Miyanaga Akihiko, Masuda Mari, Motoi Noriko, Tsuta Koji, Nakamura Yuka, Nishijima Nobuhiko, Watanabe Shun-Ichi, Asamura Hisao, Tsuchida Akihiko, Seike Masahiro, Gemma Akihiko, Yamada Tesshi
Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan; Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan.
Lung Cancer. 2020 Jul;145:85-94. doi: 10.1016/j.lungcan.2020.03.027. Epub 2020 May 5.
The majority of pulmonary carcinoid (PC) tumors can be cured by surgical resection alone, but a significant proportion of patients experience recurrence. As PC is insensitive to conventional chemotherapy, further clarification of the molecular mechanisms of metastasis is needed in order to develop targeted therapeutics.
We performed comprehensive whole-exome sequencing (WES) of primary tumors and corresponding normal lung tissues from 14 PC patients (including 4 patients who developed postsurgical distant metastasis) and RNA sequencing of primary tumors from 6 PC patients (including 4 patients who developed postsurgical distant metastasis). Exon array-based gene expression analysis was performed in 25 cases of PC.
We identified a total of 139 alterations in 136 genes. MUC6 and SPTA1 were recurrently mutated at a frequency of 21% (3/14) and 14% (2/14), respectively. Mucin protein family genes including MUC2, MUC4 and MUC6 were mutated in a mutually exclusive manner in 36% (5/14). Pathway analysis of the mutated genes revealed enrichment of genes involved in mitogen-activated protein kinase (MAPK) signaling, regulation of the actin cytoskeleton and focal adhesion, and transforming growth factor (TGF)-β signaling. RNA sequencing revealed a total of 8 novel fusion transcripts including one derived from a chromosomal translocation between the TRIB2 and PRKCE genes. All of the 8 fusion genes were detected in primary PCs that had developed metastasis after surgical resection. We identified 14 genes (DENND1B, GRID1, CLMN, DENND1B, NRP1, SEL1L3, C5orf13, TNFRSF21, TES, STK39, MTHFD2, OPN3, MET, and HIST1H3C) up-regulated in 5 PCs that had relapsed after surgical resection.
In this study we identified novel somatic mutations and chromosomal rearrangements in PC by examining clinically aggressive cases that had developed postsurgical metastasis. It will be essential to validate the clinical significance of these genetic changes in a larger independent patient cohort.
大多数肺类癌（PC）肿瘤仅通过手术切除即可治愈，但相当一部分患者会复发。由于PC对传统化疗不敏感，因此需要进一步阐明转移的分子机制以开发靶向治疗方法。
我们对14例PC患者（包括4例术后发生远处转移的患者）的原发性肿瘤及相应的正常肺组织进行了全面的全外显子组测序（WES），并对6例PC患者（包括4例术后发生远处转移的患者）的原发性肿瘤进行了RNA测序。对25例PC病例进行了基于外显子阵列的基因表达分析。
我们在136个基因中总共鉴定出139个改变。MUC6和SPTA1的复发突变频率分别为21%（3/14）和14%（2/14）。包括MUC2、MUC4和MUC6在内的粘蛋白蛋白家族基因在36%（5/14）的病例中以互斥方式发生突变。对突变基因的通路分析显示，参与丝裂原活化蛋白激酶（MAPK）信号传导、肌动蛋白细胞骨架调节和粘着斑以及转化生长因子（TGF）-β信号传导的基因富集。RNA测序共发现8种新的融合转录本，其中一种源自TRIB2和PRKCE基因之间的染色体易位。所有8种融合基因均在术后发生转移的原发性PC中检测到。我们鉴定出14个基因（DENND1B、GRID1、CLMN、DENND1B、NRP1、SEL1L3、C5orf13、TNFRSF21、TES、STK39、MTHFD2、OPN3、MET和HIST1H3C）在5例术后复发的PC中上调。
在本研究中，我们通过检查术后发生转移的临床侵袭性病例，在PC中鉴定出了新的体细胞突变和染色体重排。在更大的独立患者队列中验证这些基因变化的临床意义至关重要。
