Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
Cancer Res. 2015 Jun 1;75(11):2264-71. doi: 10.1158/0008-5472.CAN-14-3282. Epub 2015 Apr 8.
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.
本报告提供了一个由 ALK、RET 和 ROS1 癌基因融合驱动的肺腺癌（LADC）的全面遗传改变图谱。这些肿瘤由于其罕见性而难以研究。每个融合仅驱动低比例的 LADC。对一个富含融合患者的日本 LADC 队列（n=31，15.5%）进行了外显子组测序和拷贝数变异分析，随后进行了深度重测序验证。与其他 LADC 相比，驱动融合病例显示出明显的特征，即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断突变数量较少（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 个融合阳性病例（n=230）中得到验证。总之，我们的研究结果表明，ALK、RET 和 ROS1 融合的 LADC 完全依赖于这些癌基因融合而发展。融合之外的这些改变很少，这支持在融合阳性 LADC 中使用针对融合产物的酪氨酸激酶抑制剂进行单药治疗。
