Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung
Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung
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DOI：
10.1245/s10434-018-6401-1
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发表时间：
2018-06-01
影响因子：
3.7
通讯作者：
Maehara, Yoshihiko
中科院分区：
文献类型：
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作者：
Okamoto, Tatsuro;Takada, Kazuki;Maehara, Yoshihiko
肺鳞状细胞癌(LSCC)是肺癌的主要组织学亚型。在这项研究中，我们调查了LSCC中的基因组变化，并评估了LSCC中突变负荷(MB)的临床意义。MB定义为每1MBP中非同义突变的数量。免疫组织化学方法检测肿瘤细胞中程序性死亡配体1(PD-L1)蛋白的表达，其中最常见的突变是TP53基因突变(n=51/67，76.1%)，其次是细胞周期蛋白依赖性激酶抑制因子2B(CDKN2B；35.8%)、CDKN2A(31.3%)、磷酸酶和张力蛋白同源基因(30.0%)、性别决定区Y-box 2(28.3%)。高MB(大于或等于中位数MB)的肿瘤组织分化程度明显低于低MB(小于中位数MB；p=0.0446)。高MB组位于上、中叶的肿瘤多于位于下叶的肿瘤(p=0.0019)。此外，上叶或中叶癌的MB显著高于下叶癌(p=0.0005)，并且倾向于显示更高的PD-L1蛋白表达(p=0.0573)。SOX2和酪氨酸激酶非受体2扩增与高MB相关(分别为p=0.0065和p=0.0010)。喉癌中MB水平因肿瘤位置的不同而不同，提示肿瘤发生的位置可能影响肿瘤的基因组背景。
Lung squamous cell carcinoma (LSCC) is a major histological subtype of lung cancer. In this study, we investigated genomic alterations in LSCC and evaluated the clinical implications of mutation burden (MB) in LSCC.Genomic alterations were determined in Japanese patients with LSCC (N = 67) using next-generation sequencing of 415 known cancer genes. MB was defined as the number of non-synonymous mutations per 1 Mbp. Programmed death-ligand 1 (PD-L1) protein expression in cancer cells was evaluated by immunohistochemical analysis.TP53 gene mutations were the most common alteration (n = 51/67, 76.1%), followed by gene alterations in cyclin-dependent kinase inhibitor 2B (CDKN2B; 35.8%), CDKN2A (31.3%), phosphatase and tensin homolog (30.0%), and sex-determining region Y-box 2 (SOX2, 28.3%). Histological differentiation was significantly poorer in tumors with high MB (greater than or equal to the median MB) compared with that in tumors with low MB (less than the median MB; p = 0.0446). The high MB group had more tumors located in the upper or middle lobe than tumors located in the lower lobe (p = 0.0019). Moreover, cancers in the upper or middle lobes had significantly higher MB than cancers in the lower lobes (p = 0.0005), and tended to show higher PD-L1 protein expression (p = 0.0573). SOX2 and tyrosine kinase non-receptor 2 amplifications were associated with high MB (p = 0.0065 and p = 0.0010, respectively).The MB level differed according to the tumor location in LSCC, suggesting that the location of cancer development may influence the genomic background of the tumor.