NTRKs

Members

NTRK1

NTRK2

NTRK3

Neurotrophins

The neurotrophins and their receptors play an important role in regulating development of both the central and the peripheral nervous systems.

Nerve growth factor receptor (NGFR) (MIM.162010) is also referred to as p75(NTR) due to its molecular mass and its ability to bind at low affinity not only NGF (MIM.162030), but also other neurotrophins, including brain-derived neurotrophic factor (BDNF) (MIM.113505), neurotrophin-3 (NTF3) (MIM.162660), and neurotrophin-4/5 (NTF5) (MIM.162662).

As a monomer, NGFR binds NGF with low affinity. Higher affinity binding is achieved by association with higher molecular mass, low-affinity neurotrophin receptors, namely the tropomyosin receptor kinases, TRKA (NTRK1) (MIM.191315), TRKB (NTRK2) (MIM.600456), and TRKC (NTRK3) (MIM.191316).

TRKA, TRKB, and TRKC are specific for or ’preferred by’ NGF, NTF5 and BDNF, and NTF3, respectively. NTF3 also binds to TRKA and TRKB, but with significantly lower affinity.

Pathology

Chromosomal translocations involving the NTRK1, NTRK2, and NTRK3 genes (TRK fusions), which encode the neurotrophin tyrosine kinase receptors TRKA, TRKB, and TRKC, can result in constitutive activation and aberrant expression of TRK kinase.

Certain cancers almost universally harbor TRK fusions, including infantile fibrosarcoma, cellular congenital mesoblastic nephroma, secretory breast cancer, and mammary analog secretory carcinoma of the salivary gland.

TRK fusions have also been identified at lower frequencies across a broad range of other pediatric cancers, including undifferentiated sarcomas , gliomas , papillary thyroid cancers , spitzoid neoplasms , inflammatory myofibroblastic tumors, and acute leukemias.

 NTRKs gene fusions in NTRKs-associated uterine sarcomas

• Tropomyosin receptor kinase (Trk) inhibitors have shown high response rates in patients with tumors harboring NTRK fusions.
• NTRK fusion-positive uterine sarcomas can be distinguished from leiomyosarcoma and undifferentiated uterine sarcoma.
• TrkA and pan-Trk expression in leiomyosarcomas is rare and does not correlate with NTRK rearrangement.

Open references

 Detection of Tumor NTRK Gene Fusions to Identify Patients Who May Benefit from Tyrosine Kinase (TRK) Inhibitor Therapy. Hsiao SJ, Zehir A, Sireci AN, Aisner DL. J Mol Diagn. 2019 Jul;21(4):553-571. doi : 10.1016/j.jmoldx.2019.03.008 PMID: 31075511

 Testing algorithm for identification of patients with TRK fusion cancer. Penault-Llorca F, Rudzinski ER, Sepulveda AR. J Clin Pathol. 2019 Jul;72(7):460-467. doi : 10.1136/jclinpath-2018-205679 PMID: 31072837 Free

Paywall references

 NTRK Fusions Define a Novel Uterine Sarcoma Subtype With Features of Fibrosarcoma. doi : 10.1097/PAS.0000000000001055

 ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Marchiò C, Scaltriti M, Ladanyi M, Iafrate AJ, Bibeau F, Dietel M, Hechtman JF, Troiani T, López-Rios F, Douillard JY, Andrè F, Reis-Filho JS. Ann Oncol. 2019 Sep 1;30(9):1417-1427. doi : 10.1093/annonc/mdz204 PMID: 31268127

 Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms.

 Croce S, Hostein I, Longacre TA, Mills AM, Pérot G, Devouassoux-Shisheboran M, Velasco V, Floquet A, Guyon F, Chakiba C, Querleu D, Khalifa E, Mayeur L, Rebier F, Leguellec S, Soubeyran I, McCluggage WG. Mod Pathol. 2019 Jul;32(7):1008-1022. doi : 10.1038/s41379-018-0184-6 PMID: 30877273