Abstract 4348: TP53-regulome and TP53-effectome are frequently altered in Epstein-Barr virus-associated nasopharyngeal cancer

Abstract

Abstract Dysregulation of p53 signaling is central to oncogenesis. As revealed by the Cancer Genome Atlas (TCGA), mutation of tumor suppressor TP53 is the most frequent single somatic event found across human cancers. In Epstein-Barr Virus (EBV)-associated nasopharyngeal cancer (NPC), an aggressive head and neck cancer prevalent in Southeast Asia, our recent study showed that only 9% cases harbored TP53 mutation. Studies in NPC demonstrated that EBV infection alone was not sufficient to attenuate p53 signaling in EBV(+)NPC cells. As p53 signaling and function are intricately regulated by multiple pathway components, aberrations of the p53 regulatory network may also off-set p53 signaling, thus facilitating EBV(+)NPC tumorigenesis. Here, we hypothesized that in addition to TP53 aberrations, TP53-regulome (genes direct regulate TP53 expression and function), and TP53-effectome (genes responsible for executing biological functions of p53 signaling in cells) may also be genomically altered in NPC during oncogenesis. Here, we assembled the most updated TP53-regulome/-effectome genelists, including newly identified p53 regulatory components, to enable characterization of TP53-regulatory network in EBV(+)NPC patient tumors. Among the subclasses of TP53-regulome, mutations of genes regulating p53 acetylation and ubiquitination were significantly co-occurred, while TP53-effectome genes involved in p53-mediated DNA repair and p53 metabolism were co-mutated with statistical significance, for instance. Analysis of the 111 whole-exome sequenced EBV(+)NPC samples first demonstrated that 40.5% and 26.1% was affected by TP53-regulome and TP53-effectome mutations respectively, while only 9.0% cases carried TP53 mutation. In total, 55% of EBV(+)NPC harbored p53-related somatic mutations, which may implicate a wider TP53-associated genomic defect for NPC tumorigenesis. Among the 10 cases of TP53-mutated EBV(+)NPC, 5 of them co-harbored TP53-regulome mutations while 5 cases co-harbored TP53-effectome mutations. Subsequent in-depth allele frequency analysis revealed that in 4 out of 7 TP53, TP53-regulome and TP53-effectome co-mutated cases, the allele frequencies of TP53-regulome or TP53-effectome mutant genes were higher than that of TP53, implicating likely earlier events of these genetic defects than TP53 mutation during NPC tumorigenesis. In conclusion, p53 regulatory network mutations are far more frequent than TP53 mutations in this virally associated HNC, and functional study of such a wide array of p53-network mutations on p53 signaling in NPC tumorigenesis are warranted. Acknowledgments: VWYL is supported by the Start-up Fund from the Georgia Cancer Center, USA. Citation Format: Tin Yu Samuel Law, Yuen-Keng Ng, Jin Wen, Joshua Chung-Hymn Ng, Moses Man Kuen Wong, Pak Sang Tse, Vivian Wai Yan Lui. TP53-regulome and TP53-effectome are frequently altered in Epstein-Barr virus-associated nasopharyngeal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4348.