Integrated pathway analysis of nasopharyngeal carcinoma implicates the axonemal dynein complex in the Malaysian cohort

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 transcriptom...

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Bibliographic Details
Published in:International journal of cancer 2016-10, Vol.139 (8), p.1731-1739
Main Authors: Chin, Yoon‐Ming, Tan, Lu Ping, Abdul Aziz, Norazlin, Mushiroda, Taisei, Kubo, Michiaki, Mohd Kornain, Noor Kaslina, Tan, Geok Wee, Khoo, Alan Soo‐Beng, Krishnan, Gopala, Pua, Kin‐Choo, Yap, Yoke‐Yeow, Teo, Soo‐Hwang, Lim, Paul Vey‐Hong, Nakamura, Yusuke, Lum, Chee Lun, Ng, Ching‐Ching
Format: Article
Language:English
Subjects:
Cancer
Carcinoma - genetics
Carcinoma - metabolism
Case-Control Studies
Cohort Studies
Cytoskeleton
Dyneins - genetics
Dyneins - metabolism
Female
Gene expression
Gene Expression Profiling
Genome-Wide Association Study
GWAS
Humans
imputation
Laryngeal cancer
Malaysia
Male
Medical research
Models, Genetic
Nasopharyngeal Carcinoma
Nasopharyngeal Neoplasms - genetics
Nasopharyngeal Neoplasms - metabolism
pathway analysis
Polymorphism, Single Nucleotide
Proteins
RNA, Neoplasm - genetics
RNA, Neoplasm - isolation & purification
RNA, Neoplasm - metabolism
Signal Transduction
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Summary: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. What's new? By combining previously reported genome‐wide association studies and gene expression data in nasopharyngeal carcinoma tissues (NPC), the authors made an unexpected new connection with key proteins in the dynein complex present in a ciliary cytoskeletal structure called axoneme. Their findings point to a loss of function of the axonemal dynein complex in NPCs, which the authors confirmed in independent tissue studies.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.30207