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Colonic Adenocarcinomas Harboring NTRK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 16 Cases and Review of the Literature

J. Lasota, M. Chłopek, J. Lamoureux, J. Christiansen, A. Kowalik, B. Wasąg, A. Felisiak-Gołąbek, A. Agaimy, W. Biernat, V. Canzonieri, G. Centonze, E. Chmielik, O. Daum, M. Dubová, I. Dziuba, S. Goertz, S. Góźdź, A. Guttmejer-Nasierowska, C....

. 2020 ; 44 (2) : 162-173. [pub] -

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc20023185

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.

Clinical Oncology Faculty of Health Sciences Jan Kochanowski University Kielce

Department of Clinical Pathomorphology Medical University of Lublin Lublin

Department of Pathology Aichi Medical University School of Medicine Nagakute Japan

Department of Pathology and Laboratory Medicine Milan Italy

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

Department of Pathology Research Programs and HUSLAB University of Helsinki and Helsinki University Hospital Helsinki Finland

Department of Pathomorphology Copernicus Hospital Gdańsk Gdańsk

Department of Pathomorphology Jagiellonian University

Department of Pathomorphology Provincial Hospital Gorzów Wielkopolski

Department of Pathomorphology Provincial Hospital Olsztyn

Department of Surgery University of Helsinki

Department of Tumor Pathology Centre of Oncology Maria Skłodowska Curie Memorial Institute Kraków

Departments of Biology and Genetics

Departments of Molecular Diagnostics

Diagnostic Histopathology Laboratory Opole

Division of Pathology National Cancer Institute Aviano Department of Medical Surgical and Health Sciences University of Trieste Trieste

Division of Pathomorphology and Oncological Cytology Wrocław Medical University Wrocław

Health Sciences and Physical Education University of Technology and Humanities Radom

Ignyta Inc San Diego CA

Independent Laboratory of Pathology Zdunomed Szczecin

Institute of Pathology University Hospital of Erlangen Erlangen Germany

Laboratory of Pathology ElPat Elbląg Poland

Laboratory of Pathology National Cancer Institute Bethesda MD

Laboratory of Pathology National Cancer Institute Bethesda MD Departments of Molecular Diagnostics

Pathomorphology Medical University of Gdańsk

Sikl's Department of Pathology University Hospital Charles University Prague Medical Faculty in Plzeň Plzeň Czech Republic

Surgical Pathology Holycross Cancer Center

References provided by Crossref.org

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$a 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.
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