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

TitleWhole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma
Authors
KeywordsMST1R
Early-age onset
Whole-exome sequencing
Nasopharyngeal carcinoma
Cancer susceptibility genes
Issue Date2016
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings of the National Academy of Sciences, 2016, v. 113 n. 12, p. 3317-3322 How to Cite?
AbstractMultiple 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-residentmacrophages 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.
Persistent Identifierhttp://hdl.handle.net/10722/225621
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorDai, W-
dc.contributor.authorZheng, H-
dc.contributor.authorCheung, AKL-
dc.contributor.authorTang, SM-
dc.contributor.authorKo, JMY-
dc.contributor.authorWong, WY-
dc.contributor.authorLeong, ML-
dc.contributor.authorSham, PC-
dc.contributor.authorCheung, MFF-
dc.contributor.authorKwong, DLW-
dc.contributor.authorNgan, KC-
dc.contributor.authorNg, WT-
dc.contributor.authorYau, CC-
dc.contributor.authorChiang, AKS-
dc.contributor.authorLee, WMA-
dc.contributor.authorLee, VHF-
dc.contributor.authorLam, KO-
dc.contributor.authorAu, GKH-
dc.contributor.authorLung, ML-
dc.date.accessioned2016-05-20T08:09:26Z-
dc.date.available2016-05-20T08:09:26Z-
dc.date.issued2016-
dc.identifier.citationProceedings of the National Academy of Sciences, 2016, v. 113 n. 12, p. 3317-3322-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/225621-
dc.description.abstractMultiple 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-residentmacrophages 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.-
dc.languageeng-
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org-
dc.relation.ispartofProceedings of the National Academy of Sciences-
dc.rightsProceedings of the National Academy of Sciences. Copyright © National Academy of Sciences.-
dc.subjectMST1R-
dc.subjectEarly-age onset-
dc.subjectWhole-exome sequencing-
dc.subjectNasopharyngeal carcinoma-
dc.subjectCancer susceptibility genes-
dc.titleWhole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma-
dc.typeArticle-
dc.identifier.emailDai, W: weidai2@hku.hk-
dc.identifier.emailCheung, AKL: arthurhk@hku.hk-
dc.identifier.emailTang, SM: claratang@hku.hk-
dc.identifier.emailKo, JMY: joko@hku.hk-
dc.identifier.emailWong, WY: bonniewongwy@hku.hk-
dc.identifier.emailSham, PC: pcsham@hku.hk-
dc.identifier.emailCheung, MFF: cheungf@hku.hk-
dc.identifier.emailKwong, DLW: dlwkwong@hku.hk-
dc.identifier.emailNgan, KC: rkcngan@hkucc.hku.hk-
dc.identifier.emailNg, WT: ngwt1@hkucc.hku.hk-
dc.identifier.emailYau, CC: yaucc@hkucc.hku.hk-
dc.identifier.emailChiang, AKS: chiangak@hku.hk-
dc.identifier.emailLee, WMA: awmlee@hkucc.hku.hk-
dc.identifier.emailLee, VHF: vhflee@hku.hk-
dc.identifier.emailLam, KO: lamkaon@hku.hk-
dc.identifier.emailAu, GKH: hkugkhau@hku.hk-
dc.identifier.emailLung, ML: mlilung@hku.hk-
dc.identifier.authorityDai, W=rp02146-
dc.identifier.authorityCheung, AKL=rp01769-
dc.identifier.authorityTang, SM=rp02105-
dc.identifier.authorityKo, JMY=rp02011-
dc.identifier.authoritySham, PC=rp00459-
dc.identifier.authorityKwong, DLW=rp00414-
dc.identifier.authorityChiang, AKS=rp00403-
dc.identifier.authorityLee, WMA=rp02056-
dc.identifier.authorityLee, VHF=rp00264-
dc.identifier.authorityLam, KO=rp01501-
dc.identifier.authorityLung, ML=rp00300-
dc.identifier.doi10.1073/pnas.1523436113-
dc.identifier.pmid26951679-
dc.identifier.pmcidPMC4812767-
dc.identifier.scopuseid_2-s2.0-84962254911-
dc.identifier.hkuros258002-
dc.identifier.volume113-
dc.identifier.issue12-
dc.identifier.spage3317-
dc.identifier.epage3322-
dc.publisher.placeUnited States-

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