ROS1 and ALK fusions in colorectal cancer, with evidence of intratumoral heterogeneity for molecular drivers.
ROS1 and ALK fusions in colorectal cancer, with evidence of intratumoral heterogeneity for molecular drivers.
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DOI：
10.1158/1541-7786.mcr-13-0479-t
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发表时间：
2014-01
期刊：
影响因子：
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通讯作者：
Varella-Garcia M
中科院分区：
文献类型：
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作者：
Aisner DL;Nguyen TT;Paskulin DD;Le AT;Haney J;Schulte N;Chionh F;Hardingham J;Mariadason J;Tebbutt N;Doebele RC;Weickhardt AJ;Varella-Garcia M
通过基因融合，在肺腺癌中发现了活化的ALK和ROS 1酪氨酸激酶，并且对选择性激酶抑制剂高度敏感。本研究旨在使用4靶点、4色分离荧光原位杂交（FISH）试验同时确定ALK和ROS 1的基因组状态，以确定人结直肠腺癌（CRC）标本中是否存在这些重排。在分析的临床CRC标本中，观察到ALK和ROS 1均呈阳性的病例。ALK的融合伴侣被确定为EML 4，其中一例ROS 1阳性病例的融合伴侣为SLC 34 A2，另一例ROS 1阳性病例的融合伴侣仍有待确定。一小部分标本存在天然ALK和ROS 1的重复或成簇拷贝。此外，在三个病例中的两个病例中，也在携带KRAS和BRAF突变的样本中检测到重排。有趣的是，ALK阳性标本显示出明显的肿瘤内异质性，并且在高度异型增生区域也发现了重排。尽管观察到了额外的致癌事件和肿瘤异质性，但对首例ROS 1重排的阐明和ALK重排的确认支持进一步评价这些基因组融合作为CRC的潜在治疗靶点。ROS1和ALK融合发生在结直肠癌中，可能对治疗选择产生重大影响。
Activated ALK and ROS1 tyrosine kinases, through gene fusions, has been found in lung adenocarcinomas and are highly sensitive to selective kinase inhibitors. This study aimed at identifying the presence of these rearrangements in human colorectal adenocarcinoma (CRC) specimens using a 4-target, 4-color break-apart fluorescence in situ hybridization (FISH) assay to simultaneously determine the genomic status of ALK and ROS1. Among the clinical CRC specimens analyzed, rearrangement-positive cases for both ALK and ROS1 were observed. The fusion partner for ALK was identified as EML4 and the fusion partner for one of the ROS1-positive cases was SLC34A2, the partner for the other ROS1-positive case remains to be identified. A small fraction of specimens presented duplicated or clustered copies of native ALK and ROS1. In addition, rearrangements were detected in samples that also harbored KRAS and BRAF mutations in two of the three cases. Interestingly, the ALK-positive specimen displayed marked intra-tumoral heterogeneity and rearrangement was also identified in regions of high-grade dysplasia. Despite the additional oncogenic events and tumor heterogeneity observed, elucidation of the first cases of ROS1 rearrangements and confirmation of ALK rearrangements support further evaluation of these genomic fusions as potential therapeutic targets in CRC. ROS1 and ALK fusions occur in colorectal cancer and may have substantial impact in therapy selection.