Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung
Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung
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DOI：
10.1158/1078-0432.ccr-16-0355
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发表时间：
2017-02-01
影响因子：
11.5
通讯作者：
Tsuchihara, Katsuya
中科院分区：
文献类型：
--
作者：
Miyoshi, Tomohiro;Umemura, Shigeki;Tsuchihara, Katsuya
目的：肺大细胞神经内分泌癌(LCNEC)与小细胞肺癌(SCLC)有许多共同的临床特征，但其分子特征尚不清楚。实验设计：我们对78例LCNEC样本[65例手术切除病例，其中包括10例合并非小细胞肺癌(NSCLC)的病例和13例晚期病例的活检组织]进行了靶向捕获测序。结果：TP53(71%)和RB1(26%)的失活突变发生率较高，但RB1的突变频率低于SCLC(40%，P=0.039)。此外，PI3K/AKT/mTOR通路中有12例(15%)检测到PI3K/AKT/mTOR基因改变：PIK3CA 3%，PTEN4%，AKT2 4%，RICTOR 5%，mTOR1%。在KRAS(6%)、FGFR1(5%)、KIT(4%)、ERBB2(4%)、HRAS(1%)和EGFR(1%)中检测到其他激活的改变。在10例合并非小细胞肺癌的LCNECs病例中，有5例存在先前报告的驱动器基因改变，所有这些基因都在两个组件之间共享。两组分候选体细胞突变的中位符合率为71%(范围为60%~100%)。结论：LCNECs具有与小细胞肺癌相似的基因组图谱，包括PI3K/AKT/mTOR通路等有希望的治疗靶点和其他基因改变。基于测序的分子图谱在LCNEC靶向治疗中是必要的。(C)2016年AACR。
Purpose: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations.Experimental Design: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNECsamples [65 surgically resected cases, including 10 LCNECs combined with non-small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases).Results: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P = 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN4%, AKT2 4%, RICTOR 5%, andmTOR1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was71%(range, 60%-100%).Conclusions: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/ mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies. (C) 2016 AACR.