Detection ofNTRKFusions: Merits and Limitations of Current Diagnostic Platforms

Abstract

Oncogenic fusions involving NTRK1, NTRK2, and NTRK3 with various partners are diagnostic of infantile fibrosarcoma and secretory carcinoma yet also occur in lower frequencies across many types of malignancies. Recently, targeted small molecular inhibitor therapy has been shown to induce a durable response in a high percentage of patients with NTRK fusion-positive cancers, which has made the detection of NTRK fusions critical. Several techniques for NTRK fusion diagnosis exist, including pan-Trk IHC, FISH, reverse transcription PCR, DNA-based next-generation sequencing (NGS), and RNA-based NGS. Each of these assays has unique features, advantages, and limitations, and familiarity with these assays is critical to appropriately screen for NTRK fusions. Here, we review the details of each existing methodology. ImmunohistochemistryWidely available to most clinical labs, IHC has the advantages of being inexpensive, having a rapid turnaround time of

Uterine mesenchymal tumours: recent advances

“…NTRK rearrangements are oncogenic events in a wide variety of human cancers, including common and rare tumour types such as infantile fibrosarcomas, lipofibromatosis‐like neural tumours and fibrosarcoma‐like uterine sarcomas . TPM3–NTRK1 fusion is present in more than 60% of uterine sarcomas, while LMNA–NTRK1 , TPR–NTRK1 , RBPMS–NTRK3 and EML4–NTRK3 fusions are rare (Figure ).…”

“…Pan‐Trk covering TrkA, Trk and TrkC is expressed in all NTRK fusion‐positive uterine sarcomas, but staining patterns vary depending on the location of the partnering gene (Figure ) . For example, LMNA encodes a nuclear membrane protein, and fusion with NTRK1 leads to nuclear membrane accentuation of pan‐Trk expression …”

“…[16][17][18] PDGFB encodes a growth factor that binds and activates PDGF receptor tyrosine kinases important in regulating embryonic development, cell proliferation, cell migration, survival and chemotaxis. 19 NTRK rearrangements are oncogenic events in a wide variety of human cancers, 17,[20][21][22][23][24] including common and rare tumour types such as infantile fibrosarcomas, 20 lipofibromatosis-like neural tumours 20 and fibrosarcoma-like uterine sarcomas. 22,24 TPM3-NTRK1 fusion is present in more than 60% of uterine sarcomas, while LMNA-NTRK1, TPR-NTRK1, RBPMS-NTRK3 and EML4-NTRK3 fusions are rare 22,24 (Figure 3).…”

“…25 For example, LMNA encodes a nuclear membrane protein, and fusion with NTRK1 leads to nuclear membrane accentuation of pan-Trk expression. 21 NTRK fusion-positive tumours may be confused with spindle cell LMS, sarcoma with PDGFB rearrangement and UUS. Approximately 6% of LMS lacking NTRK rearrangements may be pan-Trk positive, but are overtly pleomorphic and express desmin, in contrast to the uniform nuclear atypia and lack of smooth muscle differentiation of NTRK fusion-positive sarcomas.…”

NTRKtesting: First results of theQuiP‐EQAscheme and a comprehensive map ofNTRKfusion variants and their diagnostic coverage by targetedRNA‐basedNGSassays

“…Accordingly, comparative performance data on the two different technologies and their proficiency to detect NTRK fusions are still very limited. This is particularly true for major RNA-based targeted sequencing approaches, which are best suited to identify a wide range of different fusion variants [17][18][19][20] in formalin-fixed, paraffin-embedded (FFPE) tissue with variable tumor cell content.…”