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

作者：Wei Dai, Hong Zheng, Arthur Kwok Leung Cheung, Clara Sze-Man Tang, Josephine Mun Yee Ko, Bonnie Wing Yan Wong, Merrin Man‐Long Leong, Pak C. Sham, Florence Cheung, Dora Lai‐Wan Kwong, Roger Kai Cheong Ngan, Wai Tong Ng, Chun Chung Yau, Jianji Pan, Xun Peng, Stewart Y. Tung, Zengfeng Zhang, Mingfang Ji, Aks Chiang, Anne W.M. Lee, Victor Lee, Ka-On Lam, Kwok Hung Au, Hoi Ching Cheng, Harry Ho‐Yin Yiu, Maria Li Lung · 发表于：Proceedings of the National Academy of Sciences · 年份：2016 · DOI：10.1073/pnas.1523436113 · 被引用次数：93 · 研究领域：Epigenetics and DNA Methylation、Fibroblast Growth Factor Research、Cancer-related gene regulation

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 ...