Chromosomal changes traveling withETV6-NTRK in secretory carcinoma of the breast

Gregor Krings led a multi-center group from the University of California, San Francisco, to compare histology and genetics of nine secretory carcinomas of the breast with six MASC salivary gland tumors. This post looks at breast secretory carcinoma chromosome changes that travel with the ETV6-NTRK3 gene fusion. While the TEL-TRKC fusion protein may be many vocal passengers, it seems to be only one actionable target.

Diagram showing genomic alterations in various patients with their sex and age.

A gain in the long arm or the entire chromosome 8 is seen in cases 1 and 3. A loss of the interstitial part of 15q or the entire chromosome is seen in cases 2 and 3

Chromosome 8 gains 

SC1 came from a 57 year old female. Except for a gain in the q arm of chromosome 8, her tumor is genetically unremarkable. A gain in 8q has been associated with a poor prognosis in prostate cancer, Silva 2016. These authors were particularly focused on the MYC oncogenic transcription factor on 8q. In taxane resistant breast cancer, Han and coworkers (2010) reported gains in 8q24.21 being one of many chromosomal gains.


Ensembl representation of MYC gene on chromosome 8. Inset picture shows The RAS arm of TRKC signaling results in activation of MYC.

The oncogenic transcription factor MYC is located on chromosome 8. The RAS arm of TRKC signaling results in activation of MYC.

We are making no claims whatsoever that c-Myc is up regulated in SC1 and SC3 secretory breast cancers driven by ETV6-NTRK3 gene fusions. Other genomic alterations may control how severe secretory cancers are.

Chromosome 16 gains 

Chromosome 16 gains occurred in two of the secretory carcinomas of the breast. Duplication of chromosomes X and 16 are associated with a more aggressive phenotype, Nakopoulou (2007). Strange and coworkers (2016) used high resolution genomic profiling to compare invasive ductal and invasive lobular carcinomas of the breast (IDC and ILC, respectively). They not only looked at copy number gains but also mRNA transcripts.

  • ITGAX  showed moderate over expression in ILC with 16p gain.
  • RNF40, BCL7C, and FUS showed over expression in ILC with 16p gain.
Ensembl representation of ITGAX gene on chromosome 16 with inset picture showing genes in a small region of duplicated chromosome may be over expressed in breast cancers.

Genes in a very small region of a duplicated chromosome may be over expressed in breast cancers

Presenting these data is not meant to imply that these four genes in the Strange 2016 report might also be over expressed in any secretory carcinomas. The point is that many things may be occurring at once.  There are some other proteins in the 16p11.2 neighborhood that may impact TRKC signaling. CancerIndex lists some hot spots on chromosome 16 for breast cancer.

Chromosome 12 and 15 changes 

The accounting might be a challenge in these secretory carcinomas. SC2 is interesting because it resembles a complex gene fusion (MASC5)  in which the interstitial portion of 15q would have to have been deleted. Does a copy number reduction of interstitial 15q genes contribute to the histology?  Gains and deletions of chromosomes 12 and 15 in SC3 is an accounting problem because the fusion chromosome has been duplicated. And yes, the fusion is reciprocal!

Ensembl representation of ETV6 and NTRK3 on chromosomes 12 and 15 respectively. Gene fusion between these two genes may create a very large or very small fusion chromosome if fusion is reciprocal.

Gene fusions between ETV6 and NTRK3 may create a very large and very small fusion chromosomes if the fusion is reciprocal.

Chromosome 13 gain

One interesting thing to note is that the genes for two tumor suppressors reside on chromosome 13:

The FLT1 gene codes for the vascular endothelial growth factor receptor, a receptor tyrosine kinase.

Ensembl representation of FLT1, BRCA2 and RB1 on chromosome 13.

Genes for a growth promoting receptor tyrosine kinase and two tumor suppressors both reside on chromosome 13.

