Identification of NTRK fusions in pediatric mesenchymal tumors

Breaking news

Dean Pavlick  of Foundation Medicine, Inc. and coworkers profiled 2,031 advanced cancers from pediatric patients (< 21 years) with the goal of identifying NTRK fusions. The role of one NTRK gene rearrangement, ETV6-NTRK3, was mentioned in adult mammary analog of secretory carcinoma (MASC) and secretory carcinoma of the breast.  The ETV6-NTRK3 rearrangement is found in infantile fibrosarcoma and mesoblastic nephroma.  Both of these tumors are of mesenchymal origin.

Table showing mesenchymal neoplasms in different tissue, benign and malignant types. Cartoon showing mesenchymal stem cells giving rise to different cell types

A sarcoma is a cancer that arises from transformed cells of mesenchymal origin.  Mesenchymal stem cells (MSC) may give rise to multiple cell types.

In the case of refractory pediatric sarcomas, in which complete surgical resection is not enough, pediatric sarcomas may become resistant to chemotherapies such as doxorubicin and ifosfamide. The use of small molecule Trk inhibitors, for which there is an open clinical trial, becomes attractive. Nine cases (0.44%) in the Foundation Medicine study harbored NTRK fusions.

Foundation Medicine performed the following analysis

  • Genomic DNA and total RNA were isolated from formalin-fixed paraffin-embedded (FFPE) tissue.
  • Comprehensive genomic profiling (CGP) was performed by Foundation Medicine.
  • Custom bait sets targeted at least 236 cancer related genes and 19 commonly rearranged genes.
  • Adapter ligated libraries were captured by solution hybridization.
  • All captured libraries were sequenced to high depth on Illumina HiSeq-2000 or 2500, averaging of more than 585× for DNA and more than 6,000,000 unique pairs for RNA.

 

The nine patients and six NTRK rearrangements

The following is a synopsis of the NTRK gene fusions that Foundation Medicine discovered in these pediatric patients.

ETV6-NTRK3, three patients

Three female patients harbored the ETV6-NTRK3 rearrangement.

A newborn female was diagnosed with infantile hemangioma, “morphologically c/w pericytes”. Pericytes are smooth muscle like cells found in the blood brain barrier (BBB). They help maintain the tightness of the BBB to small molecules. The newborn also had a MAP3K14 truncation. This kinase has been called NFκB inducing kinase in a report describing its potential relevance in CNS  development, neuroplasticity, and neuroinflammation. The literature on getting small molecule therapies across the blood brain barrier is extensive.  PubMed

The one year old female (infantile fibroscarcona) was also reported to harbor a mutation in the PI3KCA gene. The authors did not report the specific mutation in the catalytic subunit of phosphoinositide-3-kinase.

The 17 year old female had an inflammatory myofibroblatic tumor  as well as an additional loss of the protein tyrosine phosphatase coding PTPN2 gene.

All three secondary genomic alterations are associated with cancer. The choice of “bait” in this study might be part of it. Other genomic alterations might have been presence whose connection to cancer is less obvious. To read more about the ETV6-NTRK3 rearrangement in mammary analog of secretory carcinoma, MASC, visit our sister site.

TFG-NTRK3, one patient

Pavlick2017_TFG-NTRK3

The Trk fused gene (TFG) is generally considered a protein of the endoplasmic reticulum.  It is often fused to the NTRK1 gene in thyroid carcinomas. While Pavlick and coworkers observed amino acid 240 to be the last in the fusion, the break point for the fusion with TrkA   is considered to be between amino acids 193-194. Amino acids 237-240 appear to be a common splice site as they are missing in isoforms 2 and 4. This particular rearrangement came from a malignant solitary fibrous tumor found in a 17 year old male. These tumors carry a high risk for malignant transformation. Additional genomic alterations in this tumor included histone demethylase KDM4C amplification and homozygous loss of the CDKN2A/B locus.

Histone methylation and demethylation is part of the epigenetic phenomenon of regulation of gene transcription. We have commented on the CDKN2A/B locus on another site.

LMNA-NTRK1, two variations, two patients

Pavlick2017_LMNA-NTRK1

Variation 1 of the LMNA-NTRK1 fusion was found in a benign to low grade neuroectodermal tumor, presumably arising in a neurocristic hamartoma. This 14 year old female had no other reported driver mutations.

Follow this link, Trk inhibitor, to read about inhibition of TrkB over expressing neuroblastoma cells grown as xenographs in nude mice.

Variation 2 of the LMNA-NTRK1 fusion was found in a metastatic fibrosarcoma in a one year old male infant. The only other genomic alteration reported was a homozygous loss of the CDKN2A/B locus.

Loss of CDKN2A/B loss may affect the cell cycle.  The same Trk/ROS/ALK small molecule inhibitor can induce a G1-phase block of the cell cycle.

SQSTM1-NTRK1, one patient

Pavlick2017_SQSTM1-NTRK1

An SQSTM1-NTRK1 rearrangement was found in a newborn female with infantile fibrosarcoma. This was the sole driver genomic alteration found in her tumor.  Note only the PB1 domain of sequestosome and the kinase domain of TrkA remain in the fusion. One speculation is that this could make for a particularly oncogenic runaway kinase that does not need secondary genomic alterations.

TPM3-NTRK1, one patient

Pavlick2017_TPM3-NTRK1

This particular five year old male child had a Schwannoma  as well as homozygous loss of the CDKN2A/B locus. The authors were not clear about the location of this tumor except that it was soft tissue.   Much of tropomyosin 3 as well as the transmembrane helix of TrkA is found in this TPM3-NTRK1 gene product.   Schwannomas can be CNS and protected by the blood brain barrier (BBB).

The BBB issue has been addressed in a recent publication describing the successful treatment with a Trk inhibitor of  BCAN-NTRK1 driven glioneuronal tumor.

TPR-NTRK1, one patient

Pavlick2017_TPR-NTRK1

The translocated promoter region fusion to TrkA was the sole driver genomic alteration of an interdigitating dendritic cell sarcoma in a 20 year old male. Note the rather enormous size of the TPR gene product also known as nucleoprotein TPR, the nuclear basket protein, and   translocation promoter region protein. The TPR-NTRK1 rearrangement was reported in 1992 by Greco and coworkers PubMed.  Russell and coworkers demonstrated thyroid tumorgenicity in a trangenic mouse model PubMed.

Pavlick2017_nuclearporecomplex

Important information.

One of the  NTRK gene rearrangements discovered in the Pavlick 2017 study was in patient over the age of 18.  Two of the other nine patients were 17 years old. A TRK clinical trial is open to test small molecule inhibitor of Trk, ROS, and ALK fusion driven cancers in patients 18 years old or older.

 

Pavlick D, Schrock AB, Malicki D, Stephens PJ, Kuo DJ, Ahn H, Turpin B, Badizadegan K, Ross JS, Miller VA, Wong V, Ali SM. (2017) Identification of NTRK fusions in pediatric mesenchymal tumors. Pediatr Blood Cancer. 2017 Jan 18 PubMed

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