Exome and genome sequencing of nasopharynx cancer identifies NF-κB 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-kB 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-kB signalling, and we observed mutual exclusivity among tumours with somatic NF-kB pathway aberrations and LMP1-overexpression, suggesting that NF-kB activation is selected for by both somatic and viral events during NPC pathogenesis.

Genomic Analysis of Nasopharyngeal Carcinoma Reveals TME-Based Subtypes

“…Previous studies have indicated that the frequency of somatic genomic alterations in NPC is low (18)(19)(20). However, prior work has identified several recurrent genomic alterations in NPC, including deletion of the p16-locus on cytoband 9p21, CCND1 amplification, TP53 mutation, inactivating mutations in negative regulators of the NF-kB pathway, mutations in MAPK and PI3K signaling pathways, and mutations in epigenetic regulators like MLL3 (18,19,21).…”

Beating 'Guangdong cancer': a review and update on nasopharyngeal cancer

“…22 The researchers also revealed major histocompatibility complex class I gene aberrations in some of the samples, and the efficacy of immune checkpoint inhibitors (discussed below) may be affected in this subgroup of NPC patients. 22 Although much in this field remains to be elucidated, it is expected that the genetic research will aid in the development of powerful biomarkers for the diagnosis, prognosis, and evaluation of the treatment for NPC. 21 …”

“…20 Epigenetic alterations of various chromosomal regions, especially those regions with tumoursuppressor genes, were also found in NPC patients. 21 Li et al 22 recently identified genomic aberrations of multiple negative regulators of the nuclear factor-κB (NF-κB) pathway in 111 EBV-positive NPC samples in another whole-exome sequencing study, suggesting the pivotal role of activating the NF-κB signalling pathway in NPC and the potential therapeutic applications of NF-κB inhibitors. 22 The researchers also revealed major histocompatibility complex class I gene aberrations in some of the samples, and the efficacy of immune checkpoint inhibitors (discussed below) may be affected in this subgroup of NPC patients.…”

“…21 Li et al 22 recently identified genomic aberrations of multiple negative regulators of the nuclear factor-κB (NF-κB) pathway in 111 EBV-positive NPC samples in another whole-exome sequencing study, suggesting the pivotal role of activating the NF-κB signalling pathway in NPC and the potential therapeutic applications of NF-κB inhibitors. 22 The researchers also revealed major histocompatibility complex class I gene aberrations in some of the samples, and the efficacy of immune checkpoint inhibitors (discussed below) may be affected in this subgroup of NPC patients. 22 Although much in this field remains to be elucidated, it is expected that the genetic research will aid in the development of powerful biomarkers for the diagnosis, prognosis, and evaluation of the treatment for NPC.…”

The Pharmacogenomic Era in Asia: Potential Roles and Challenges for Asian Pharmacists

“…A recent study showed that Asian colorectal cancers are more likely to be BRAF wildtype and without KRAS mutations, implicating a significantly lower frequency of occurrence of a resistance genotype to EGFR TKI in Asian colorectal cancer patients [8]. As for other Asian-prevalent cancers, such as liver cancer [9], esophageal cancer [10], and nasopharyngeal cancer [11], the genomic findings have recently been revealed and it is anticipated that more pharmacogenomic biomarkers will be developed in the near future. Immunotherapy is a very promising effective anticancer therapy, which sought to awaken the host's immune response to elicit specific anti-tumor activity against one's tumor.…”