LUAD/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
KEGG_FOCAL_ADHESION 201 11 2.06393403190352 6.78218335232762e-05 0.0134085930772973 BRAF,ERBB2,ITGA11,LAMB4,LAMA1,LAMA3,SOS2,EGFR,RELN,TNC,COL4A6
KEGG_LONG_TERM_POTENTIATION 70 7 2.91919893892251 3.6787902056953e-05 0.0134085930772973 GRIN2B,PLCB1,BRAF,GRM1,KRAS,ITPR2,CACNA1C
KEGG_GNRH_SIGNALING_PATHWAY 101 8 2.59727084403515 5.21578274645203e-05 0.0134085930772973 ADCY2,EGFR,KRAS,CACNA1C,PLCB1,MAP3K1,SOS2,ITPR2
ST_G_ALPHA_I_PATHWAY 34 5 3.4755922874469 7.65112301129659e-05 0.0134085930772973 SOS2,PLCB1,EGFR,BRAF,ITPR2
KEGG_ECM_RECEPTOR_INTERACTION 84 7 2.65616453308872 0.000118925518603148 0.0166733577081613 RELN,TNC,ITGA11,LAMB4,COL4A6,LAMA1,LAMA3
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
REACTOME_CELL_CYCLE_MITOTIC 304 41 1.2587004416364 1.26297237094202e-07 8.85343632030359e-05 AURKA,CDCA8,ANAPC1,RFC4,ZWINT,NEK2,TK1,NUF2,ALMS1,CDC20,NDC80,CDT1,DYNLL1,BUB1,FEN1,PRKAR2B,RAD21,SGOL2,SOX2,SPC25,TUBB2A,PSMB6,GINS1,CASC5,CDKN1A,UBE2E1,E2F2,KIF2C,CDC45L,MCM8,RANBP2,BUB1B,MAPRE1,PSMB10,RPA1,CENPA,KIF18A,CENPF,SFI1,CDC25A,ORC3L
KEGG_HEMATOPOIETIC_CELL_LINEAGE 88 17 1.84422136893349 2.92307326415694e-06 0.00102453717908701 CD44,CD3D,IL6R,HLA-DRA,CSF2,ITGB3,IL7R,CD1C,ITGA1,CD1B,ITGA2,CD1A,ITGA3,ITGA4,CD1E,CD59,EPOR
REACTOME_MITOTIC_PROMETAPHASE 92 17 1.71297683565523 1.06072303098536e-05 0.00247855614906913 KIF2C,CDCA8,RAD21,RANBP2,SGOL2,ZWINT,BUB1B,MAPRE1,SPC25,CENPA,BUB1,NUF2,KIF18A,CASC5,CENPF,CDC20,NDC80
REACTOME_MITOTIC_M_M_G1_PHASES 157 23 1.37801715762729 1.86569292307227e-05 0.00326962684768414 CDCA8,RAD21,SGOL2,ZWINT,SPC25,PSMB6,NUF2,CASC5,NDC80,CDC20,E2F2,CDT1,KIF2C,MCM8,RANBP2,BUB1B,MAPRE1,PSMB10,CENPA,BUB1,KIF18A,CENPF,ORC3L
KEGG_ECM_RECEPTOR_INTERACTION 84 15 1.66364912329166 5.24275100700049e-05 0.00735033691181469 CD47,CD44,TNC,ITGB3,COL6A3,COL6A2,COL6A1,TNN,ITGA1,ITGA2,ITGA3,ITGA4,COL4A6,ITGA9,LAMA3
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
REACTOME_CELL_CYCLE_MITOTIC 304 100 1.89126308980755 6.00074342261197e-33 4.20652113925099e-30 AURKA,PTTG1,AURKB,PRIM1,CDCA8,INCENP,NUP37,SKP2,MBD1,ORC1L,RFC5,MAD2L1,RFC2,ZWINT,TUBA4A,CCDC99,TK1,FBXO5,SKA2,CDC20,NDC80,CDC27,DHFR,PCNA,CDT1,CCNE2,CCNE1,DYNLL1,TUBB3,CDC7,CDC6,DSN1,CCND3,RRM2,NUP107,DYNC1I2,POLA2,BUB3,CEP135,BIRC5,PSMD14,CCNB2,KIF20A,DBF4,KNTC1,PKMYT1,SGOL2,SGOL1,FGFR1OP,PSMA7,PSMB4,SPC25,TUBB2A,POLE2,PSMB3,ORC6L,ERCC6L,GINS1,GINS2,GINS4,CASC5,DNA2,PLK4,PSMC4,PSMC2,E2F1,KIF23,KIF2C,CDC45L,MCM8,MCM7,TUBA1A,KIF2A,CDC2,CDK6,NUP85,MCM2,UBE2C,MCM4,CDK2,MCM6,BUB1B,CKS1B,HAUS2,TYMS,TUBGCP6,ORC2L,CENPO,CENPN,CENPM,CENPQ,CENPP,KIF18A,CENPF,CENPE,CENPK,CDC25C,MLF1IP,CDC25A,CENPH
