Genomic Analysis of Nasopharyngeal Carcinoma Reveals TME-Based Subtypes

Abstract

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) associated cancer characterized by a poor prognosis and a high level of lymphocyte infiltrate. Genetic hallmarks of NPC are not completely known but include deletion of the p16 (CDKN2A) locus and mutations in NF-kB pathway components, with a relatively low total mutational load. To better understand the genetic landscape, an integrated genomic analysis was performed using a large clinical cohort of treatment-na€ ve NPC tumor specimens. This genomic analysis was generally concordant with previous studies; however, three subtypes of NPC were identified by differences in immune cell gene expression, prognosis, tumor cell morphology, and genetic characteristics. A gene expression signature of proliferation was poorly prognostic and associated with either higher mutation load or specific EBV gene expression patterns in a subtype-specific manner. Finally, higher levels of stromal tumor-infiltrating lymphocytes associated with good prognosis and lower expression of a WNT and TGFb pathway activation signature.

Immune checkpoint inhibitors in advanced nasopharyngeal carcinoma: Beyond an era of chemoradiation?

“…54,55 Endemic NPC cases (WHO class 2/3) are associated with EBV and subsequently demonstrate a low tumour mutation burden. 28 Given the information above, this observation may suggest a reason to be cautious regarding early anti-PD1 clinical outcomes for the published NPC trials. 4,31,33 Somewhat paradoxically, two recent studies, for HPV 56 and polyomavirus 57 associated cancers, respectively, report superior overall survival in patients undergoing anti-PD1 treatment despite having low tumour mutation rates.…”

“…Endemic NPC cases (WHO class 2/3) are associated with EBV and subsequently demonstrate a low tumour mutation burden . Given the information above, this observation may suggest a reason to be cautious regarding early anti‐PD1 clinical outcomes for the published NPC trials .…”

“…12,13,27 Zhang et al recently characterized treatment-naïve NPC patients into three categories based on tumour genomics, stromal compartments and the immune microenvironment. 28 Subtype III, with high expression of T effector genes and high IFNγ signature, may be enriched for potential responders to checkpoint blockade therapy. 26 This review differs from previous articles by providing a comprehensive analysis of both current and future immunotherapy NPC trials.…”

Rediscovery of NF‐κB signaling in nasopharyngeal carcinoma: How genetic defects of NF‐κB pathway interplay with EBV in driving oncogenesis?

“…Several studies suggested genetic variations of NF‐κB signaling confers increase risk for multiple cancers including NPC (Suzairi, Aizat, Aminudin, Nurfatimah, & Ankathil, ; Wang et al, ; Zhang et al, ; Zhou et al, ). Recently, whole‐exome sequencing studies from different groups consistently documented loss of function (LOF) mutations on multiple negative regulators of the NF‐κB pathway occur in nearly half of somatic NPC, including NFKBIA (Li, Chung, et al, ; Zhang, MacIsaac, et al, ; Zheng et al, ), CYLD (Li, Chung, et al, ; Zhang, MacIsaac, et al, ; Zheng et al, ), TRAF3 (Li, Chung, et al,; Zhang, MacIsaac, et al, ; Zheng et al, ), and TNFAIP3 (Zheng et al, ), NLRC5 (Li, Chung, et al, ; Zhang, MacIsaac, et al, ). These finding undoubtedly reinforce the crucial role of NF‐κB pathway in NPC.…”

“…Table summarized the main known NF‐κB pathway components mutations occurring in NPC (Table ). NF‐κB mutation status was associated with higher stromal tumor‐infiltrating lymphocytes (TILs) but lower intra‐tumoral TILs (Zhang, MacIsaac, et al, ), reflecting a central role of NF‐κB signaling in host inflammatory response. Among these mutated genes, functional analysis confirmed that both NFKBIA (Zheng et al, ) and CYLD (Li, Chung, et al, ) are tumor suppressive in NPC cell growth.…”