Original ArticlesColonic Adenocarcinomas Harboring NTRK Fusion Genes A Clinicopathologic and Molecular Genetic Study of 16 Cases and Review of the LiteratureLasota, Jerzy MD*; Chłopek, Małgorzata PhD*,†; Lamoureux, Jennifer PhD‡; Christiansen, Jason PhD‡; Kowalik, Artur PhD†; Wasąg, Bartosz PhD§; Felisiak-Gołąbek, Anna PhD*; Agaimy, Abbas MD∥; Biernat, Wojciech MD¶; Canzonieri, Vincenzo MD#,**; Centonze, Giovanni MSc††; Chmielik, Ewa MD‡‡; Daum, Ondrej MD§§; Dubová, Magdalena MD§§; Dziuba, Ireneusz MD∥∥; Goertz, Sebastian MD¶¶; Góźdź, Stanisław MD##,***; Guttmejer-Nasierowska, Anna MD†††; Haglund, Caj MD‡‡‡; Hałoń, Agnieszka MD§§§; Hartmann, Arndt MD∥; Inaguma, Shingo MD∥∥∥; Iżycka-Świeszewska, Ewa MD¶¶; Kaczorowski, Maciej MD§§§; Kita, Paweł MD‡‡; Kołos, Małgorzata MD†††; Kopczyński, Janusz MD¶¶¶; Michal, Michal MD§§; Milione, Massimo MD††; Okoń, Krzysztof MD###; Pęksa, Rafał MD¶; Pyzlak, Michał MD****; Ristimäki, Ari MD††††; Ryś, Janusz MD‡‡‡‡; Szostak, Blażej MD§§§§; Szpor, Joanna MD###; Szumiło, Justyna MD∥∥∥∥; Teresiński, Leszek MD¶¶¶¶; Waloszczyk, Piotr MD####; Wejman, Jarosław MD****; Wesołowski, Wojciech MD*****; Miettinen, Markku MD*Author Information *Laboratory of Pathology, National Cancer Institute, Bethesda, MD Departments of †Molecular Diagnostics ##Clinical Oncology ¶¶¶Surgical Pathology, Holycross Cancer Center ***Faculty of Health Sciences, Jan Kochanowski University, Kielce Departments of §Biology and Genetics ¶Pathomorphology, Medical University of Gdańsk ¶¶Department of Pathomorphology, Copernicus Hospital Gdańsk, Gdańsk ‡‡Diagnostic Histopathology Laboratory, Opole ∥∥Health Sciences and Physical Education, University of Technology and Humanities, Radom †††Department of Pathology, Central Clinical Hospital of the Ministry of Interior ****Department of Pathology, Prof. Orłowski-Memorial Independent Public Clinical Hospital and Center for Medical Postgraduate Education, Warsaw §§§Division of Pathomorphology and Oncological Cytology, Wrocław Medical University, Wrocław ###Department of Pathomorphology, Jagiellonian University ‡‡‡‡Department of Tumor Pathology, Centre of Oncology, Maria Skłodowska-Curie Memorial Institute, Kraków §§§§Department of Pathomorphology, Provincial Hospital, Olsztyn ∥∥∥∥Department of Clinical Pathomorphology, Medical University of Lublin, Lublin ¶¶¶¶Department of Pathomorphology, Provincial Hospital, Gorzów Wielkopolski ####Independent Laboratory of Pathology, Zdunomed, Szczecin *****Laboratory of Pathology ElPat, Elbląg, Poland ‡Ignyta Inc., San Diego, CA ∥Institute of Pathology, University Hospital of Erlangen, Erlangen, Germany #Division of Pathology, National Cancer Institute, Aviano **Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste ††Department of Pathology and Laboratory Medicine, Milan, Italy §§Sikl’s Department of Pathology, University Hospital, Charles University in Prague, Medical Faculty in Plzeň, Plzeň, Czech Republic ‡‡‡Department of Surgery, University of Helsinki ††††Department of Pathology, Research Programs and HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland ∥∥∥Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan A.A., W.B., V.C., G.C., E.C., O.D., M.D., I.D., S.Goertz, S.Góźdź, A.G-N., C.H., A.Hałoń, A.Hartmann, S.I., E.I.-Ś., M.Kaczorowski, P.K., M.Kołos, J.K., M.Michal, M.Milione, K.O., R.P., M.P, A.R., J.R., B.S., J.Szpor, J.Szumiło, L.T., P.W., J.W., and W.W. contributed equally. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Jerzy Lasota, MD, Laboratory of Pathology, National Cancer Institute, Room B1B47, 10 Center Drive (Building 10), Bethesda, MD 20892 (e-mail: firstname.lastname@example.org). Online date: September 23, 2019 The American Journal of Surgical Pathology: February 2020 - Volume 44 - Issue 2 - p 162-173 doi: 10.1097/PAS.0000000000001377 Buy SDC Metrics Abstract This study was undertaken to determine the frequency, and the clinicopathologic and genetic features, of colon cancers driven by neurotrophic receptor tyrosine kinase (NTRK) gene fusions. Of the 7008 tumors screened for NTRK expression using a pan-Trk antibody, 16 (0.23%) had Trk immunoreactivity. ArcherDx assay detected TPM3-NTRK1 (n=9), LMNA-NTRK1 (n=3), TPR-NTRK1 (n=2) and EML4-NTRK3 (n=1) fusion transcripts in 15 cases with sufficient RNA quality. Patients were predominantly women (median age: 63 y). The tumors involved the right (n=12) and left colon unequally and were either stage T3 (n=12) or T4. Local lymph node and distant metastases were seen at presentation in 6 and 1 patients, respectively. Lymphovascular invasion was present in all cases. Histologically, tumors showed moderate to poor (n=11) differentiation with a partly or entirely solid pattern (n=5) and mucinous component (n=10), including 1 case with sheets of signet ring cells. DNA mismatch repair–deficient phenotype was seen in 13 cases. Tumor-infiltrating CD4/CD8 lymphocytes were prominent in 9 cases. Programmed death-ligand 1 positive tumor-infiltrating immune cells and focal tumor cell positivity were seen in the majority of cases. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 cases. No mutations in BRAF, RAS, and PIK3CA were identified. However, other genes of the PI3K-AKT/MTOR pathway were mutated. In several cases, components of Wnt/β-catenin (APC, AMER1, CTNNB1), p53, and TGFβ (ACVR2A, TGFBR2) pathways were mutated. However, no SMAD4 mutations were found. Two tumors harbored FBXW7 tumor suppressor gene mutations. NTRK fusion tumors constitute a distinct but rare subgroup of colorectal carcinomas. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.