Exome sequencing deciphers a germline MET mutation in familial epidermal growth factor receptor-mutant lung cancer.
Exome sequencing deciphers a germline MET mutation in familial epidermal growth factor receptor-mutant lung cancer.
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DOI：
10.1111/cas.13233
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发表时间：
2017-06
期刊：
影响因子：
5.7
通讯作者：
Ichinose M
中科院分区：
文献类型：
--
作者：
Tode N;Kikuchi T;Sakakibara T;Hirano T;Inoue A;Ohkouchi S;Tamada T;Okazaki T;Koarai A;Sugiura H;Niihori T;Aoki Y;Nakayama K;Matsumoto K;Matsubara Y;Yamamoto M;Watanabe A;Nukiwa T;Ichinose M
伴有表皮生长因子受体（EGFR）基因体细胞激活突变的肺癌，与靶向治疗的显著临床应答相关，常见于从不吸烟的亚洲腺癌女性。虽然这意味着遗传因素的致癌作用，病因仍不清楚。为了深入了解致病机制，我们对一个家族性EGFR突变型肺腺癌家族的6个兄弟姐妹（4个受影响的兄弟姐妹和2个未受影响的兄弟姐妹）的外周血DNA中的外显子组进行了测序。我们在所有四个受影响的兄弟姐妹中发现了MET原癌基因p.Asn375Lys的杂合错义突变。结合MET杂合性的体细胞丢失，日本测序数据库中较高的等位基因频率支持MET突变在EGFR突变型肺癌中的致病作用。功能分析表明，突变降低了MET对其配体肝细胞生长因子的结合亲和力，并损害了随后的细胞过程，包括增殖、克隆形成、运动和致瘤性。进一步观察到MET突变消除了ERBB3介导的AKT信号转导，该信号转导由EGFR下游共享。这些发现提供了一种病因学观点，即MET突变参与EGFR突变型肺癌的发病机制，因为它产生致癌应激，诱导EGFR代偿性激活。在一个家族性EGFR突变型肺癌家族中鉴定MET，不仅对家族性，而且对通过强调MET相关信号分子来探索散发性EGFR突变型肺癌的致病机制具有深刻意义。
Lung cancer accompanied by somatic activating mutations in the epidermal growth factor receptor (EGFR) gene, which is associated with a significant clinical response to the targeted therapy, is frequently found in never‐smoking Asian women with adenocarcinoma. Although this implies genetic factors underlying the carcinogenesis, the etiology remains unclear. To gain insight into the pathogenic mechanisms, we sequenced the exomes in the peripheral‐blood DNA from six siblings, four affected and two unaffected siblings, of a family with familial EGFR‐mutant lung adenocarcinoma. We identified a heterozygous missense mutation in MET proto‐oncogene, p.Asn375Lys, in all four affected siblings. Combined with somatic loss of heterozygosity for MET, the higher allele frequency in a Japanese sequencing database supports a causative role of the MET mutation in EGFR‐mutant lung cancer. Functional assays showed that the mutation reduces the binding affinity of MET for its ligand, hepatocyte growth factor, and damages the subsequent cellular processes, including proliferation, clonogenicity, motility and tumorigenicity. The MET mutation was further observed to abrogate the ERBB3‐mediated AKT signal transduction, which is shared downstream by EGFR. These findings provide an etiological view that the MET mutation is involved in the pathogenesis of EGFR‐mutant lung cancer because it generates oncogenic stress that induces compensatory EGFR activation. The identification of MET in a family with familial EGFR‐mutant lung cancer is insightful to explore the pathogenic mechanism of not only familial, but also sporadic EGFR‐mutant lung cancer by underscoring MET‐related signaling molecules.