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

Jerzy Lasota, Małgorzata Chłopek, Jennifer Lamoureux, Jason Christiansen, Artur Kowalik, Bartosz Wasąg, Anna Felisiak-Gołąbek, Abbas Agaimy, Wojciech Biernat, Vincenzo Canzonieri, Giovanni Centonze, Ewa Chmielik, Ondrej Daum, Magdalena Dubová, Ireneusz Dziuba, Sebastian Goertz, Stanisław Góźdź, Anna Guttmejer-Nasierowska, Caj Haglund, Agnieszka HałońArndt Hartmann, Shingo Inaguma, Ewa Iżycka-Świeszewska, Maciej Kaczorowski, Paweł Kita, Małgorzata Kołos, Janusz Kopczyński, Michal Michal, Massimo Milione, Krzysztof Okoń, Rafał Pȩksa, Michał Pyzlak, Ari Ristimäki, Janusz Ryś, Blażej Szostak, Joanna Szpor, Justyna Szumiło, Leszek Teresiński, Piotr Waloszczyk, Jarosław Wejman, Wojciech Wesołowski, Markku Miettinen

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)162-173
Number of pages12
JournalAmerican Journal of Surgical Pathology
Volume44
Issue number2
DOIs
Publication statusPublished - Feb 1 2020

Keywords

  • colorectal carcinoma
  • fusion genes
  • immunohistochemistry
  • next-generation sequencing
  • NTRK1, 2 and 3
  • TRK expression

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

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