Category: Molecular pathology

Recent molecular studies have revealed that,  several tumors harbor TRK fusion. However fusion frequencies vary. 

Several NTRK1/2/3 (neurotrophic tyrosine receptor kinase) fusions have been reported. It is important to identify them since they serve as potential targets for therapy

The NTRK1, 2, and 3 genes encode a family of tyrosine kinase receptors with an active role
in neural development.

They are encoded by three different NTRK genes:

1. NTRK1 located on chromosome 1q21-q22 – corresponding receptor TrkA binds to NGF (nerve growth factor)

2. NTRK2 on chromosome 9q22.1- corresponding receptor TrkB binds to BDNF (brain derived natriuretic factor)

3. NTRK3 on chromosome 15q25- corresponding receptor TrkC.

NTRK oncogenic fusions can be encountered in two main different scenarios:

1. Consists of rare tumors in which NTRK fusions are found at very high frequencies, as dominant oncogenes.
2. Comprises common tumors in which NTRK fusions are identified at low frequencies, including both solid and hematological malignancies.

Here are a few tumors with high frequency TRK gene fusion – [ETV6-NTRK3 fusion]  – t(12;15)

1.Mammary analogue secretory carcinoma (MASC)- >75%-  Some MASC harbour ETV6- RET fusion -t(10;12)- They have poor outcome since they are non-responsive to TRK fusion therapy.

2.Secretory carcinoma of breast- >75%

3. Cellular and mixed mesoblastic nephroma (>75%)

4. Infantile fibrosarcoma. >75%

5. Ossifying renal tumor of infancy

DIAGNOSIS :  As yet, there are no FDA-approved NTRK gene fusion tests.

IHC : Pan-Trk IHC has the power to become an incredibly rapid and efficient screening tool for NTRK rearrangements.

NGS : Molecular methods like NGS and reverse transcription polymerase chain reaction (RT-PCR) provide a more comprehensive look at the NTRK genes, these tests are expensive and slow, potentially delaying treatment.

TREATMENT: Entrectinib and Larotrectinib are TRK inhibitors

Other tumors with NTRK fusion  partners is shown below.

Reference: Federica Zito Marino et.al. NTRK Fusions, from the Diagnostic Algorithm to Innovative Treatment in the Era of Precision Medicine. Int. J. Mol. Sci. 2020, 21, 0.

Click below for summary and a mnemonic.