Genetic alterations in squamous cell lung cancer associated with idiopathic pulmonary fibrosis
Genetic alterations in squamous cell lung cancer associated with idiopathic pulmonary fibrosis
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DOI：
10.1002/ijc.33499
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发表时间：
2021-02-19
影响因子：
6.4
通讯作者：
Kaneda, Atsushi
中科院分区：
文献类型：
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作者：
Hata, Atsushi;Nakajima, Takahiro;Kaneda, Atsushi
特发性肺纤维化（IPF）患者发生肺癌（包括鳞状细胞肺癌（SCC））的风险较高，通常预后不良。虽然IPF后癌症发展的分子基础尚未得到充分研究，但我们最近报道了两种表观遗传表型，其特征在于SCC中频繁和罕见的DNA超甲基化，以及罕见的超甲基化表型与IPF相关SCC的相关性。在此，我们使用人类肺癌检测试剂盒对伴和不伴IPF的SCC进行靶向外显子测序，以研究IPF相关SCC的遗传基础。伴和不伴IPF的SCC的总突变数量相当（137 +/- 22 vs 131 +/- 27，P = .5），非同义突变（72 +/- 14 vs 69 +/- 16，P = .5），插入缺失（3.0 +/- 3.5 vs 3.0 +/- 3.9，P = 1）和同义突变（62 +/- 9.1 vs 60 +/- 12，P = .5）。特征1是伴和不伴IPF的SCC中的主要特征。SETD 2和NFE 2L 2突变与IPF显著相关（SETD 2为44% vs 13%，P = 0.03; NFE 2L 2为38% vs 10%，P = 0.04）。通过拷贝数变异分析评估的MYC扩增也与IPF显著相关（18.8% vs 0%，P = 0.04）。TP 53和CDKN 2A的突变在具有频繁高甲基化的SCC中相对频繁地观察到（TP 53的P = 0.02，CDKN 2A的P = 0.06）。生存分析显示，SETD 2突变与预后不良显著相关（P = 0.04）。总的来说，我们发现SETD 2和NFE 2L 2突变和MYC扩增频繁参与SCC伴IPF，并且SETD 2突变与预后较差相关。
Patients with idiopathic pulmonary fibrosis (IPF) are at higher risk of developing lung cancers including squamous cell lung carcinoma (SCC), which typically carries a poor prognosis. Although the molecular basis of cancer development subsequent to IPF has not been fully investigated, we recently reported two epigenetic phenotypes characterized by frequent and infrequent DNA hypermethylation in SCC, and an association of the infrequent hypermethylation phenotype with IPF-associated SCCs. Here, we conducted targeted exon sequencing in SCCs with and without IPF using the Human Lung Cancer Panel to investigate the genetic basis of IPF-associated SCC. SCCs with and without IPF displayed comparable numbers of total mutations (137 +/- 22 vs 131 +/- 27, P = .5), nonsynonymous mutations (72 +/- 14 vs 69 +/- 16, P = .5), indels (3.0 +/- 3.5 vs 3.0 +/- 3.9, P = 1) and synonymous mutations (62 +/- 9.1 vs 60 +/- 12, P = .5). Signature 1 was the predominant signature in SCCs with and without IPF. SETD2 and NFE2L2 mutations were significantly associated with IPF (44% vs 13%, P = .03 for SETD2; 38% vs 10%, P = .04 for NFE2L2). MYC amplification, assessed by copy number variant analysis, was also significantly associated with IPF (18.8% vs 0%, P = .04). Mutations in TP53 and CDKN2A were observed relatively frequently in SCCs with frequent hypermethylation (P = .02 for TP53 and P = .06 for CDKN2A). Survival analysis revealed that the SETD2 mutation was significantly associated with worse prognosis (P = .04). Collectively, we found frequent involvement of SETD2 and NFE2L2 mutations and MYC amplification in SCCs with IPF, and an association of a SETD2 mutation with poorer prognosis.