Human papillomavirus and the landscape of secondary genetic alterations in oral cancers
Human papillomavirus and the landscape of secondary genetic alterations in oral cancers
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DOI：
10.1101/gr.241141.118
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发表时间：
2019-01-01
期刊：
影响因子：
7
通讯作者：
Symer, David E.
中科院分区：
文献类型：
--
作者：
Gillison, Maura L.;Akagi, Keiko;Symer, David E.
人乳头瘤病毒（HPV）是口腔鳞状细胞癌（OSCCs）的一个必要但不充分的原因，其频率显着增加。为了确定这些癌症的继发性遗传改变，我们使用综合基因组学方法比较了149对hpv阳性和335对hpv阴性的OSCC肿瘤/正常配对。两种OSCC类型的不同行为风险因素反映在不同的基因组突变特征中。在hpv阳性的oscc中，与抗病毒免疫相关的APOBEC胞嘧啶脱氨酶编辑的特征与总体突变负担密切相关。相反，在hpv阴性的OSCCs中，序列上下文5‘-ATN-3’中的tb> C替换与烟草暴露相关。HPV E6*1和E7癌基因的普遍表达是HPV阳性OSCCs的必要条件。在PIK3CA、KMT2D、FGFR3、FBXW7、DDX3X、PTEN、TRAF3、RB1、CYLD、RIPK4、ZNF750、EP300、CASZ1、TAF5、RBL1、IFNGR1和NFKBIA中已证实或新发现体细胞突变显著富集。其中，许多影响已经被HPV癌蛋白靶向的宿主途径，包括p53和pRB途径，或破坏宿主对病毒感染的防御，包括干扰素（IFN）和核因子κ B信号传导。频繁的拷贝数变化与基因表达的一致性变化有关。Chr 11q（包括CCND1）和14q（包括DICER1和AKT1）在hpv阳性的oscc中反复丢失，而在hpv阴性的oscc中则增加。高变异等位基因分数暗示ZNF750、PIK3CA和EP300突变是hpv阳性癌症的候选驱动事件。我们的结论是，病毒与宿主的相互作用共同塑造了这些癌症的独特遗传特征，将它们与hpv阴性的癌症区分开来。
Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCCs) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/ normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCCs, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. In contrast, in HPV-negative OSCCs, T>C substitutions in the sequence context 5'-ATN-3' correlated with tobacco exposure. Universal expression of HPV E6*1 and E7 oncogenes was a sine qua non of HPV-positive OSCCs. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D, FGFR3, FBXW7, DDX3X, PTEN, TRAF3, RB1, CYLD, RIPK4, ZNF750, EP300, CASZ1, TAF5, RBL1, IFNGR1, and NFKBIA. Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon (IFN) and nuclear factor kappa B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr 11q (including CCND1) and 14q (including DICER1 and AKT1) were recurrently lost in HPV-positive OSCCs, in contrast to their gains in HPV-negative OSCCs. High-ranking variant allele fractions implicated ZNF750, PIK3CA, and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.