Identification and characterization of a novel SCYL3-NTRK1 rearrangement in a colorectal cancer patient

// Massimo Milione 1 , Elena Ardini 2 , Jason Christiansen 3 , Emanuele Valtorta 4 , Silvio Veronese 4 , Roberta Bosotti 2 , Alessio Pellegrinelli 1 , Adele Testi 1 , Filippo Pietrantonio 5 , Giovanni Fucà 6 , Ge Wei 3 , Danielle Murphy 3 , Salvatore Siena 4, 5 , Antonella Isacchi 2 and Filippo De Braud 5, 6 1 1st Division of Pathology, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 2 Nerviano Medical Sciences S.r.l., Milan, Italy 3 Ignyta, Inc., San Diego, CA, United States of America 4 Division of Pathology, Department of Laboratory Medicine, Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy 5 Dipartimento di Oncologia e Emato-Oncologia, Università degli Studi di Milano, Milan, Italy 6 Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Correspondence to: Massimo Milione, email: Massimo.milione@istitutotumori.mi.it Keywords: NTRK1, TRKA, entrectinib, CRC, rearrangement Received: April 12, 2017      Accepted: July 12, 2017      Published: July 24, 2017 ABSTRACT In colorectal cancer patients, chromosomal rearrangements involving NTRK1 gene (encoding the TRKA protein) are shown in a small subset of patients and are associated with the constitutive activation of the kinase domain of TRKA. In turn, activated TRKA-fusion proteins are associated with proliferation and survival in colorectal cancer tumors. Here we report the identification and functional characterization of a new SCYL3-NTRK1 fusion gene in a 61-year-old colorectal cancer patient. To our knowledge, this fusion protein has never been previously documented in oncological patients. We show that this novel fusion is oncogenic and sensitive to TRKA inhibitors. As suggested by other pieces of evidence, entrectinib - an orally available pan-TRK, ROS1 and ALK inhibitor - may have particular efficacy in patients with NTRK rearrangements. Therefore, screening for rearrangements involving NTRK genes may help identifying a subset of patients able to derive benefit from treatment with entrectinib or other targeted inhibitors.