TY - JOUR
T1 - Colonic Adenocarcinomas Harboring NTRK Fusion Genes
T2 - A Clinicopathologic and Molecular Genetic Study of 16 Cases and Review of the Literature
AU - Lasota, Jerzy
AU - Chłopek, Małgorzata
AU - Lamoureux, Jennifer
AU - Christiansen, Jason
AU - Kowalik, Artur
AU - Wasąg, Bartosz
AU - Felisiak-Gołąbek, Anna
AU - Agaimy, Abbas
AU - Biernat, Wojciech
AU - Canzonieri, Vincenzo
AU - Centonze, Giovanni
AU - Chmielik, Ewa
AU - Daum, Ondrej
AU - Dubová, Magdalena
AU - Dziuba, Ireneusz
AU - Goertz, Sebastian
AU - Góźdź, Stanisław
AU - Guttmejer-Nasierowska, Anna
AU - Haglund, Caj
AU - Hałoń, Agnieszka
AU - Hartmann, Arndt
AU - Inaguma, Shingo
AU - Iżycka-Świeszewska, Ewa
AU - Kaczorowski, Maciej
AU - Kita, Paweł
AU - Kołos, Małgorzata
AU - Kopczyński, Janusz
AU - Michal, Michal
AU - Milione, Massimo
AU - Okoń, Krzysztof
AU - Pȩksa, Rafał
AU - Pyzlak, Michał
AU - Ristimäki, Ari
AU - Ryś, Janusz
AU - Szostak, Blażej
AU - Szpor, Joanna
AU - Szumiło, Justyna
AU - Teresiński, Leszek
AU - Waloszczyk, Piotr
AU - Wejman, Jarosław
AU - Wesołowski, Wojciech
AU - Miettinen, Markku
N1 - Publisher Copyright:
© 2019 Wolters Kluwer Health, Inc. All rights reserved.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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.
AB - 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.
KW - colorectal carcinoma
KW - fusion genes
KW - immunohistochemistry
KW - next-generation sequencing
KW - NTRK1, 2 and 3
KW - TRK expression
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U2 - 10.1097/PAS.0000000000001377
DO - 10.1097/PAS.0000000000001377
M3 - Article
VL - 44
SP - 162
EP - 173
JO - American Journal of Surgical Pathology
JF - American Journal of Surgical Pathology
SN - 0147-5185
IS - 2
ER -