Simple Trk Mutations in Colorectal Carcinoma

The discovery of the NTRK gene fusion by way of it’s colon cancer driving fusion protein is covered on another site.  The NTRK genes were discovered before the sparingly expressed kinases.  It is rather ironic that scientists looked at simple mutations in Trk kinases in colon cancer long after Trk kinases were discovered serendipitously by way of a complex NTRK gene fusion in colon cancer.

Simple mutations in the protein coding portions of genes were introduced on the Trk Mutations page of this site. Normally these simple mutations are repaired without incident thanks to the diligence of our DNA mismatch repair (MMR) enzymes. This is such an important function, bacteria have these enzymes too. Microsatellite instability (MSI) is a manifestation of defect(s) in the MMR apparatus.

Figure showing how Mismatch Repair prevents mutations from propagating

Fig. 1. Mismatch Repair (MMR) prevents mutations from propagating A. MSH2/3 find the mispaired bases B. Other enzymes come in to remove the defective strand and repair it returning to C the original sequence. D. Defects in this process, as indicated by high microsatellite instability (MSI-H), are associated with a higher frequency in TRK mutations in genes.

Cancer associated defects in MMR enzymes lead to more mutations in TRK genes

Deihimi and coworkers (2017) compared colorectal carcinomas (CRCs) overall mutation rates

  • 26 MSI-High (MSI-H)  50%
  • 558 non-MSI-H   14%

revealing a significant difference.  (p < 0.0001).

Deihimi and coworkers (2017) also compared specific TRK1,2,3 mutation rates

  • 26 MSI-High (MSI-H)  40%
  • 558 non-MSI-H   16%

revealing a significant difference.  (p= 0.0003).

mutations in TRK genes that result in amino acid substitutions

Fig. 2. Mutations in TRK genes that result in amino acid substitutions


We will not concern ourselves with the synonymous mutations that result in the same amino acid in the translated protein.  Let us instead look at each change in the translated Trk that Deihimi (2017) observed


G613V Natural variant VAR_009629 G → V  (613)

Not much information is available for this structural variant.  It is in a well conserved coil region.

I699V Natural variant VAR_077476 I → T (699) in CIPA

  • partially decreased N-glycosylation
  • reduced expression at the plasma membrane
  • reduced basal autophosphorylation
  • complete loss of NGF-induced autophosphorylation
  • loss of NGF-stimulated calcium flux.

UniProt lists the G613V substitution as a natural variant yet references publications associated with congenital insensitivity to pain with anhidrosis (CIPA).  Compared to the CIPA associated I699T substitution, I699V seems to be pretty conservative.


P716S Proline may have longer range affects. It tends to form secondary structure edges and/or disrupt secondary structures such as α-helices and β-sheets. P175 is in between some β-strands and a 3/10-helix that precedes a series of α-helices. All of these are in the kinase domain of TrkB. ( It is conceivable that this substitution may affect protein function.

R675H right next to active site. D676 is the proton acceptor in the wild type enzyme.

A662T The region of 650-669 is an α-helix (


Information is also obtained from

R678* This premature stop codon terminates the translation of the protein before the active site proton acceptor D679. This protein is surely inactive.

R745L.   R745 resides in a linker region between two α-helices in the kinase domain. It is conceivable that this radical substitution could alter protein function.   UniProt lists an R745P in a lung carcinoma sample; somatic mutation. – VAR_046523.

Deihimi and coworkers (2017) speculated that mutations in the inactivation loops of the Trk kinases could result in an unregulated kinase.

TrkA I699V

TrkB P716S

TrkC R745L

These authors speculated that these constitutively active kinases could present targets for small molecule inhibitors.We have covered  Trk activation loop mutations on another post of this site.

Important Information

Maybe, one day, when there is proof that a simple mutation in a receptor tyrosine kinaes like the Trk family results in a constitutively active kinase, there will be a clinical trial.  For now there is an open Trk inhibitor clinical trial for cancers driven by NTRK or TRK gene rearrangements that result in wild type kinase domains minus the N-terminal regulatory domains.  In most cases, these fusion kinases are constitutively active.  The Trk inhibitor entrectinib as well as regulation of Trk activity can be understood by watching a video.


Deihimi S, Lev A, Slifker M, Shagisultanova E, Xu Q, Jung K, Vijayvergia N, Ross EA, Xiu J, Swensen J, Gatalica Z, Andrake M, Dunbrack RL, El-Deiry WS.(2017) BRCA2, EGFR, and NTRK mutations in mismatch repair-deficient colorectal cancers with MSH2 or MLH1 mutations. Oncotarget. 2017 May 23. doi: 10.18632/oncotarget.18098. [Epub ahead of print] PubMed