Exome and genome sequencing of nasopharynx cancer identifies NF-? B pathway activating mutations

Yvonne Y. Li; Grace T.Y. Chung; Vivian W.Y. Lui; Ka Fai To; Brigette B.Y. Ma; Chit Chow; John K.S. Woo; Kevin Y. Yip; Jeongsun Seo; Edwin P. Hui; Michael K.F. Mak; Maria Rusan; Nicole G. Chau; Yvonne Y.Y. Or; Marcus H.N. Law; Peggy P.Y. Law; Zoey W.Y. Liu; Hoi Lam Ngan; Pok Man Hau; Krista R. Verhoeft; Peony H.Y. Poon; Seong Keun Yoo; Jong Yeon Shin; Sau Dan Lee; Samantha W.M. Lun; Lin Jia; Anthony W.H. Chan; Jason Y.K. Chan; Paul B.S. Lai; Choi Yi Fung; Suet Ting Hung; Lin Wang; Ann Margaret V. Chang; Simion I. Chiosea; Matthew L. Hedberg; Sai Wah Tsao; Andrew C. Van Hasselt; Anthony T.C. Chan; Jennifer R. Grandis; Peter S. Hammerman; Kwok Wai Lo

doi:10.1038/ncomms14121

Exome and genome sequencing of nasopharynx cancer identifies NF-? B pathway activating mutations

Yvonne Y. Li, Grace T.Y. Chung, Vivian W.Y. Lui, Ka Fai To, Brigette B.Y. Ma, Chit Chow, John K.S. Woo, Kevin Y. Yip, Jeongsun Seo, Edwin P. Hui, Michael K.F. Mak, Maria Rusan, Nicole G. Chau, Yvonne Y.Y. Or, Marcus H.N. Law, Peggy P.Y. Law, Zoey W.Y. Liu, Hoi Lam Ngan, Pok Man Hau, Krista R. VerhoeftPeony H.Y. Poon, Seong Keun Yoo, Jong Yeon Shin, Sau Dan Lee, Samantha W.M. Lun, Lin Jia, Anthony W.H. Chan, Jason Y.K. Chan, Paul B.S. Lai, Choi Yi Fung, Suet Ting Hung, Lin Wang, Ann Margaret V. Chang, Simion I. Chiosea, Matthew L. Hedberg, Sai Wah Tsao, Andrew C. Van Hasselt, Anthony T.C. Chan, Jennifer R. Grandis, Peter S. Hammerman, Kwok Wai Lo

Research output: Contribution to journal › Article › peer-review

231 Scopus citations

Abstract

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-? B pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-? B signalling, and we observed mutual exclusivity among tumours with somatic NF-? B pathway aberrations and LMP1-overexpression, suggesting that NF-? B activation is selected for by both somatic and viral events during NPC pathogenesis.

Original language	English (US)
Article number	14121
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14121
State	Published - Jan 18 2017
Externally published	Yes

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms14121

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Li, Y. Y., Chung, G. T. Y., Lui, V. W. Y., To, K. F., Ma, B. B. Y., Chow, C., Woo, J. K. S., Yip, K. Y., Seo, J., Hui, E. P., Mak, M. K. F., Rusan, M., Chau, N. G., Or, Y. Y. Y., Law, M. H. N., Law, P. P. Y., Liu, Z. W. Y., Ngan, H. L., Hau, P. M., ... Lo, K. W. (2017). Exome and genome sequencing of nasopharynx cancer identifies NF-? B pathway activating mutations. Nature communications, 8, Article 14121. https://doi.org/10.1038/ncomms14121

Li, YY, Chung, GTY, Lui, VWY, To, KF, Ma, BBY, Chow, C, Woo, JKS, Yip, KY, Seo, J, Hui, EP, Mak, MKF, Rusan, M, Chau, NG, Or, YYY, Law, MHN, Law, PPY, Liu, ZWY, Ngan, HL, Hau, PM, Verhoeft, KR, Poon, PHY, Yoo, SK, Shin, JY, Lee, SD, Lun, SWM, Jia, L, Chan, AWH, Chan, JYK, Lai, PBS, Fung, CY, Hung, ST, Wang, L, Chang, AMV, Chiosea, SI, Hedberg, ML, Tsao, SW, Van Hasselt, AC, Chan, ATC, Grandis, JR, Hammerman, PS & Lo, KW 2017, 'Exome and genome sequencing of nasopharynx cancer identifies NF-? B pathway activating mutations', Nature communications, vol. 8, 14121. https://doi.org/10.1038/ncomms14121

@article{65a0e86db7dc43e98df59eab26905bed,

title = "Exome and genome sequencing of nasopharynx cancer identifies NF-? B pathway activating mutations",

abstract = "Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-? B pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-? B signalling, and we observed mutual exclusivity among tumours with somatic NF-? B pathway aberrations and LMP1-overexpression, suggesting that NF-? B activation is selected for by both somatic and viral events during NPC pathogenesis.",

