An Oncogenic ALK Fusion and an RRAS Mutation in KRAS Mutation-Negative Pancreatic Ductal Adenocarcinoma

Rare oncogenic aberrations, such as the ALK fusion and RRAS mutation, may drive pancreatic carcinogenesis independent of the KRAS mutation. The Oncologist 2017;22:158-164Implications for Practice: The oncogenic DCTN1-ALK fusion and the RRAS mutation were associated with the development of pancreatic ductal adenocarcinoma (PDAC) in the absence of the KRAS mutation. Constitutional activation of DCTN1-ALK fusion protein was suppressed by the anaplastic lymphoma kinase tyrosine kinase inhibitors crizotinib and alectinib. Thus, a small subset of PDAC patients might benefit from therapy using these inhibitors. 摘要 目的. KRAS基因致癌性突变是众所周知的胰腺癌驱动事件, 95%以上的胰腺癌病例均携带这一突变。本研究的目的是在不携带KRAS突变的胰腺癌患者中鉴定驱动致癌基因畸变。 方法. 从一个含100例病例的队列中鉴别出了4例KRAS突变阴性胰腺导管腺癌病例, 随后对其进行全外显子组和转录组测序。 结果. 1例病例携带致癌性DCTN1‐ALK融合。该融合基因可使Ba/F3细胞的生长不依赖于白细胞介素‐3, 从而使其对间变性淋巴瘤激酶酪氨酸激酶抑制剂克唑替尼和Alectinib敏感。断点连接处的结构表明, DCTN1外显子DNA片段与ALK内含子DNA片段的非同源末端彼此连接后产生了一个隐蔽的剪接位点, 从而引起基因融合。另一病例携带致癌性RRAS突变, 该突变激活了RRAS蛋白的GTP酶。 结论. 诸如ALK融合和RRAS突变等罕见的致癌性畸变可能引发不依赖于KRAS突变的胰腺癌变。 The Oncologist 2017;22:158–164 对临床实践的提示：致癌性DCTN1‐ALK融合和RRAS突变可在不伴KRAS突变的情况下引发胰腺导管腺癌（PADC）。间变性淋巴瘤激酶酪氨酸激酶抑制剂克唑替尼和Alectinib可抑制DCTN1‐ALK融合蛋白的结构性活化。因此, 少部分PDAC患者可从上述抑制剂治疗中获益。

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.

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.

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.