University of Colorado School of Medicine Anschutz Medical Campus, 12801 East 17th Avenue, L18-8118, Mail Stop 8117, Aurora, CO 80045.
Mol Cancer Res. 2014 Jan;12(1):111-8. doi: 10.1158/1541-7786.MCR-13-0479-T. Epub 2013 Dec 2.
Activated anaplastic lymphoma kinase (ALK) and ROS1 tyrosine kinases, through gene fusions, have 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 specimens using a 4-target, 4-color break-apart FISH assay to simultaneously determine the genomic status of ALK and ROS1. Among the clinical colorectal cancer 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 intratumoral 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 colorectal cancer.
ROS1 and ALK fusions occur in colorectal cancer and may have substantial impact in therapy selection.
已在肺腺癌中发现通过基因融合激活的间变性淋巴瘤激酶（ALK）和 ROS1 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 靶标、4 色分离 FISH 测定法来鉴定这些重排在人类结直肠腺癌标本中的存在，以同时确定 ALK 和 ROS1 的基因组状态。在所分析的临床结直肠癌标本中，观察到 ALK 和 ROS1 的重排阳性病例。ALK 的融合伙伴被鉴定为 EML4，一个 ROS1 阳性病例的融合伙伴是 SLC34A2，另一个 ROS1 阳性病例的融合伙伴仍有待确定。一小部分标本呈现出 native ALK 和 ROS1 的重复或簇集拷贝。此外，在三个病例中的两个中，在存在 KRAS 和 BRAF 突变的样本中也检测到了重排。有趣的是，ALK 阳性标本显示出明显的肿瘤内异质性，并且在高级别发育不良区域也鉴定到了重排。尽管观察到了额外的致癌事件和肿瘤异质性，ROS1 重排的首例病例的阐明以及 ALK 重排的证实支持进一步评估这些基因组融合作为结直肠癌潜在的治疗靶点。
ROS1 和 ALK 融合发生在结直肠癌中，并且可能在治疗选择中具有重大影响。
