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Proc Natl Acad Sci U S A. 2016 Mar 22;113(12):3317-22. doi: 10.1073/pnas.1523436113. Epub 2016 Mar 7.

Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma.

Author information

1
Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China;
2
Department of Psychiatry, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China;
3
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;
4
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;
5
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;
6
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;
7
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;
8
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;
9
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;
10
Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, 515041 Shantou, People's Republic of China;
11
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;
12
Department of Pathology, Guangxi Medical University, 530021 Guangxi, People's Republic of China;
13
Cancer Research Institute, Cancer Research Institute of Zhongshan City, 528403 Zhongshan, People's Republic of China;
14
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.
15
Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong (Special Administrative Region), People's Republic of China;
16
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.

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.

KEYWORDS:

MST1R; cancer susceptibility genes; early-age onset; nasopharyngeal carcinoma; whole-exome sequencing

PMID:
26951679
PMCID:
PMC4812767
DOI:
10.1073/pnas.1523436113
[Indexed for MEDLINE]
Free PMC Article

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