author = "Li, {Yvonne Y.} and Chung, {Grace T.Y.} and Lui, {Vivian W.Y.} and To, {Ka Fai} and Ma, {Brigette B.Y.} and Chit Chow and Woo, {John K.S.} and Yip, {Kevin Y.} and Jeongsun Seo and Hui, {Edwin P.} and Mak, {Michael K.F.} and Maria Rusan and Chau, {Nicole G.} and Or, {Yvonne Y.Y.} and Law, {Marcus H.N.} and Law, {Peggy P.Y.} and Liu, {Zoey W.Y.} and Ngan, {Hoi Lam} and Hau, {Pok Man} and Verhoeft, {Krista R.} and Poon, {Peony H.Y.} and Yoo, {Seong Keun} and Shin, {Jong Yeon} and Lee, {Sau Dan} and Lun, {Samantha W.M.} and Lin Jia and Chan, {Anthony W.H.} and Chan, {Jason Y.K.} and Lai, {Paul B.S.} and Fung, {Choi Yi} and Hung, {Suet Ting} and Lin Wang and Chang, {Ann Margaret V.} and Chiosea, {Simion I.} and Hedberg, {Matthew L.} and Tsao, {Sai Wah} and {Van Hasselt}, {Andrew C.} and Chan, {Anthony T.C.} and Grandis, {Jennifer R.} and Hammerman, {Peter S.} and Lo, {Kwok Wai}",

note = "Funding Information: This study is supported by Core Utilities of Cancer Genomics and Pathobiology, Themebased Research Scheme (T12-401/13-R), Research Grant Council, Hong Kong. K.-W.L. is funded by Research Grant Council, Hong Kong (#471413, 470312, 471211, 1404415, 14138016, General Research Fund), Focused Innovations Scheme and Faculty Strategic Research (4620513) of Faculty of Medicine, and VC's One-off Discretionary Fund (VCF2014017, VCF2014015), The Chinese University of Hong Kong. S.-W.T. is supported by AoE/M-06/08. V.W.Y.L. is funded by the Research Grant Council, Hong Kong (#17114814, General Research Fund), and the Start-up Fund from the School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong. K.-F.T. is funded by the Research Grant Council, Hong Kong (General Research Fund #14138016 and #14104415). M.L.H. is supported by NCI F30CA180235. P.S.H. is supported by NCI K08 CA163677.",

year = "2017",

month = jan,

day = "18",

doi = "10.1038/ncomms14121",

language = "English (US)",

volume = "8",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Exome and genome sequencing of nasopharynx cancer identifies NF-? B pathway activating mutations

AU - Li, Yvonne Y.

AU - Chung, Grace T.Y.

AU - Lui, Vivian W.Y.

AU - To, Ka Fai

AU - Ma, Brigette B.Y.

AU - Chow, Chit

AU - Woo, John K.S.

AU - Yip, Kevin Y.

AU - Seo, Jeongsun

AU - Hui, Edwin P.

AU - Mak, Michael K.F.

AU - Rusan, Maria

AU - Chau, Nicole G.

AU - Or, Yvonne Y.Y.

AU - Law, Marcus H.N.

AU - Law, Peggy P.Y.

AU - Liu, Zoey W.Y.

AU - Ngan, Hoi Lam

AU - Hau, Pok Man

AU - Verhoeft, Krista R.

AU - Poon, Peony H.Y.

AU - Yoo, Seong Keun

AU - Shin, Jong Yeon

AU - Lee, Sau Dan

AU - Lun, Samantha W.M.

AU - Jia, Lin

AU - Chan, Anthony W.H.

AU - Chan, Jason Y.K.

AU - Lai, Paul B.S.

AU - Fung, Choi Yi

AU - Hung, Suet Ting

AU - Wang, Lin

AU - Chang, Ann Margaret V.

AU - Chiosea, Simion I.

AU - Hedberg, Matthew L.

AU - Tsao, Sai Wah

AU - Van Hasselt, Andrew C.

AU - Chan, Anthony T.C.

AU - Grandis, Jennifer R.

AU - Hammerman, Peter S.

AU - Lo, Kwok Wai

N1 - Funding Information: This study is supported by Core Utilities of Cancer Genomics and Pathobiology, Themebased Research Scheme (T12-401/13-R), Research Grant Council, Hong Kong. K.-W.L. is funded by Research Grant Council, Hong Kong (#471413, 470312, 471211, 1404415, 14138016, General Research Fund), Focused Innovations Scheme and Faculty Strategic Research (4620513) of Faculty of Medicine, and VC's One-off Discretionary Fund (VCF2014017, VCF2014015), The Chinese University of Hong Kong. S.-W.T. is supported by AoE/M-06/08. V.W.Y.L. is funded by the Research Grant Council, Hong Kong (#17114814, General Research Fund), and the Start-up Fund from the School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong. K.-F.T. is funded by the Research Grant Council, Hong Kong (General Research Fund #14138016 and #14104415). M.L.H. is supported by NCI F30CA180235. P.S.H. is supported by NCI K08 CA163677.

PY - 2017/1/18

Y1 - 2017/1/18

N2 - Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-? B pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-? B signalling, and we observed mutual exclusivity among tumours with somatic NF-? B pathway aberrations and LMP1-overexpression, suggesting that NF-? B activation is selected for by both somatic and viral events during NPC pathogenesis.

AB - Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-? B pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-? B signalling, and we observed mutual exclusivity among tumours with somatic NF-? B pathway aberrations and LMP1-overexpression, suggesting that NF-? B activation is selected for by both somatic and viral events during NPC pathogenesis.

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U2 - 10.1038/ncomms14121

DO - 10.1038/ncomms14121

M3 - Article

C2 - 28098136

AN - SCOPUS:85010443067

SN - 2041-1723

VL - 8

JO - Nature communications

JF - Nature communications

M1 - 14121

ER -

Exome and genome sequencing of nasopharynx cancer identifies NF-? B pathway activating mutations

Abstract

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UN SDGs

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