Mesoblastic Nephroma : ETV6-NTRK3 Fusion
Section Editor: Dharam M. Ramnani, MD
Virginia Urology, Richmond, VA, USA
Image Description
Molecular Genetics: Congenital cellular mesoblastic nephroma (CCMN) contains t(12;15)(p13;q25) translocation resulting in ETS variant 6 (ETV6)-neurotrophic tyrosine receptor kinase 3 (NTRK3) gene fusion. This molecular event is identical to that seen in infantile fibrosarcoma, suggesting that CCMN may be a renal form of infantile fibrosarcoma. TRK fusion is not seen in classic mesoblastic nephroma.
ETV6-NTRK3 fusion transcript encodes a chimeric protein that causes uninterrupted activation of multiple signaling cascades, including RAS-MAP kinase and PI3K-AKT pathways. This leads to increased cell survival, growth, and proliferation leading to tumorigenesis.
NTRK fusions act as a oncogenic drivers in a diverse array of adult and pediatric tumors, including CCMN (85%), infantile fibrosarcoma (90-100%), secretory breast carcinoma (>90%), mammary analog secretory carcinoma of salivary glands (90-100%), acute leukemias (both myeloid and lymphoid), papillary thyroid carcinoma (15%; usually radiation-associated), inflammatory myofibroblastic tumor, and infrequently in some other rare tumors.
Absence of ETV6-NTRK3 does not exclude the diagnosis of CCMN. Several variant fusions have been described, including the less common EML4-NTRK3 fusion and LMNA-NTRK1 (in infantile fibrosarcoma). NTRK gene fusions can be detected by a variety of methods, including immunohistochemistry, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, and DNA- or RNA-based next-generation sequencing.
In patients with TRK-fusion positive cancers, the use of selective TRK inhibitors such as Larotrectinib and Entrectinib or multi-kinase inhibitors is an active area of investigation. High response rates have been seen in metastatic setting.
Image Source: Penault Llorca F, Rudzinski ER, Sepulveda AR. Testing algorithm for identification of patients with TRK fusion cancer. J Clin Pathol 2019;0:1-8. doi:10.1136/jclinpath-2018-205679; open access; used under Creative Commons Attribution-NonCommercial 4.0 International.
ETV6-NTRK3 fusion transcript encodes a chimeric protein that causes uninterrupted activation of multiple signaling cascades, including RAS-MAP kinase and PI3K-AKT pathways. This leads to increased cell survival, growth, and proliferation leading to tumorigenesis.
NTRK fusions act as a oncogenic drivers in a diverse array of adult and pediatric tumors, including CCMN (85%), infantile fibrosarcoma (90-100%), secretory breast carcinoma (>90%), mammary analog secretory carcinoma of salivary glands (90-100%), acute leukemias (both myeloid and lymphoid), papillary thyroid carcinoma (15%; usually radiation-associated), inflammatory myofibroblastic tumor, and infrequently in some other rare tumors.
Absence of ETV6-NTRK3 does not exclude the diagnosis of CCMN. Several variant fusions have been described, including the less common EML4-NTRK3 fusion and LMNA-NTRK1 (in infantile fibrosarcoma). NTRK gene fusions can be detected by a variety of methods, including immunohistochemistry, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, and DNA- or RNA-based next-generation sequencing.
In patients with TRK-fusion positive cancers, the use of selective TRK inhibitors such as Larotrectinib and Entrectinib or multi-kinase inhibitors is an active area of investigation. High response rates have been seen in metastatic setting.
Image Source: Penault Llorca F, Rudzinski ER, Sepulveda AR. Testing algorithm for identification of patients with TRK fusion cancer. J Clin Pathol 2019;0:1-8. doi:10.1136/jclinpath-2018-205679; open access; used under Creative Commons Attribution-NonCommercial 4.0 International.