title: Integrated pathway analysis of nasopharyngeal carcinoma implicates the axonemal dynein complex in the Malaysian cohort.
abstract: Nasopharyngeal carcinoma (NPC) is an epithelial squamous cell carcinoma on the mucosal lining of the nasopharynx. The etiology of NPC remains elusive despite many reported studies. Most studies employ a single platform approach, neglecting the cumulative influence of both the genome and transcriptome toward NPC development. We aim to employ an integrated pathway approach to identify dysregulated pathways linked to NPC. Our approach combines imputation NPC GWAS data from a Malaysian cohort as well as published expression data GSE12452 from both NPC and non-NPC nasopharynx tissues. Pathway association for GWAS data was performed using MAGENTA while for expression data, GSA-SNP was used with gene p values derived from differential expression values from GEO2R. Our study identified NPC association in the gene ontology (GO) axonemal dynein complex pathway (pGWAS-GSEA  = 1.98 × 10(-2) ; pExpr-GSEA  = 1.27 × 10(-24) ; pBonf-Combined  = 4.15 × 10(-21) ). This association was replicated in a separate cohort using gene expression data from NPC and non-NPC nasopharynx tissues (pAmpliSeq-GSEA  = 6.56 × 10(-4) ). Loss of function in the axonemal dynein complex causes impaired cilia function, leading to poor mucociliary clearance and subsequently upper or lower respiratory tract infection, the former of which includes the nasopharynx. Our approach illustrates the potential use of integrated pathway analysis in detecting gene sets involved in the development of NPC in the Malaysian cohort.
authors.affiliation: Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Yoon-Ming
authors.initials: YM
authors.lastname: Chin
authors.affiliation: Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur, Malaysia.
authors.forename: Lu Ping
authors.initials: LP
authors.lastname: Tan
authors.affiliation: Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur, Malaysia.
authors.forename: Norazlin
authors.initials: N
authors.lastname: Abdul Aziz
authors.affiliation: Laboratory for Pharmacogenetics, RIKEN Center for Integrative Medical Sciences, Tsurumi-Ku, Yokohama, Kanagawa, Japan.
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.affiliation: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Tsurumi-Ku, Yokohama, Kanagawa, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Pathology, Faculty of Medicine, University Technology MARA (UiTM), Malaysia.
authors.forename: Noor Kaslina
authors.initials: NK
authors.lastname: Mohd Kornain
authors.affiliation: Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur, Malaysia.
authors.forename: Geok Wee
authors.initials: GW
authors.lastname: Tan
authors.affiliation: Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur, Malaysia.
authors.forename: Alan Soo-Beng
authors.initials: AS
authors.lastname: Khoo
authors.affiliation: Department of Otorhinolaryngology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Gopala
authors.initials: G
authors.lastname: Krishnan
authors.affiliation: Department of Otorhinolaryngology, Pulau Pinang General Hospital, Georgetown, Pulau Pinang, Malaysia.
authors.forename: Kin-Choo
authors.initials: KC
authors.lastname: Pua
authors.affiliation: Department of Surgery, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.|Department of Otorhinolaryngology, Kuala Lumpur General Hospital, Kuala Lumpur, Malaysia.
authors.forename: Yoke-Yeow
authors.initials: YY
authors.lastname: Yap
authors.affiliation: Cancer Research Malaysia, Sime Darby Medical Centre, Subang Jaya, Selangor, Malaysia.
authors.forename: Soo-Hwang
authors.initials: SH
authors.lastname: Teo
authors.affiliation: Tung Shin Hospital, Jalan Pudu, Kuala Lumpur, Malaysia.
authors.forename: Paul Vey-Hong
authors.initials: PV
authors.lastname: Lim
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Otorhinolaryngology, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia.
authors.forename: Chee Lun
authors.initials: CL
authors.lastname: Lum
authors.affiliation: Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Ching-Ching
authors.initials: CC
authors.lastname: Ng
mesh_terms: D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D015331:Cohort Studies; D004398:Dyneins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D008296:Malaysia; D008297:Male; D008957:Models, Genetic; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D012334:RNA, Neoplasm; D004398:Dyneins
keywords: GWAS; gene expression; imputation; nasopharyngeal carcinoma; pathway analysis