肺鳞状细胞癌中的突变特征。
Mutational signatures in squamous cell carcinoma of the lung.
作者信息
Osoegawa Atsushi, Takada Kazuki, Okamoto Tatsuro, Sato Seijiro, Nagahashi Masayuki, Tagawa Tetsuzo, Tsuchida Masanori, Oki Eiji, Okuda Shujiro, Wakai Toshifumi, Mori Masaki
机构信息
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Division of Thoracic and Cardiovascular Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
出版信息
J Thorac Dis. 2021 Feb;13(2):1075-1082. doi: 10.21037/jtd-20-2602.
BACKGROUND
Tumor mutational burden (TMB) has been identified as one of the predictors for the response to anti-programmed cell death-1 (anti-PD-1) antibody therapy and reported to correlate with smoking history in lung adenocarcinoma. However, in squamous cell carcinoma of the lung, the association between TMB and clinicopathological background factors, such as smoking history, has not been reported, including in our previous study. The mutational signature is a tool to identify the mutagens that are contributing to the mutational spectrum of a tumor by investigating the pattern of DNA changes. Here, we analyzed the mutational signature in lung squamous cell carcinoma to identify mutagens affecting the TMB.
METHODS
Seven representative mutational signatures including signature 7 (SI7) [ultraviolet (UV)-related], SI4 (smoking), SI6/15 [mismatch repair (MMR)], SI2/13 [apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)], and SI5 (clock-like) were analyzed in Japanese patients with lung squamous cell carcinoma (n=67) using data generated by next-generation sequencing consisting of a 415-gene panel. The relationships between signatures and clinico-pathological data including TMB and programmed death-ligand 1 (PD-L1) expression were analyzed.
RESULTS
Although the reconstructed mutational counts were small with targeted sequencing (median: 30.1, range: 13.3-98.7), the distributions of signatures were comparable among samples, with 56 cases containing more than four signatures. The smoking-related SI4 was found in 45 cases and was significantly related with pack-year index (PYI) (P=0.026). The reconstructed mutation counts were highly correlated with SI4 (r=0.51, P<0.0001), whereas the correlation was weak with SI6/15 (MMR-related) and SI2/13 (APOBEC-related). There was no mutational signature related with PD-L1 expression. Some patients exhibited unique signatures; the patient with the highest mutational counts had a MMR signature, and another patient with a prominent UV signature had occupational exposure to UV, as he was employed as a neon sign engineer.
CONCLUSIONS
Mutational signatures can predict the cause of lung squamous cell carcinoma. Tobacco smoking is the mutagen most related with TMB.
背景
肿瘤突变负荷（TMB）已被确定为抗程序性细胞死亡蛋白1（anti-PD-1）抗体治疗反应的预测指标之一，且据报道在肺腺癌中与吸烟史相关。然而，在肺鳞状细胞癌中，TMB与临床病理背景因素（如吸烟史）之间的关联尚未见报道，包括在我们之前的研究中。突变特征是一种通过研究DNA变化模式来识别导致肿瘤突变谱的诱变剂的工具。在此，我们分析了肺鳞状细胞癌中的突变特征，以识别影响TMB的诱变剂。
方法
使用由415个基因组成的下一代测序生成的数据，对67例日本肺鳞状细胞癌患者分析了7种代表性突变特征，包括特征7（SI7）[紫外线（UV）相关]、特征4（吸烟）、特征6/15[错配修复（MMR）]、特征2/13[载脂蛋白B mRNA编辑酶，催化多肽样（APOBEC）]和特征5（时钟样）。分析了这些特征与包括TMB和程序性死亡配体1（PD-L1）表达在内的临床病理数据之间的关系。
结果
尽管靶向测序重建的突变计数较少（中位数：30.1，范围：13.3 - 98.7），但样本间特征分布具有可比性，56例样本包含四种以上特征。4个病例中发现了与吸烟相关的SI4，且与包年指数（PYI）显著相关（P = 0.026）。重建的突变计数与SI4高度相关（r = 0.51，P < 0.0001），而与SI6/15（MMR相关）和SI2/13（APOBEC相关）的相关性较弱。没有与PD-L1表达相关的突变特征。一些患者表现出独特的特征；突变计数最高的患者具有MMR特征，另一名具有显著UV特征的患者有职业性UV暴露，因为他是一名霓虹灯工程师。
结论
突变特征可以预测肺鳞状细胞癌的病因。吸烟是与TMB最相关的诱变剂。
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