TRK Fusions

Trk fusions may result from

  1. deletions of regions of the same chromosome fusing genes that are in the same reading frame
  2. inversions of regions of the same chromosome
  3. chromosome rearrangements involving different chromosomes

We have discussed the protein biochemistry aspects of the translated products of gene fusions on another site. We have not discussed the genes themselves and the shuffling that must occur for fusions to occur.

I.  Fusions within Chromosome 1

Chromosome 1 is a good place to start. The TRK1, LMNA, and TPM3 genes all reside on a region of chromosome 1 between 1q21.1 and 1q23.3. Let’s take a closer look at these genes. The LMNA and TRK1 genes read in the sense direction. The TPM3 gene reads in the anti-sense direction. In other words, it resides on the complement strand.

Figure 1 Some Chromosome 1 examples of TRK1 gene fusions

 

 

If this is still confusing, let us color the sense strand red and the anti-sense strand green. Our fusion genes are the same colors as in Figure 1:  TPM3 cyan, LMNA yellow, and TRK1 purple.  Hypothetically, a TPM3-TRK1 gene fusion would not require any deletion of portions of chromosome 1. Do both ends fuse to create  TRK1-TPM3  and TPM3-TRK1 fusions? So far as we know, no one has looked. A TRK1-TPM3 hypothetical fusion would be under the control of the TRK1 promoter. Since TrkA is not a highly expressed protein, one would think that this particular fusion would not cause too much trouble to the cell. What happens to the region of chromosome 1 deleted to create the LMNA-TRK1 fusion?

Figure 2 Some Chromosome 1 acrobats need to create TPM3-TRK1 and LMNA-TRK1  Start.  Note the direction of the genes.  Only TPM3 is in the direction of the centromer.   If genes read in opposite directions, the resulting fusion by inversion gene would read in one direction. .  Genes may already read in the same direction in fusion by deletion.

 

 

There is something about Chromosome 1

The table in Figure 3 is adapted from study of colorectal cancer (Pietrantonio 2017). Note the over representation of TRK1 fusions in these tumors.

Figure 3 TRK fusions in colorectal carcinoma

 

Pietrantonio F, Di Nicolantonio F, Schrock AB, Lee J, Tejpar S, Sartore-Bianchi A, Hechtman JF, Christiansen J, Novara L, Tebbutt N, Fuca G, Antoniotti C, Kim ST, Danielle Murphy, Rosa Berenato, Morano F, Min JB, Stephens PJ, Chen M, Cremolini C (2017)ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer JNCI J Natl Cancer Inst 109(12): djx089

II.  Inter-Chromosomal Rearrangements

Chromosomal rearrangements are a smaller category of gene fusions. Many of the TRK1 gene rearrangements that we have examined involve gene deletions and inversions of regions on the same chromosome.  A wealth of information exists for us to explore what fusions between different chromosomes might mean.

A.  The ETV6-TRK3 gene fusion

Involvement of two chromosomes is the case for the gene rearrangement of mammary analog of secretory carcinoma treatmentMASC. The human ETV6 gene is located on chromosome 12 and reads in the “sense” direction. The human TRK3 gene is located on chromosome 15 and reads in the “antisense” direction.

Figure 4 The ETV6-TRK3 rearrangement.  The inset is from Tognon (2002).

 

It was uncertain from Tognon (2002) if they observed a small portion of chromosome 12 fusing with the q arm of chromosome 15.

Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, Becker L, Carneiro F, MacPherson N, Horsman D, Poremba C, Sorensen PH.(2002) Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002 Nov;2(5):367-76. PubMed.

B. The QKI-TRK2 gene fusion

We have discussed the fusion protein consequences of the QKI-TRK2 gene rearrangement on another website. What does it mean to rearrange chromosomes 6 of the QKI gene and chromosome 9 of the TRK2 gene?

Figure 5. The QKI-TRK2 gene fusion a. Both genes read in the same direction b. a closer look at the QKI gene c. a closer look at the TRK2 gene.

 

a.  Both the QKI and TRK2 genes read in the sense direction

A closer examination shows that both genes are in the sense direction(red arrows).  Distances in base pairs go from the end of the p arm to the end of the q arm.   Note that the QKI gene is towards the end of the q arm.

b.  closer look at the QKI gene

The QKI gene resides on cytogenetic band 6q26.  The telomer tip of he q arm of chromosome 6 is split off taking the 3′ end of QKI and all genes down stream with it.  In the gene fusion chromosome 6 derivative, a fusion with a piece of chromosome 9 is proposed to create a slightly longer chromosome 6 (der).

  • In the anti-sense direction on the 5’end of the QKI gene is  CAHM “colon adenocarcinoma hypermethylated” non-protein coding transcript has been shown to decrease in colorectal carcinomas PubMed. The presence of hypermethylated CAHM promoter DNA has even been shown to increase in the blood plasma of CRC patients.
  • The literature is lacking on the  lost is the melanoma associated transcript MEAT6
  • CCR6 codes for a chemokine receptor.
  • THBS2 codes for thombospondin, a glycoprotein that mediates cell to cell and cell to matrix adhesion. These proteins inhibit cell growth and angiogenesis.

What happens to this piece of chromosome 6? Does this copy of the THBS2 gene still get transcribed or is the tumor getting by with just one copy of this gene?

c.  closer look at the TRK2 gene

The TRK2 gene resides on cytogenetic band 9q21.33. What would happen if the 3’ region of the TRK2 gene is removed from chromosome 9?

  •  The 3’ end of the NTRK2 gene overlaps with the gene for the non protein coding LOC105376118 transcript. NCBI even has tissue distribution of this transcript.
  • A large portion of chromosome 9, 9(der), the 5- end, would remain.
  • The gene for the non protein coding mRNA, LOC102724036 , would remain very close to the severed end.
  • SLC28A3 codes for a sodium/nucleoside cotransporter that may help acquire raw materials for DNA replication.
  • UBLN1 gene codes for ubiquilin 1, a ubiquitin-like protein that is also associated with protein degradation.
  • HNRNPK, Heterogeneous nuclear ribonucleoprotein K, plays a role in the p53/TP53 response to DNA damage.

Are these regions of 9(der) wrapped up in histones or are they “out flapping in the breeze” waiting for some transcription factors and RNA polymerase to come along?

Important Information

TRK gene rearrangement, or fusions, may affect more things than just the signaling pathways impacted by the fusion proteins.  The good news is that there is an open clinical trial testing a specific Trk kinase inhibitor.  Details of this Trk treatment are available on line.