Notch1 mutations are drivers of oral tumorigenesis.
Notch1 mutations are drivers of oral tumorigenesis.
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DOI：
10.1158/1940-6207.capr-14-0257
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发表时间：
2015-04
期刊：
影响因子：
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通讯作者：
Sidransky D
中科院分区：
文献类型：
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作者：
Izumchenko E;Sun K;Jones S;Brait M;Agrawal N;Koch W;McCord CL;Riley DR;Angiuoli SV;Velculescu VE;Jiang WW;Sidransky D
最近在头颈癌中发现了NOTCH1信号的破坏。本研究旨在评估口腔鳞状细胞癌（OSCC）进展中NOTCH1的改变，并比较这些突变在中国和高加索人群中的发生率。我们使用基于高通量PCR的富集技术和下一代测序（NGS）对在中国收集的144个样本中的NOTCH1进行测序。49个样本是来自接受口腔手术的患者的正常口腔粘膜，45个是口腔白斑活检组织，50个是未经放化疗的OSCC样本，其中22个是来自邻近未受影响区域的配对正常组织。在54%的原发性OSCC和60%的癌前病变中发现了NOTCH1突变。重要的是，几乎60%的白斑患者突变的NOTCH1携带突变，也确定在口腔鳞状细胞癌，表明这些克隆事件在早期肿瘤的进展中的重要作用。然后，我们比较了所有已知的NOTCH1突变确定在中国的OSCC患者与那些报告在高加索人的日期。虽然我们发现了NOTCH1关键调控结构域改变的明显重叠，并确定了两组共有的特定突变，但可能的功能获得性突变主要见于中国人群。我们的研究结果表明，癌前病变在早期阶段显示NOTCH1突变，因此是OSCC进展的真正驱动因素。此外，我们的研究结果表明，NOTCH 1在不同种族人群的患者中促进了不同的致瘤机制。
Disruption of NOTCH1 signaling was recently discovered in head and neck cancer. This study aims to evaluate NOTCH1 alterations in the progression of oral squamous cell carcinoma (OSCC) and compare the occurrence of these mutations in Chinese and Caucasian populations. We used a high-throughput-PCR-based enrichment technology and next generation sequencing (NGS) to sequence NOTCH1 in 144 samples collected in China. Forty nine samples were normal oral mucosa from patients undergoing oral surgery, 45 were oral leukoplakia biopsies and 50 were chemoradiation naïve OSCC samples with 22 paired-normal tissues from the adjacent unaffected areas. NOTCH1 mutations were found in 54% of primary OSCC and 60% of pre-malignant lesions. Importantly, almost 60% of leukoplakia patients with mutated NOTCH1 carried mutations that were also identified in OSCC, indicating an important role of these clonal events in the progression of early neoplasms. We then compared all known NOTCH1 mutations identified in Chinese OSCC patients with those reported in Caucasians to date. Although we found obvious overlaps in critical regulatory NOTCH1 domains alterations and identified specific mutations shared by both groups, possible gain-of-function mutations were predominantly seen in Chinese population. Our findings demonstrate that pre-malignant lesions display NOTCH1 mutations at an early stage and are thus bona fide drivers of OSCC progression. Moreover, our results reveal that NOTCH1 promotes distinct tumorigenic mechanisms in patients from different ethnical populations.