRAK4,IRAK3,ITGB7,TEK,TRAF6,FN1,ITK,VAV1,ORC3L,ITGA6,CD8B,PDCD1,MAPKAP1,ESAM,SLC7A11,PRKCQ,CD86,LCK,ULBP2,UBB,JAM2,JAM3,VCAM1,CD2,CD4,SELPLG,PIK3R2,PTPRC,OLR1,MAP3K7IP2
KEGG_CELL_ADHESION_MOLECULES_CAMS 134 39 1.76303522243262 2.82263291072097e-12 9.893328352077e-10 SPN,PTPRM,HLA-A,HLA-C,HLA-B,HLA-G,HLA-F,ITGAL,ITGB7,HLA-DRB5,HLA-DOA,ITGA9,ITGA6,ITGA8,CD58,CLDN8,CD8B,PDCD1,SDC3,CNTNAP2,ESAM,ICAM1,ICAM3,CD86,CLDN1,JAM2,JAM3,HLA-DQB1,CLDN18,CLDN19,CDH2,NEO1,CDH5,VCAM1,CD2,CD4,SELPLG,PTPRC,CLDN23
KEGG_AXON_GUIDANCE 129 29 1.36929712495423 1.16759438278108e-06 0.00013641394372159 PLXNB1,EFNB1,PLXNB3,CHP2,RND1,PLXNC1,GNAI1,EPHB3,EPHB2,EPHB6,EPHA2,NELL1,FES,PAK7,CXCR4,SEMA3F,SEMA3E,SEMA3B,LIMK2,SLIT1,CFL2,SRGAP3,SEMA4B,SEMA4A,ABLIM1,ABLIM2,CHP,NTNG1,GSK3B
REACTOME_HEMOSTASIS 273 49 1.0272478194637 8.12299379858176e-07 0.00013641394372159 GNGT2,CD47,F12,F5,GNAI1,HGF,CD58,SERPINA1,ANGPT1,SLC3A2,APBB1IP,DGKE,CD177,F2RL2,GNA14,GNA15,SLC7A8,TGFB2,SLC7A7,SPN,ACTN2,THBD,ITGAL,ITGB3,FGG,FGA,TEK,SRGN,FN1,VAV1,ITGA6,TBXA2R,HABP4,ESAM,SLC7A11,PRKCB,LCK,JAM2,JAM3,CD9,RASGRP3,RASGRP2,CD2,NRG1,FIGF,SELPLG,PIK3R2,OLR1,PSAP
REACTOME_IMMUNOREGULATORY_INTERACTIONS_BETWEEN_A_LYMPHOID_AND_A_NON_LYMPHOID_CELL 106 20 1.71340445470802 1.03370048408479e-06 0.00013641394372159 B2M,CD3G,CD3D,HLA-A,HLA-C,HLA-B,HLA-G,HLA-F,HCST,LILRB1,LILRB2,ITGAL,ITGB7,TYROBP,CD8B,ICAM1,ICAM3,KLRG1,ULBP2,VCAM1
Methods & Data
Input

genes with copy number gain/loss: identified by the CopyNumber_Gistic2 pipeline

genes with mutation: identified by the Mutation_Significance pipeline

copy number gain/loss correlate with mRNA expression: identified by the Correlate_CopyNumber_vs_mRNA pipeline

marker genes of identified cancer subtypes: identified by the mRNAConsensusClustering pipeline

Enrichment

Let genes with copy number gain/loss 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 gain/loss 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.

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)