Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P.R. China.
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, P.R. China.
Cancer Res. 2019 Dec 1;79(23):5930-5943. doi: 10.1158/0008-5472.CAN-18-3845. Epub 2019 Sep 4.
The genetic events occurring in recurrent nasopharyngeal carcinoma (rNPC) are poorly understood. Here, we performed whole-genome and whole-exome sequencing in 55 patients with rNPC and 44 primarily diagnosed NPC (pNPC), with 7 patients having paired rNPC and pNPC samples. Previously published pNPC exome data were integrated for analysis. rNPC and pNPC tissues had similar mutational burdens, however, the number of clonal mutations was increased in rNPC samples. TP53 and three NF-κB pathway components (, and ) were significantly mutated in both pNPC and rNPC. Notably, mutations in , and were all clonal in rNPC, however, 55.6% to 57.9% of them were clonal in pNPC. In general, the number of clonal mutations in NF-κB pathway-associated genes was significantly higher in rNPC than in pNPC. The NF-κB mutational clonality was selected and/or enriched during NPC recurrence. The amount of NF-κB translocated to the nucleus in samples with clonal NF-κB mutants was significantly higher than that in samples with subclonal NF-κB mutants. Moreover, the nuclear abundance of NF-κB protein was significantly greater in pNPC samples with locoregional relapse than in those without relapse. Furthermore, high nuclear NF-κB levels were an independent negative prognostic marker for locoregional relapse-free survival in pNPC. Finally, inhibition of NF-κB enhanced both radiosensitivity and chemosensitivity and . In conclusion, NF-κB pathway activation by clonal mutations plays an important role in promoting the recurrence of NPC. Moreover, nuclear accumulation of NF-κB is a prominent biomarker for predicting locoregional relapse-free survival. SIGNIFICANCE: This study uncovers genetic events that promote the progression and recurrence of nasopharyngeal carcinoma and has potential prognostic and therapeutic implications..
复发性鼻咽癌（rNPC）中发生的遗传事件知之甚少。在这里，我们对 55 例 rNPC 患者和 44 例初诊鼻咽癌（pNPC）患者进行了全基因组和全外显子组测序，其中 7 例患者有配对的 rNPC 和 pNPC 样本。整合了先前发表的 pNPC 外显子组数据进行分析。rNPC 和 pNPC 组织具有相似的突变负担，但 rNPC 样本中的克隆突变数量增加。TP53 和三个 NF-κB 通路成分（、和）在 pNPC 和 rNPC 中均显著突变。值得注意的是，在 rNPC 中，和均为克隆突变，但在 pNPC 中，有 55.6%至 57.9%为克隆突变。总体而言，NF-κB 通路相关基因中的克隆突变数量在 rNPC 中明显高于 pNPC。NF-κB 突变的克隆性在 NPC 复发过程中被选择和/或富集。在具有克隆 NF-κB 突变体的样本中，NF-κB 向核内转移的量明显高于具有亚克隆 NF-κB 突变体的样本。此外，在具有局部区域复发的 pNPC 样本中，NF-κB 蛋白的核内丰度明显高于无复发的样本。此外，高核 NF-κB 水平是 pNPC 局部区域无复发生存的独立负预后标志物。最后，NF-κB 抑制增强了放射敏感性和化疗敏感性。总之，克隆突变激活 NF-κB 通路在促进 NPC 的复发中起着重要作用。此外，NF-κB 的核积累是预测局部区域无复发生存的一个突出的生物标志物。意义：本研究揭示了促进鼻咽癌进展和复发的遗传事件，并具有潜在的预后和治疗意义。
