Development of lung adenocarcinomas with exclusive dependence on oncogene fusions.
Development of lung adenocarcinomas with exclusive dependence on oncogene fusions.
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DOI：
10.1158/0008-5472.can-14-3282
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发表时间：
2015-06
期刊：
影响因子：
11.2
通讯作者：
M. Saito;Yoko Shimada;K. Shiraishi;H. Sakamoto;K. Tsuta;Hirohiko Totsuka;S. Chiku;H. Ichikawa;
中科院分区：
文献类型：
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作者：
M. Saito;Yoko Shimada;K. Shiraishi;H. Sakamoto;K. Tsuta;Hirohiko Totsuka;S. Chiku;H. Ichikawa;
该报告提供了由 ALK、RET 和 ROS1 癌基因融合驱动的肺腺癌 (LADC) 的全面遗传改变概况。这些肿瘤由于罕见而难以研究。每种方法仅驱动一小部分 LADC。对富含融合患者（n = 31，15.5%）的日本 LADC 队列（n = 200）进行全外显子组测序和拷贝数变异分析，然后进行深度重测序进行验证。驱动融合病例表现出明显的特征，与其他 LADC 相比，癌症相关基因中的非同义突变或 SWI/SNF 染色质重塑复合物基因中的截短突变数量较少 (P < 0.0001)。这种较低的突变率与年龄、性别、吸烟状况、病理分期和肿瘤分化无关 (P < 0.0001)，并在来自美国 LADC 队列的 9 例融合阳性病例 (n = 230) 中得到验证。总之，我们的研究结果表明，具有 ALK、RET 和 ROS1 融合的 LADC 完全通过依赖这些癌基因融合而发育。融合之外的如此少的改变的存在支持使用针对融合阳性 LADC 中的融合产物的酪氨酸激酶抑制剂的单一疗法。
This report delivers a comprehensive genetic alteration profile of lung adenocarcinomas (LADC) driven by ALK, RET, and ROS1 oncogene fusions. These tumors are difficult to study because of their rarity. Each drives only a low percentage of LADCs. Whole-exome sequencing and copy-number variation analyses were performed on a Japanese LADC cohort (n = 200) enriched in patients with fusions (n = 31, 15.5%), followed by deep resequencing for validation. The driver fusion cases showed a distinct profile with smaller numbers of nonsynonymous mutations in cancer-related genes or truncating mutations in SWI/SNF chromatin remodeling complex genes than in other LADCs (P < 0.0001). This lower mutation rate was independent of age, gender, smoking status, pathologic stage, and tumor differentiation (P < 0.0001) and was validated in nine fusion-positive cases from a U.S. LADCs cohort (n = 230). In conclusion, our findings indicate that LADCs with ALK, RET, and ROS1 fusions develop exclusively via their dependence on these oncogene fusions. The presence of such few alterations beyond the fusions supports the use of monotherapy with tyrosine kinase inhibitors targeting the fusion products in fusion-positive LADCs.