The mutational landscape of recurrent versus nonrecurrent human papillomavirus-related oropharyngeal cancer
The mutational landscape of recurrent versus nonrecurrent human papillomavirus-related oropharyngeal cancer
复制标题
DOI：
10.1172/jci.insight.99327
复制
发表时间：
2018-07-16
期刊：
影响因子：
8
通讯作者：
Mendez, Eduardo
中科院分区：
文献类型：
--
作者：
Harbison, R. Alex;Kubik, Mark;Mendez, Eduardo
背景人乳头状瘤病毒相关（HPV相关）口咽鳞状细胞癌（OPSCC）对铂类化疗的反应率非常高。原发性HPV相关OPSCC复发或不复发之间的基因组差异尚不清楚。此外，还不清楚复发的HPV相关OPSCC是否与HPV阴性头颈癌（HNC）共享基因组景观。我们利用全外显子组测序分析了51例原发性HPV相关OPSCC中的体细胞核苷酸（SNV）和拷贝数变异（CNV），其中包括35例未复发和16例复发。我们评估了12例异时复发性OPSCC（7例伴有配对原发性OPSCC）和33例原发性HPV无关口腔和OPSCC。KMT 2D是原发性HPV相关OPSCC（n = 51; 14%）和异时复发性OPSCC（n = 12; 42%）中最常见的突变基因。复发的原发性HPV相关OPSCC与未复发的原发性HPV相关OPSCC共享基因组景观。然而，TSC 2，BRIP 1，NBN和NFE 2L 2突变发生在复发的原发性OPSCC中，而不是在那些没有复发的OPSCC中。此外，复发的原发性HPV相关OPSCC具有HPV无关HNC的特征，特别是包括MAPK、JAK/STAT和分化信号传导途径畸变。异时复发性OPSCC与HPV无关的HNC具有相同的基因组结构，包括TP 53、CASP 8、FAT 1、HLA-A、AJUBA和NSD 1的高频率基因组改变。总体而言，复发的原发性HPV相关OPSCC与非复发性OPSCC共享基因组景观。异时复发性OPSCC与HPV阴性HNC具有相同的基因组特征。这些数据旨在指导未来的降级努力和功能实验。经费本研究由美国癌症协会（RSG TBG-123653）、RAH资金支持（T32 DC 00018，耳鼻喉科研究培训，华盛顿大学）、西雅图转化肿瘤研究（Fred哈钦森癌症研究中心）向EM提供的资金以及Fred哈钦森癌症研究中心向EM提供的中心资金支持。UD由退伍军人事务部，生物医学实验室研究与发展（BLR&D），拨款IO 1-oo 23456以及匹兹堡基金会和PNC基金会的资金支持。
BACKGROUND. Human papillomavirus-related (HPV-related) oropharyngeal squamous cell carcinomas (OPSCCs) have an excellent response rate to platinum-based chemoradiotherapy. Genomic differences between primary HPV-related OPSCCs that do or do not recur are unknown. Furthermore, it is unclear if HPV-related OPSCCs that recur share a genomic landscape with HPVnegative head and neck cancers (HNCs).METHODS. We utilized whole exome sequencing to analyze somatic nucleotide (SNVs) and copy number variants (CNVs) among a unique set of 51 primary HPV-related OPSCCs, including 35 that did not recur and 16 that recurred. We evaluated 12 metachronous recurrent OPSCCs (7 with paired primary OPSCCs) and 33 primary HPV-unrelated oral cavity and OPSCCs.RESULTS. KMT2D was the most frequently mutated gene among primary HPV-related OPSCCs (n = 51; 14%) and among metachronous recurrent OPSCCs (n = 12; 42%). Primary HPV-related OPSCCs that recurred shared a genomic landscape with primary HPV-related OPSCCs that did not recur. However, TSC2, BRIP1, NBN, and NFE2L2 mutations occurred in primary OPSCCs that recurred but not in those that did not recur. Moreover, primary HPV-related OPSCCs that recur harbor features of HPV-unrelated HNCs, notably including MAPK, JAK/STAT, and differentiation signaling pathway aberrations. Metachronous recurrent OPSCCs shared a genomic landscape with HPV-unrelated HNCs, including a high frequency of TP53, CASP8, FAT1, HLA-A, AJUBA, and NSD1 genomic alterations.CONCLUSION. Overall, primary HPV-related OPSCCs that recur share a genomic landscape with nonrecurrent OPSCCs. Metachronous recurrent OPSCCs share genomic features with HPV-negative HNCs. These data aim to guide future deescalation endeavors and functional experiments. FUNDING. This study is supported by the American Cancer Society (RSG TBG-123653), funding support for RAH (T32DC00018, Research Training in Otolaryngology, University of Washington), funds to EM from Seattle Translational Tumor Research (Fred Hutchinson Cancer Research Center), and center funds from the Fred Hutchinson Cancer Research Center to EM. UD is supported by the Department of Veterans Affairs, Biomedical Laboratory Research and Development (BLR&D), grant IO1-oo23456, and funds from the Pittsburgh Foundation and PNC Foundation.