Whole-exome sequencing identifies NF-kappaB pathway regulators frequently mutated in nasopharyngeal carcinoma

Conference Theme: Bayer to Present New Data on Advancing Oncology PortfolioSession: Molecular and Cellular Biology, GeneticsThis journal suppl. is Proceedings: AACR 107th Annual Meeting 2016INTRODUCTION: Nasopharyngeal carcinoma (NPC) is a unique epithelial malignancy with a high prevalence in Southeast Asia. To date, the genomic abnormalities leading to the pathogenesis of NPC remain unclear. Thus, we sought to characterize the mutational landscape in NPC tumors using next-generation sequencing approaches and to identify significantly mutated genes and pathways. METHODS: 124 NPC primary tumors were examined to define the mutational landscape with whole-exome sequencing (WES) and targeted re-sequencing. Mean target coverage of tumor and blood samples was 70X and 49X in WES, and 190X and 68X in targeted resequencing, respectively. Somatic SNPs and INDELs were called with MuTect and VarScan2, respectively. MutSigCV was applied to identify potential driver events in tumorigenesis. Verification rate for somatic mutations was 95%. The functional consequences of mutations in candidate genes were evaluated by the luciferase promoter, cell proliferation, and colony formation assays. RESULTS: The mutation rate of NPC is relatively low, with a median of 0.9 somatic mutations per megabase. Mutational signature analysis revealed two signatures in NPC, the ubiquitous signature in cancer characterized by C>T transitions predominantly occurring at NpCpG trinucleotides and the APOBEC-related signature characterized by C>G and C>T mutations at TpCpN trinucleotides, which is related to the innate immune APOBEC family of cytidine deaminases. MutSigCV analysis identified significantly mutated genes, NFKBIA, TP53, CYLD, KMT2D, DMXL1, KMT2C, GPR144, RYR2, BOD1L1, AKAP9, and CEP192, with q values less than 0.1. Pathway and gene ontology analysis identified several pathways/terms with enriched somatic mutations including cell cycle phase transition, chromatin modification, cell death, immune response, p53 pathway, viral carcinogenesis, and the canonical NF-κB signaling pathways. TP53 is the most frequently mutated gene (7.3%, 9/124). Almost all somatic mutations fall into the DNA binding domain of TP53, including well-known hotspot and gain-of-function mutations. Multiple loss-of-function (LOF) mutations were detected in NF-kB negative regulators, including NFKBIA (encodes IκBα protein), CYLD, and TNFAIP3. Mutations in NFKBIA were shown to alter the tumor suppressive function of IκBα. CONCLUSIONS: In this study we detected an APOBEC-related signature in NPC. Several NF-kB negative regulators, including NFKBIA and CYLD, were mutated in a subset of NPC primary tumors, which may contribute to pathogenesis of NPC through NF-kB signaling pathway. These data provide an enhanced road map for understanding the molecular basis underlying NPC and also provide insight for exploring new therapies