Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Exactis Innovation, Montreal, Quebec, Canada.
Mol Cancer Ther. 2019 Sep;18(9):1628-1636. doi: 10.1158/1535-7163.MCT-19-0105. Epub 2019 Jun 26.
Rearrangements in the anaplastic lymphoma kinase () gene are found in approximately 5% of non-small cell lung carcinoma (NSCLC). Here, we present a comprehensive genomic landscape of 11 patients with ALK+ NSCLC and investigate its relationship with response to crizotinib. Using whole-exome sequencing and RNAseq data, we identified four rare ALK fusion partners (, and ) and one novel partner (). At the mutation level, was the most frequently mutated gene and was only observed in patients with the shortest progression-free survival (PFS). Of note, only 4% of the genes carrying mutations are present in more than 1 patient. Analysis of somatic copy number aberrations (SCNA) demonstrated that a gain in EML4 was associated with longer PFS, and a loss of or gain in was associated with shorter PFS. This study is the first to report a comprehensive view of the ALK+ NSCLC copy number landscape and to identify SCNA regions associated with clinical outcome. Our data show the presence of mutation as a strong prognostic indication of poor clinical response in ALK+ NSCLC. Furthermore, new and rare ALK fusion partners were observed in this cohort, expanding our knowledge in ALK+ NSCLC.
在大约 5%的非小细胞肺癌（NSCLC）中发现间变性淋巴瘤激酶（ALK）基因重排。在这里，我们展示了 11 例 ALK+ NSCLC 的全面基因组图谱，并研究了其与克唑替尼反应的关系。使用全外显子组测序和 RNAseq 数据，我们鉴定了四个罕见的 ALK 融合伙伴（、和）和一个新的伙伴（）。在突变水平上，是最常突变的基因，仅在无进展生存期（PFS）最短的患者中观察到。值得注意的是，只有 4%的携带突变的基因存在于超过 1 位患者中。体细胞拷贝数异常（SCNA）分析表明，EML4 的获得与较长的 PFS 相关，而缺失或获得则与较短的 PFS 相关。这项研究首次报告了 ALK+ NSCLC 拷贝数图谱的全面视图，并确定了与临床结果相关的 SCNA 区域。我们的数据显示，ALK+ NSCLC 中存在 突变是对临床反应不良的强烈预后指标。此外，在该队列中观察到新的和罕见的 ALK 融合伙伴，扩展了我们对 ALK+ NSCLC 的认识。
