Intra-tumor and Inter-tumor Heterogeneity in MET Exon 14 Skipping Mutations and Co-mutations in Pulmonary Pleomorphic Carcinomas
Intra-tumor and Inter-tumor Heterogeneity in MET Exon 14 Skipping Mutations and Co-mutations in Pulmonary Pleomorphic Carcinomas
复制标题
肺多形性癌中 MET 外显子 14 跳跃突变和共突变的肿瘤内和肿瘤间异质性
DOI：
10.1016/j.cllc.2021.09.005
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发表时间：
2021
影响因子：
3.6
通讯作者：
Mitsudomi Tetsuya
中科院分区：
文献类型：
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作者：
Fujino Toshio;Suda Kenichi;Sakai Kazuko;Murakami Isao;Shimizu Shigeki;Ohara Shuta;Koga Takamasa;Hamada Akira;Soh Junichi;Nishio Kazuto;Mitsudomi Tetsuya
metexon 14跳变突变是肺癌的一种驱动突变，在肺多形性癌（PPCs）中高度富集。metexon 14跳跃性是否存在肿瘤内或肿瘤间的异质性，或由metexon 14跳跃性驱动的肺癌中共同发生的遗传改变是否存在异质性尚不清楚。方法对23例PPC患者的肿瘤标本（10例尸检，13例手术切除）进行分析。RT-PCR检测METexon 14跳变。对于metexon 14跳过突变的患者，进行进一步的分析。从每位接受手术切除的患者的各种组织学成分中提取基因组DNA (gDNA)（以评估肿瘤内异质性）。在尸检的患者中，从所有转移性病变中提取gDNA和总RNA（以评估肿瘤间异质性）。结果4例患者（4/23,17.4%）检测到metexon 14跳变，其中2例手术切除，2例尸检。在这些患者中，我们没有发现metexon 14跳变状态的肿瘤内或肿瘤间异质性。我们观察到肿瘤内和肿瘤间癌症相关基因拷贝数变化和/或突变状态的异质性；其中一些差异可能会影响MET酪氨酸激酶抑制剂（TKI）的疗效。在我们对4例病例的探索性分析中，我们观察到metexon 14跳跃性突变在整个组织成分和转移灶之间均匀分布。我们的研究结果还表明，在共同发生的遗传改变中存在明显的肿瘤间和肿瘤内异质性，这种异质性的治疗意义应在未来的研究中进行评估。
BackgroundMETexon 14 skipping mutation is a driver mutation in lung cancer and is highly enriched in pulmonary pleomorphic carcinomas (PPCs). Whether there is intratumor or intertumor heterogeneity inMETexon 14 skipping status or in co-occurring genetic alterations in lung cancers driven byMETexon 14 skipping is unknown.MethodsWe analyzed tumor specimens obtained from 23 PPC patients (10 autopsied and 13 surgically resected).METexon 14 skipping was detected by RT-PCR. For patients withMETexon 14 skipping mutation, further analyses were performed. Genomic DNA (gDNA) was extracted from various histological components for each patient who underwent surgical resection (to assess intratumor heterogeneity). In autopsied patients, gDNA and total RNA were extracted from all metastatic lesions (to assess intertumor heterogeneity).ResultsMETexon 14 skipping mutation was detected in 4 patients (4/23, 17.4%): two surgically resected and two autopsied patients. We found no intratumor or intertumor heterogeneity inMETexon 14 skipping mutation status in these patients. We observed intratumor and intertumor heterogeneity in the copy number variations and/or mutational status of cancer-related genes; some of these differences may have an impact on MET tyrosine kinase inhibitor (TKI) efficacy.ConclusionIn our exploratory analysis of four cases, we observed thatMETexon 14 skipping mutations are distributed homogeneously throughout histological components and between metastatic lesions. Our results also suggest that there is marked intertumor and intratumor heterogeneity in co-occurring genetic alterations, and therapeutic implications of such heterogeneity should be evaluated in future studies.