title: Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma.
abstract: Multiple factors, including host genetics, environmental factors, and Epstein-Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage-stimulating 1 receptor (MST1R) and NPC. We identified 13 independent cases carrying the MST1R pathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating that MST1R germline variants are relevant to disease early-age onset (EAO) (age of ≤20 y). In total, five MST1R missense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs. 1.2%, P = 7.94 × 10(-12)). The validation study, including 2,160 cases and 2,433 controls, showed that the MST1R variant c.G917A:p.R306H is highly associated with NPC (odds ratio of 9.0). MST1R is predominantly expressed in the tissue-resident macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Importantly, MST1R expression is detected in the ciliated epithelial cells in normal nasopharyngeal mucosa and plays a role in the cilia motility important for host defense. Although no somatic mutation of MST1R was identified in the sporadic NPC tumors, copy number alterations and promoter hypermethylation at MST1R were often observed. Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of the MST1R-mediated signaling pathways.
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Wei
authors.initials: W
authors.lastname: Dai
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Arthur Kwok Leung
authors.initials: AK
authors.lastname: Cheung
authors.affiliation: Department of Psychiatry, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Clara Sze-man
authors.initials: CS
authors.lastname: Tang
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Josephine Mun Yee
authors.initials: JM
authors.lastname: Ko
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Bonnie Wing Yan
authors.initials: BW
authors.lastname: Wong
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Merrin Man Long
authors.initials: MM
authors.lastname: Leong
authors.affiliation: Department of Psychiatry, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China; Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Pak Chung
authors.initials: PC
authors.lastname: Sham
authors.affiliation: Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China; Department of Pathology, University of Hong Kong-Shenzhen Hospital, 518048 Shenzhen, People's Republic of China;
authors.forename: Florence
authors.initials: F
authors.lastname: Cheung
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China; Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Dora Lai-Wan
authors.initials: DL
authors.lastname: Kwong
authors.affiliation: Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China; Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Roger Kai Cheong
authors.initials: RK
authors.lastname: Ngan
authors.affiliation: Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China; Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Wai Tong
authors.initials: WT
authors.lastname: Ng
authors.affiliation: Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China; Department of Oncology, Princess Margaret Hospital, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Chun Chung
authors.initials: CC
authors.lastname: Yau
authors.affiliation: Fujian Provincial Cancer Hospital and Fujian Provincial Key Laboratory of Translational Cancer Medicine (Fujian Provincial Cancer Hospital, Fujian Medical University Union Hospital), 350011 Fuzhou, People's Republic of China;
authors.forename: Jianji
authors.initials: J
authors.lastname: Pan
authors.affiliation: Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, 515041 Shantou, People's Republic of China;
authors.forename: Xun
authors.initials: X
authors.lastname: Peng
authors.affiliation: Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China; Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Stewart
authors.initials: S
authors.lastname: Tung
authors.affiliation: Department of Pathology, Guangxi Medical University, 530021 Guangxi, People's Republic of China;
authors.forename: Zengfeng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Cancer Research Institute, Cancer Research Institute of Zhongshan City, 528403 Zhongshan, People's Republic of China;
authors.forename: Mingfang
authors.initials: M
authors.lastname: Ji
authors.affiliation: Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China; Department of Pediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China.
authors.forename: Alan Kwok-Shing
authors.initials: AK
authors.lastname: Chiang
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China; Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Anne Wing-Mui
authors.initials: AW
authors.lastname: Lee
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China; Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Victor Ho-Fun
authors.initials: VH
authors.lastname: Lee
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China; Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Ka-On
authors.initials: KO
authors.lastname: Lam
authors.affiliation: Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China; Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Kwok Hung
authors.initials: KH
authors.lastname: Au
authors.affiliation: Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Hoi Ching
authors.initials: HC
authors.lastname: Cheng
authors.affiliation: Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong (Special Administrative Region), People's Republic of China;
authors.forename: Harry Ho-Yin
authors.initials: HH
authors.lastname: Yiu
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China; Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China; mlilung@hku.hk.
authors.forename: Maria Li
authors.initials: ML
authors.lastname: Lung
mesh_terms: D000293:Adolescent; D000328:Adult; D002277:Carcinoma; D016022:Case-Control Studies; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017421:Sequence Analysis; D055815:Young Adult
chemical_list: C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases
keywords: MST1R; cancer susceptibility genes; early-age onset; nasopharyngeal carcinoma; whole-exome sequencing