Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions.
Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions.
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DOI：
10.1158/1078-0432.ccr-12-0838
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发表时间：
2012-12-15
期刊：
影响因子：
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通讯作者：
Ladanyi M
中科院分区：
文献类型：
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作者：
Suehara Y;Arcila M;Wang L;Hasanovic A;Ang D;Ito T;Kimura Y;Drilon A;Guha U;Rusch V;Kris MG;Zakowski MF;Rizvi N;Khanin R;Ladanyi M
肺癌中主要致癌基因的互斥模式表明存在其他互斥的癌基因。我们对酪氨酸激酶(TK)融合进行了系统的研究，方法是筛选所有TK，寻找相对于更多5‘外显子的3’激酶域(KD)外显子的异常高RNA表达水平。我们研究了69例肺腺癌患者(包括5名从不吸烟的人和现在或以前吸烟者)，所有KRAS、EGFR、BRAF、MEK1和HER2的主要突变和ALK融合(称为“全阴性”)均为阴性。设计了一种基于纳米串的分析方法，在两个点上查询90个TKS的转录本：KD的5‘端和KD内的KD或KD的3’端。将肿瘤RNA与纳米串探针杂交，并分析异常值3‘至5’的表达比率。通过快速扩增cDNA端(RACE)和确认性RT-PCR和FISH对推测的新融合事件进行研究。我们在ROS1和RET中分别发现1例3‘~5’比值异常。RACE在前者中分离到GOPC-ROS1(FIG-ROS1)融合，在后者中分离到KIF5B-RET融合，经RT-PCR证实。FISH也证实了RET重排。KIF5B-RET患者是该队列中仅有的5名从不吸烟者之一。KIF5B-RET融合定义了一个额外的肺癌亚集，其潜在的靶向驱动癌基因在从不吸烟的“泛阴性”肺腺癌患者中丰富。我们还首次报道了在肺癌中，GOPC-ROS1融合以前在胶质瘤中的特征。
The mutually exclusive pattern of the major driver oncogenes in lung cancer suggests that other mutually exclusive oncogenes exist. We performed a systematic search for tyrosine kinase (TK) fusions by screening all TKs for aberrantly high RNA expression levels of the 3′ kinase domain (KD) exons relative to more 5′ exons. We studied 69 patients (including 5 never smokers and 64 current or former smokers) with lung adenocarcinoma negative for all major mutations in KRAS, EGFR, BRAF, MEK1, and HER2, and for ALK fusions (termed “pan-negative”). A NanoString-based assay was designed to query the transcripts of 90 TKs at two points: 5′ to the KD and within the KD or 3′ to it. Tumor RNAs were hybridized to the NanoString probes and analyzed for outlier 3′ to 5′ expression ratios. Presumed novel fusion events were studied by rapid amplification of cDNA ends (RACE) and confirmatory RT-PCR and FISH. We identified 1 case each of aberrant 3′ to 5′ ratios in ROS1 and RET. RACE isolated a GOPC-ROS1 (FIG-ROS1) fusion in the former and a KIF5B-RET fusion in the latter, both confirmed by RT-PCR. The RET rearrangement was also confirmed by FISH. The KIF5B-RET patient was one of only 5 never smokers in this cohort. The KIF5B-RET fusion defines an additional subset of lung cancer with a potentially targetable driver oncogene enriched in never smokers with “pan-negative” lung adenocarcinomas. We also report for the first time in lung cancer the GOPC-ROS1 fusion previously characterized in glioma.