An Oncogenic ALK Fusion and an RRAS Mutation in KRAS Mutation-Negative Pancreatic Ductal Adenocarcinoma
An Oncogenic ALK Fusion and an RRAS Mutation in KRAS Mutation-Negative Pancreatic Ductal Adenocarcinoma
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DOI：
10.1634/theoncologist.2016-0194
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发表时间：
2017-01-01
期刊：
影响因子：
5.8
通讯作者：
Hiraoka, Nobuyoshi
中科院分区：
文献类型：
--
作者：
Shimada, Yoko;Kohno, Takashi;Hiraoka, Nobuyoshi
目的. KRAS基因中的致癌突变是众所周知的驱动事件，发生在>95%的胰腺癌中。本研究的目的是确定无KRAS突变的胰腺癌中的驱动癌基因畸变。对100例KRAS突变阴性的胰腺导管腺癌患者进行全外显子组和转录组测序。1例病例存在致癌性DCTN 1-ALK融合。融合基因使Ba/F3细胞能够不依赖白细胞介素-3生长，并使其对间变性淋巴瘤激酶酪氨酸激酶抑制剂克唑替尼和阿来替尼敏感。断裂点连接的结构表明，融合是通过DCTN 1外显子DNA片段和ALK内含子DNA片段之间的非同源末端连接产生的，导致产生隐蔽剪接位点。另1例患者存在致癌RRAS突变，该突变激活了RRAS蛋白的GT3。罕见的致癌畸变，如ALK融合和RRAS突变，可能独立于KRAS突变驱动胰腺癌发生。
Purpose. Oncogenic mutations in the KRAS gene are a well-known driver event, occurring in >95% of pancreatic cancers. The objective of this study was to identify driver oncogene aberrations in pancreatic cancers without the KRAS mutation.Methods. Whole-exome and transcriptome sequencing was performed on four cases of KRAS mutation-negative pancreatic ductal adenocarcinoma, which were identified in a cohort of 100 cases.Results. One case harbored an oncogenic DCTN1-ALK fusion. The fusion gene enabled interleukin-3-independent growth of Ba/F3 cells and rendered them susceptible to the anaplastic lymphoma kinase tyrosine kinase inhibitors crizotinib and alectinib. The structure of the breakpoint junction indicated that the fusion was generated by nonhomologous end joining between a segment of DCTN1 exon DNA and a segment of ALK intron DNA, resulting in the generation of a cryptic splicing site. Another case harbored an oncogenic RRAS mutation that activated the GTPase of the RRAS protein.Conclusion. Rare oncogenic aberrations, such as the ALK fusion and RRAS mutation, may drive pancreatic carcinogenesis independent of the KRAS mutation.