REACTOME_MITOTIC_M_M_G1_PHASES 157 55 1.98207337810944 3.93693078721536e-20 1.37989424091898e-17 KNTC1,AURKB,CDCA8,INCENP,NUP37,SGOL2,SGOL1,ORC1L,MAD2L1,ZWINT,CCDC99,PSMA7,PSMB4,SPC25,PSMB3,ORC6L,FBXO5,SKA2,ERCC6L,CASC5,NDC80,CDC20,PSMC4,PSMC2,E2F1,KIF23,CDT1,KIF2C,MCM8,MCM7,KIF2A,CDC6,DSN1,NUP85,MCM2,MCM4,MCM6,BUB1B,NUP107,ORC2L,BUB3,CENPO,CENPN,CENPM,CENPQ,CENPP,KIF18A,CENPF,BIRC5,CENPE,CENPK,MLF1IP,CENPH,PSMD14,KIF20A
REACTOME_MITOTIC_PROMETAPHASE 92 35 2.10105547436436 1.41914222052169e-14 3.31606232195236e-12 KNTC1,AURKB,KIF2C,CDCA8,INCENP,NUP37,KIF2A,DSN1,SGOL2,SGOL1,NUP85,MAD2L1,ZWINT,BUB1B,NUP107,CCDC99,SPC25,SKA2,BUB3,ERCC6L,CENPO,CENPN,CENPM,CENPQ,CENPP,KIF18A,CASC5,CENPF,CDC20,CENPE,BIRC5,NDC80,CENPK,MLF1IP,CENPH
REACTOME_G1_S_TRANSITION 102 36 1.99283407294723 8.88477689519569e-14 1.55705715088304e-11 DBF4,PRIM1,SKP2,ORC1L,PSMA7,TK1,PSMB4,POLE2,PSMB3,ORC6L,FBXO5,DHFR,PSMC4,PSMC2,PCNA,E2F1,CDT1,CCNE2,CCNE1,MCM8,CDC45L,MCM7,CDC7,CDC2,CDC6,MCM2,MCM4,CDK2,MCM6,RRM2,CKS1B,POLA2,TYMS,ORC2L,CDC25A,PSMD14
KEGG_CELL_CYCLE 128 40 1.8630661979769 1.16939061088622e-13 1.63948563646248e-11 DBF4,PKMYT1,PTTG2,PTTG1,CDKN2D,RBL2,RBL1,SKP2,ESPL1,ORC1L,MAD2L1,CHEK1,ORC6L,TFDP2,CDC20,CDC27,PCNA,E2F1,CCNE2,CCNE1,CDC45L,MCM7,CDC7,CDC6,CDC2,CDK6,MCM2,MCM4,CDK2,MCM6,CCND3,MDM2,BUB1B,YWHAZ,ORC2L,BUB3,CDC25C,CDC25A,CCNB2,YWHAQ
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
KEGG_ECM_RECEPTOR_INTERACTION 84 34 2.16431824499125 6.94264145223942e-15 4.86679165801983e-12 CHAD,CD44,SV2A,COL11A1,SDC1,COL1A2,LAMC2,COL1A1,TNC,COL3A1,ITGA11,ITGB3,HMMR,ITGAV,COL6A3,COL6A2,COL6A1,GP1BA,THBS1,LAMB1,THBS2,FN1,SPP1,COL4A4,ITGA1,ITGA2,ITGA3,COL5A3,COL5A2,COL5A1,LAMA4,LAMA3,ITGA5,ITGA7
KEGG_FOCAL_ADHESION 201 51 1.50497354794751 3.00423776203428e-12 1.05298533559302e-09 ACTG1,MYLK2,VEGFC,VEGFA,LAMC2,ITGA11,RAC2,LAMB1,SPP1,LAMA4,LAMA3,COL11A1,FLNC,CCND3,PARVB,COL3A1,COL6A3,COL6A2,COL6A1,THBS1,THBS2,CHAD,VCL,ACTN1,COL1A2,COL1A1,CAV2,ITGB3,MYL9,ITGAV,FN1,ITGA1,ITGA2,ITGA3,VAV1,ITGA5,ITGA7,MYLK,ZYX,AKT3,TNC,PPP1R12A,PIK3R3,FIGF,ACTB,COL4A4,FLT1,COL5A3,COL5A2,COL5A1,GRLF1
REACTOME_HEMOSTASIS 273 51 1.05413532724082 2.81744368279108e-07 6.58342673878849e-05 A2M,ATP1B3,SERPINE1,GNG7,F12,PLAUR,VEGFC,PPBP,VEGFA,TUBA4A,CALU,FCER1G,CD58,PLAU,PRSS8,LYN,GNB4,GNG12,THBS1,THBS2,SLC16A3,GNG10,SLC7A8,TGFB3,SLC7A7,VCL,SLC16A1,ACTN1,COL1A2,COL1A1,PPIL2,CLU,ITGB3,ITGAM,TIMP1,ITGAV,ADRA2C,SRGN,FN1,ITGA2,ITGA3,VAV1,ITGA5,TBXA2R,AKT3,TREM1,LCP2,LEFTY2,GP1BA,FIGF,SPARC
REACTOME_POST_CHAPERONIN_TUBULIN_FOLDING_PATHWAY 19 10 2.62117591996472 7.04541767961391e-07 0.000123470944835234 TBCA,TBCD,TUBA3C,TUBA3D,TUBB6,TUBA4A,TUBA1A,TUBA1B,TUBA1C,TUBB3
REACTOME_AXON_GUIDANCE 160 33 1.20068399059377 3.6413523045916e-06 0.000370362639147482 PLXNA2,SEMA7A,ROBO2,PLXNB1,PLXNB3,COL1A2,COL1A1,MYL6,CACNB4,MYL9,RAC2,ITGA1,ABL2,NELL1,RHOC,PRSS8,RHOG,ARHGEF12,NCK1,PRNP,COL3A1,COL9A2,COL6A3,COL6A2,COL6A1,COL4A4,PTPRC,COL4A3,SERPINB8,DPYSL3,COL5A2,COL5A1,GRLF1
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)