Targeted Therapy and Immunotherapy for Nasopharyngeal Carcinoma
Medical radiology(2023)
摘要
The mutational landscape of NPC has been elucidated by several whole-exome (WES) and whole-genome (WGS) sequencing studies of NPC published since 2014 (Dai et al. 2020; Li et al. 2017; Lin et al. 2014; Zheng et al. 2016; Bruce et al. 2021). Collectively, these studies have shown that over 90% of Epstein-Barr virus-positive (EBV +ve) NPCs are driven by genomic aberrations and EBV-encoded oncoprotein LMP-1, which lead to constitutive activation of the NF-κB pathway (Bruce et al. 2021). Other key driver events in the pathogenesis of NPC include the loss of TGFBR2 function, activation of the PI3K-MAPK signaling pathway, cell cycle dysregulation, defects in the DNA repair machinery, and chromatin remodeling. The interplay between these somatic aberrations and EBV gene expression contributed to impairments in both innate and adoptive immunity (Li et al. 2017; Bruce et al. 2021). The tumor mutational burden of NPC ranges between 0.9 and >50 mutations per mega base pair, which is relatively low compared with lung and other cancers (Li et al. 2017; Bruce et al. 2021). Furthermore, less than 5% of primary NPC tumors are known to harbor the known “druggable” kinase mutations in the ERBB1/2, PI3K, and MAPK pathways, drug-sensitive gene fusions such as ALK or NTRK, or microsatellite instability/mismatch repair (MMR) defects that may portend sensitivity to immunotherapy (Li et al. 2017). In contrast to primary tumors, WES of NPC has identified an enrichment of genes that activate PI3K signaling in metastatic NPC tissues (Li et al. 2017). Of the four mutational signatures uncovered from the WES studies, Signature 3 is found in 64.3% of NPCs and is associated with high-somatic-copy-number alterations (SCNA) H-gain, presence of BRCA2 germline or somatic alterations (7.8%), and inferior overall survival (OS) (Dai et al. 2020; Bruce et al. 2021).
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关键词
nasopharyngeal carcinoma,immunotherapy
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