ROS1 and ALK Fusions in Colorectal Cancer, with Evidence of Intratumoral Heterogeneity for Molecular Drivers
| Autor: | Andrew Weickhardt, Diego D'Ávila Paskulin, Teresa Nguyen, Dara L. Aisner, Robert C. Doebele, Fiona Chionh, Niall C. Tebbutt, Jenny Hardingham, Anh T. Le, Nathan Schulte, Marileila Varella-Garcia, John M. Mariadason, Jerry Haney |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Proto-Oncogene Proteins B-raf Cancer Research Lung Neoplasms Oncogene Proteins Fusion Bevacizumab Colorectal cancer Recombinant Fusion Proteins Cell Cycle Proteins Adenocarcinoma Biology medicine.disease_cause Sodium-Phosphate Cotransporter Proteins Type IIb Article Proto-Oncogene Proteins p21(ras) Carcinoma Non-Small-Cell Lung Proto-Oncogene Proteins hemic and lymphatic diseases ROS1 medicine Humans Anaplastic lymphoma kinase Anaplastic Lymphoma Kinase Molecular Biology Aged Aged 80 and over Gene Rearrangement Serine Endopeptidases Receptor Protein-Tyrosine Kinases Cancer Gene rearrangement Protein-Tyrosine Kinases medicine.disease Molecular biology Oncology Mutation ras Proteins Cancer research Female KRAS Colorectal Neoplasms Microtubule-Associated Proteins medicine.drug |
| Zdroj: | Molecular Cancer Research. 12:111-118 |
| ISSN: | 1557-3125 1541-7786 |
| Popis: | 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. Implications: ROS1 and ALK fusions occur in colorectal cancer and may have substantial impact in therapy selection. Mol Cancer Res; 12(1); 111–8. ©2013 AACR. |
| Databáze: | OpenAIRE |
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