title: ROS1 and ALK fusions in colorectal cancer, with evidence of intratumoral heterogeneity for molecular drivers.
abstract: 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.
  
  
  CONCLUSIONS
  ROS1 and ALK fusions occur in colorectal cancer and may have substantial impact in therapy selection.
authors.affiliation: University of Colorado School of Medicine Anschutz Medical Campus, 12801 East 17th Avenue, L18-8118, Mail Stop 8117, Aurora, CO 80045. marileila.garcia@ucdenver.edu.
authors.forename: Dara L
authors.initials: DL
authors.lastname: Aisner
authors.forename: Teresa T
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Diego D
authors.initials: DD
authors.lastname: Paskulin
authors.forename: Anh T
authors.initials: AT
authors.lastname: Le
authors.forename: Jerry
authors.initials: J
authors.lastname: Haney
authors.forename: Nathan
authors.initials: N
authors.lastname: Schulte
authors.forename: Fiona
authors.initials: F
authors.lastname: Chionh
authors.forename: Jenny
authors.initials: J
authors.lastname: Hardingham
authors.forename: John
authors.initials: J
authors.lastname: Mariadason
authors.forename: Niall
authors.initials: N
authors.lastname: Tebbutt
authors.forename: Robert C
authors.initials: RC
authors.lastname: Doebele
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Weickhardt
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000556:secondary; D018797:Cell Cycle Proteins / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C117307:KRAS protein, human; D008869:Microtubule-Associated Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C493557:SLC34A2 protein, human; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C415585:EML4 protein, human; D012697:Serine Endopeptidases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins