Liu Xiaodong, Li Yanjin, Zhou Xiang, Zhu Sinan, Kaya Neslihan A, Chan Yun Shen, Ma Liang, Xu Miao, Zhai Weiwei
School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Cancers (Basel). 2023 Feb 15;15(4):1243. doi: 10.3390/cancers15041243.
As one of few viral-positive cancers, nasopharyngeal carcinoma (NPC) is extremely rare across the world but very frequent in several regions of the world, including Southern China (known as the Cantonese cancer). Even though several genomic studies have been conducted for NPC, their sample sizes are relatively small and systematic comparison with other cancer types has not been explored. In this study, we collected four-hundred-thirty-one samples from six previous studies and provided the first integrative analysis of NPC genomes. Combining several statistical methods for detecting driver genes, we identified 25 novel drivers for NPC, including and NLRC5. Many of these novel drivers are enriched in several important pathways, such as autophagy and immunity. By comparing NPC with many other cancer types, we found NPC is a unique cancer type in which a high proportion of patients (45.2%) do not have any known driver mutations (termed as "missing driver events") but have a preponderance of deletion events, including chromosome 3p deletion. Through signature analysis, we identified many known and novel signatures, including single-base signatures ( = 12), double-base signatures ( = 1), indel signatures ( = 9) and copy number signatures ( = 8). Many of these new signatures are involved in DNA repair and have unknown etiology and genome instability, implying an unprecedented dynamic mutational process possibly driven by complex interactions between viral and host genomes. By combining clinical, molecular and intra-tumor heterogeneity features, we constructed the first integrative survival model for NPC, providing a strong basis for patient prognosis and stratification. Taken together, we have performed one of the first integrative analyses of NPC genomes and brought unique genomic insights into tumorigenesis of a viral-driven cancer.
作为少数几种病毒阳性癌症之一，鼻咽癌（NPC）在全球极为罕见，但在世界上的几个地区却很常见，包括中国南方（被称为广东癌）。尽管已经对鼻咽癌进行了多项基因组研究，但其样本量相对较小，且尚未探索与其他癌症类型的系统比较。在本研究中，我们从之前的六项研究中收集了431个样本，并首次对鼻咽癌基因组进行了综合分析。结合多种检测驱动基因的统计方法，我们鉴定出25个鼻咽癌的新驱动基因，包括[具体基因]和NLRC5。这些新驱动基因中的许多都富集于几个重要通路，如自噬和免疫。通过将鼻咽癌与许多其他癌症类型进行比较，我们发现鼻咽癌是一种独特的癌症类型，其中很大一部分患者（45.2%）没有任何已知的驱动基因突变（称为“驱动基因缺失事件”），但存在大量缺失事件，包括3号染色体短臂缺失。通过特征分析，我们鉴定出许多已知和新的特征，包括单碱基特征（n = 12）、双碱基特征（n = 1）、插入缺失特征（n = 9）和拷贝数特征（n = 8）。这些新特征中的许多都参与DNA修复且病因不明以及基因组不稳定，这意味着可能由病毒和宿主基因组之间复杂相互作用驱动的前所未有的动态突变过程。通过结合临床、分子和肿瘤内异质性特征，我们构建了首个鼻咽癌综合生存模型，为患者预后和分层提供了有力依据。综上所述，我们进行了首批鼻咽癌基因组综合分析之一，并为病毒驱动癌症的肿瘤发生带来了独特的基因组见解。
