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Review
. 2019 Jul;72(7):460-467.
doi: 10.1136/jclinpath-2018-205679. Epub 2019 May 9.

Testing Algorithm for Identification of Patients With TRK Fusion Cancer

Affiliations
Free PMC article
Review

Testing Algorithm for Identification of Patients With TRK Fusion Cancer

Frédérique Penault-Llorca et al. J Clin Pathol. .
Free PMC article

Abstract

The neurotrophic tyrosine receptor kinase (NTRK) gene family encodes three tropomyosin receptor kinases (TRKA, TRKB, TRKC) that contribute to central and peripheral nervous system development and function. NTRK gene fusions are oncogenic drivers of various adult and paediatric tumours. Several methods have been used to detect NTRK gene fusions including immunohistochemistry, fluorescence in situ hybridisation, reverse transcriptase polymerase chain reaction, and DNA- or RNA-based next-generation sequencing. For patients with TRK fusion cancer, TRK inhibition is an important therapeutic target. Following the FDA approval of the selective TRK inhibitor, larotrectinib, as well as the ongoing development of multi-kinase inhibitors with activity in TRK fusion cancer, testing for NTRK gene fusions should become part of the standard diagnostic process. In this review we discuss the biology of NTRK gene fusions, and we present a testing algorithm to aid detection of these gene fusions in clinical practice and guide treatment decisions.

Keywords: TRKA; TRKB; TRKC; cancer screening; ntrk gene fusions; trk fusion cancer; tumour-agnostic biomarker; tyrosine kinase inhibitor.

Conflict of interest statement

Competing interests: FP-L has participated in advisory boards for Bayer, Roche, Illumina and Nanostring, and been involved in studies sponsored by Bayer. ERR has had a role as an expert consultant, participated in a meeting and participated in an advisory board for Bayer Healthcare Pharmaceuticals. ARS has had a role as an expert consultant for Merck US, Bristol Meyers Squibb and Bayer Healthcare Pharmaceuticals; participated in meetings for Merck US, Bristol Meyers Squibb and Bayer Healthcare Pharmaceuticals; participated in advisory boards for Merck US, Bristol Meyers Squibb and Bayer Healthcare Pharmaceuticals; and received honoraria from Amgen.

Figures

Figure 1
Figure 1
Schematic figure showing the TRK receptor tyrosine kinases, activating neurotrophins and the major signal transduction pathways (A) and the genomic structures of NTRK1, NTRK2, and NTRK3, with the size of each gene in parentheses (B). The ETV6 and NTRK3 gene fusion and the resultant constitutively active TRK fusion protein is a typical example. GSK3ß, glycogen synthase kinase 3 beta; Ig, immunoglobulin; mRNA, messenger ribonucleic acid; NTRK, neurotrophic tyrosine receptor kinase; PI3K, phosphoinositide-3-kinase; SAM, sterile alpha motif; TRK, tropomyosin receptor kinase.
Figure 2
Figure 2
Secretory carcinoma of the breast aka juvenile carcinoma: low-grade basal tumour. (A) Immunohistochemistry. Nuclear staining of TRK detected by pan-TRK IHC. (B) FISH. t(12:15) ETV6-NTRK3 fusion using an ETV6 break-apart probe. Due to the prevalence of ETV6-NTRK3 gene fusions, an ETV6 break-apart probe is typically used. FISH image provided by courtesy of Dr Hanina Hibshoosh, Columbia University. FISH, fluorescence in situ hybridisation; IHC, immunohistochemistry; TRK, tropomyosin receptor kinase.
Figure 3
Figure 3
Testing algorithm for TRK fusion cancer. CMN, congenital mesoblastic nephroma; FISH, fluorescence in situ hybridisation; IFS, infantile fibrosarcoma; IHC, immunohistochemistry; MASC, mammary analogue secretory carcinoma; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; NTRK, neurotrophic tyrosine receptor kinase; SBC, secretory breast carcinoma; TRK, tropomyosin receptor kinase.

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References

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    1. Hugo Gene Nomenclature Committee (HGNC). Symbol report: NTRK1. Available: https://www.genenames.org/cgi-bin/gene_symbol_report?hgnc_id=HGNC:8031 [Accessed 12 Sep 2018].
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