title: Whole-exome sequencing identifies multiple loss-of-function mutations of NF-κB pathway regulators in nasopharyngeal carcinoma.
abstract: Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with a unique geographical distribution. The genomic abnormalities leading to NPC pathogenesis remain unclear. In total, 135 NPC tumors were examined to characterize the mutational landscape using whole-exome sequencing and targeted resequencing. An APOBEC cytidine deaminase mutagenesis signature was revealed in the somatic mutations. Noticeably, multiple loss-of-function mutations were identified in several NF-κB signaling negative regulators NFKBIA, CYLD, and TNFAIP3 Functional studies confirmed that inhibition of NFKBIA had a significant impact on NF-κB activity and NPC cell growth. The identified loss-of-function mutations in NFKBIA leading to protein truncation contributed to the altered NF-κB activity, which is critical for NPC tumorigenesis. In addition, somatic mutations were found in several cancer-relevant pathways, including cell cycle-phase transition, cell death, EBV infection, and viral carcinogenesis. These data provide an enhanced road map for understanding the molecular basis underlying NPC.
authors.affiliation: Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Dai
authors.affiliation: Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Arthur Kwok Leung
authors.initials: AK
authors.lastname: Cheung
authors.affiliation: Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Josephine Mun Yee
authors.initials: JM
authors.lastname: Ko
authors.affiliation: Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kan
authors.affiliation: Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Bonnie Wing Yan
authors.initials: BW
authors.lastname: Wong
authors.affiliation: Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Merrin Man Long
authors.initials: MM
authors.lastname: Leong
authors.affiliation: Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Mingdan
authors.initials: M
authors.lastname: Deng
authors.affiliation: Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Tommy Chin Tung
authors.initials: TC
authors.lastname: Kwok
authors.affiliation: Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong, People's Republic of China; Department of Surgery, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Jimmy Yu-Wai
authors.initials: JY
authors.lastname: Chan
authors.affiliation: Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China; Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Dora Lai-Wan
authors.initials: DL
authors.lastname: Kwong
authors.affiliation: Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China; Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Anne Wing-Mui
authors.initials: AW
authors.lastname: Lee
authors.affiliation: Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong, People's Republic of China; Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Hong Kong, People's Republic of China.
authors.forename: Wai Tong
authors.initials: WT
authors.lastname: Ng
authors.affiliation: Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong, People's Republic of China; Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, People's Republic of China.
authors.forename: Roger Kai Cheong
authors.initials: RK
authors.lastname: Ngan
authors.affiliation: Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong, People's Republic of China; Department of Oncology, Princess Margaret Hospital, Hong Kong, People's Republic of China.
authors.forename: Chun Chung
authors.initials: CC
authors.lastname: Yau
authors.affiliation: Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong, People's Republic of China; Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong, People's Republic of China.
authors.forename: Stewart
authors.initials: S
authors.lastname: Tung
authors.affiliation: Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China; Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Victor Ho-Fun
authors.initials: VH
authors.lastname: Lee
authors.affiliation: Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China; Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Ka-On
authors.initials: KO
authors.lastname: Lam
authors.affiliation: Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong, People's Republic of China; Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, People's Republic of China.
authors.forename: Chung Kong
authors.initials: CK
authors.lastname: Kwan
authors.affiliation: Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong, People's Republic of China; Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, People's Republic of China.
authors.forename: Wing Sum
authors.initials: WS
authors.lastname: Li
authors.affiliation: Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, People's Republic of China.
authors.forename: Stephen
authors.initials: S
authors.lastname: Yau
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Kwok-Wah
authors.initials: KW
authors.lastname: Chan
authors.affiliation: Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China; Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong, People's Republic of China; mlilung@hku.hk.
authors.forename: Maria Li
authors.initials: ML
authors.lastname: Lung
mesh_terms: D002277:Carcinoma / Q000235:genetics*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D000073658:Loss of Function Mutation / Q000235:genetics*; D059645:Mutation Rate; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D000073359:Exome Sequencing / Q000379:methods*
chemical_list: D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha
keywords: APOBEC-mediated signature; NF-κB signaling; nasopharyngeal carcinoma; somatic mutation landscape; whole-exome sequencing