There is absolutely no way of knowing if copy number gains in chromosome 13 in SC4 led to increased expression of either of these two tumor suppressors or the vascular endothelial growth factor receptor. The reader is invited to explore the Cancer Index of cancer associated genes on chromosome 13 to gain an understanding of just how “complicated” genomic alterations that drive and travel with cancer can be.

A complex fusion in SC8

Ensembl representation of ETV6 and PLEKHAS gene on chromosome 12. For fusion to occur, everything in between must be deleted.

The ETV6 and PLEKHAS genes are in the same reading frame. For fusion to occur, everything in between must be deleted.

SC8 was genetically interesting because it was an ETV6-PLEKHA5–NTRK3 fusion that came from a 13 year old female.  We have covered the pediatric ETV6 rearrangement history on this site.  Both the ETV6 and the PLEKHA5 genes are located on the p arm of chromosome 12. They both read in the sense direction. The plekstrin homology domain containing family member 5 can bind to phosphoinositol 3-phosphate phospholipids.  It is not clear if PIP binding ability exists in the  fusion protein. It is not clear if  dimerization domains of the ETV6 gene product, TEL, are in the fusion protein. At 0.5 cm, this tumor was the smallest in the group. Very little IHC was performed. It is uncertain that this cancer was even remotely aggressive.

We can surmise from data on CancerIndex, this region of chromosome 12 is a hot zone for cancer associated mutations. To get a better idea of the implication of this region of 12p, the reader is advised to sort the Cancer Index by location. An IHC marker of an active TRKC kinase might be helpful to rule out other potential participants in the 12p12-12p14 region.

Testing for TRK

Two points may be gleaned from chromosomal data presented in this post.

  1. Some chromosomal gains and deletions were observed to be traveling with the ETV6-NTRK3 gene fusion in secretory carcinoma of the breast. Extensive research has shown some of these gains and deletions to be predictors of outcome.  In some cases inidividual proteins have been targeted.
  2. The one complex fusion observed in this set seemed to be relatively benign clinically. One wanders if the fusion kinase was that active.

As part of the Trailblaze® molecular diagnostics program, Ignyta is now offering Trailblaze Pharos, a suite of molecular diagnostic assays and services, including proprietary companion diagnostic tests, to accompany its molecularly targeted oncology programs.

Trailblaze Pharos™ is a multiplex assay for identifying actionable fusions in NTRK1, NTRK2, NTRK3, ROS1, and ALK genes, resulting in solid tumors that can be treated with entrectinib, to support testing for the STARTRK-2 clinical trial.


Han S, Park K, Shin E, Kim HJ, Kim JY, Kim JY, Gwak G. (2010) Genomic change of chromosome 8 predicts the response to taxane-based neoadjuvant chemotherapy in node-positive breast cancer. Oncol Rep. 2010 Jul;24(1):121-8. PubMed

Krings G, Joseph NM, Bean GR, Solomon D, Onodera C, Talevich E1, Yeh I, Grenert JP, Hosfield E, Crawford ED, Jordan RC, van Zante A, Zaloudek C, Shin SJ, Chen YY. (2017) Genomic profiling of breast secretory carcinomas reveals distinct genetics from other breast cancers and similarity to mammary analog secretory carcinomas. Mod Pathol. 30(8):1086-1099. PubMed

Nakopoulou L, Panayotopoulou EG, Giannopoulou I, Tsirmpa I, Katsarou S, Mylona E, Alexandrou P, Keramopoulos A. (2007) Extra copies of chromosomes 16 and X in invasive breast carcinomas are related to aggressive phenotype and poor prognosis. J Clin Pathol.60(7):808-15. PubMed

Silva MP, Barros-Silva JD, Ersvær E, Kildal W, Hveem TS, Pradhan M, Vieira J, Teixeira MR, Danielsen HE. (2016) Cancer Prognosis Defined by the Combined Analysis of 8q, PTEN and ERG.
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