TP53 mutational landscape of metastatic head and neck cancer reveals patterns of mutation selection
TP53 mutational landscape of metastatic head and neck cancer reveals patterns of mutation selection
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DOI：
10.1016/j.ebiom.2020.102905
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发表时间：
2020-08-01
期刊：
影响因子：
11.1
通讯作者：
Rampias, Theodoros
中科院分区：
文献类型：
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作者：
Klinakis, Apostolos;Rampias, Theodoros
背景：头颈鳞状细胞癌是一种就原发肿瘤的解剖部位而言的异质性疾病。另一方面，它的复发率很高，一旦发生转移，预后不良。 TP53是原发病中最常见的突变基因。 TP53突变发生在蛋白质的不同结构元件中，而生物学结果可能多种多样。方法：在这里，我们旨在发现原发性疾病和转移性疾病中TP53突变谱的差异，以及TP53突变对转移、特定拷贝数改变、肿瘤突变负荷和对免疫检查点抑制剂的反应的影响。研究了 512 个原发性活检和 134 个转移性活检的体细胞突变和临床数据。结果：与原发性肿瘤相比，转移性肿瘤的总体 TP53 突变频率显着较低。另一方面，DNA 结合区的错义突变在转移中显着富集，并与 11 号染色体上常见的脆弱位点相关，导致在转移中具有既定作用的基因扩增和过度表达。最后，TP53 突变与转移性而非原发性肿瘤中较高的 TMB 评分相关，并且后者对免疫检查点抑制剂的反应较差。解释：TP53 突变影响头颈肿瘤发生的临床和分子方面，包括转移、遗传改变和治疗反应。资金：这项工作得到了 AK 的 Horizon 2020 拨款 (801347) 的支持，以及 希腊研究与技术总秘书处和希腊研究与创新基金会向 TR 提供赠款 (472-EpiNotch)。 (c) 2020 作者。由 Elsevier B.V. 出版
Background: Head and neck squamous cell carcinoma is a heterogeneous disease with respect to the anatomic site of the primary tumor. On the other hand, it is highly recurrent, and once metastatic, it is associated with poor prognosis. TP53 is the most commonly mutated gene in primary disease. TP53 mutations occur in different structural elements of the protein while the biological outcome can be diverse.Methods: Here we aimed to find differences in the mutation profile of TP53 in primary and metastatic disease and the impact of TP53 mutations in metastasis, specific copy number alterations, tumor mutation burden and response to immune checkpoint inhibitors. Somatic mutation and clinical data for 512 primary and 134 metastatic biopsies were studied.Findings: Overall TP53 mutation frequency is significantly lower in metastases compared to primary tumors. One the other hand, missense mutations in the DNA binding region are significantly enriched in metastases and are associated with a common fragile site in chromosome 11, leading to amplification and overexpression of genes with established role in metastasis. Finally, TP53 mutations are associated with higher TMB score in metastatic but not primary tumors, and poorer response to immune checkpoint inhibitors for the latter.Interpretation: TP53 mutations affect clinical and molecular aspects of head and neck tumorigenesis including metastasis, genetic alterations and therapeutic response.Funding: This work was supported by a Horizon 2020 grant (801347) to AK, and a Greek General Secretariat for Research and Technology and the Hellenic Foundation for Research and Innovation grant (472-EpiNotch) to TR. (c) 2020 The Authors. Published by Elsevier B.V.