Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma
Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma
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DOI：
10.1172/jci82066
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发表时间：
2016-01-01
影响因子：
15.9
通讯作者：
Grandis, Jennifer R.
中科院分区：
文献类型：
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作者：
Hedberg, Matthew L.;Goh, Gerald;Grandis, Jennifer R.
背景超过一半的头颈部鳞状细胞癌（HNSCC）患者发生复发和/或转移，这些事件对长期生存构成最大威胁。我们着手鉴定复发性/转移性HNSCC的遗传改变。对从新鲜冷冻的全血和来自13名具有同步淋巴结转移的HNSCC患者和10名具有异时复发肿瘤的患者的患者匹配的肿瘤对提取的基因组DNA进行全外显子组测序（WES）。肿瘤对内和肿瘤对之间的突变一致性用于分析个体患者HNSCC的时空演变，并确定潜在的治疗靶点进行功能评估。在同步淋巴结转移和异时复发肿瘤中，分别鉴定出约86%和60%的单体细胞核苷酸变异（SSNV）是从原发性索引肿瘤传播的。在一个以上的转移性或复发性肿瘤中突变，但在相应的原发性肿瘤中不突变的基因包括C17 orf 104、肌醇1，4，5-三磷酸受体3型（ITPR 3）和盘状结构域受体酪氨酸激酶2（DDR2）。选择DDR2突变已显示在其他恶性肿瘤中赋予对SRC家族激酶（SFK）抑制剂的增强的敏感性。同样，携带内源性DDR2突变和工程化DDR2突变的HNSCC细胞株对SFK抑制剂达沙替尼的敏感性高于携带野生型DDR2突变的细胞株。在这项对HNSCC患者匹配肿瘤对的WES研究中，我们发现同步淋巴结转移与其配对的原发性肿瘤比异时复发性肿瘤在遗传上更相似。这项研究概述了原发性，转移性和/或复发性HNSCC癌症的体细胞突变的概要，对精准医学方法具有潜在的影响。
BACKGROUND. Recurrence and/or metastasis occurs in more than half of patients with head and neck squamous cell carcinoma (HNSCC), and these events pose the greatest threats to long-term survival. We set out to identify genetic alterations that underlie recurrent/metastatic HNSCC.METHODS. Whole-exome sequencing (WES) was performed on genomic DNA extracted from fresh-frozen whole blood and patient-matched tumor pairs from 13 HNSCC patients with synchronous lymph node metastases and 10 patients with metachronous recurrent tumors. Mutational concordance within and between tumor pairs was used to analyze the spatiotemporal evolution of HNSCC in individual patients and to identify potential therapeutic targets for functional evaluation.RESULTS. Approximately 86% and 60% of single somatic nucleotide variants (SSNVs) identified in synchronous nodal metastases and metachronous recurrent tumors, respectively, were transmitted from the primary index tumor. Genes that were mutated in more than one metastatic or recurrent tumor, but not in the respective primary tumors, include C17orf104, inositol 1,4,5-trisphosphate receptor, type 3 (ITPR3), and discoidin domain receptor tyrosine kinase 2 (DDR2). Select DDR2 mutations have been shown to confer enhanced sensitivity to SRC-family kinase (SFK) inhibitors in other malignancies. Similarly, HNSCC cell lines harboring endogenous and engineered DDR2 mutations were more sensitive to the SFK inhibitor dasatinib than those with WT DDR2.CONCLUSION. In this WES study of patient-matched tumor pairs in HNSCC, we found synchronous lymph node metastases to be genetically more similar to their paired index primary tumors than metachronous recurrent tumors. This study outlines a compendium of somatic mutations in primary, metastatic, and/or recurrent HNSCC cancers, with potential implications for precision medicine approaches.