Chromosomal changes traveling with ETV6-NTRK3 in secretory carcinoma of the salivary glands

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 salivary gland secretory carcinoma chromosome changes in the Krings study that were not observed in breast secretory carcinomas.

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

A summary of genomic alterations traveling with the ETV6-NTRK3 gene fusion.

Gain of chromosome 20, loss of chromosome 18

These changes were only seen in the MASC1 case and do not seem to constitute a trend.  Chromosome 16 gain does seem to be a trend in this limited data set and has been covered on another post. Only one gene on chromosome 18 is associated with salivary gland cancer, MIB1. There are no obvious links between chromosome 20 changes and salivary cancer on PubMed and Cancer Index.

 Chromosome 12 and 15 bookkeeping

MASC2 is unusual in that it came from a 59 year old male. There were gains in the  chromosome 12 (distal) and 15 (proximal). The ETV6-NTRK3 fusion chromosome is duplicated. The authors claim SC (of the breast) like nuclear features.

Two genes on chromosome 15 involved in a complex fusion with ETV6

MASC4 is particularly interesting in that it involves a complex fusion with ETV6-HERC2-NTRK3. HERC2 and NTRK3 are located on opposite ends of the long (q arm) of chromosome 15. Krings and coworkers commented on the resemblance of MASC4 to SC2, a tumor in which the interstitial region of 15q has been deleted.

Location of HERC2 and NTRK3 on opposite ends of the long (q arm) of chromosome 15 as shown by Ensembl.

supplement to Krings 2017 Figure 1m

Both HERC2 and NTRK3 reside on the anti-sense strand. It wasn’t clear how much of the HERC2 gene product, if any, makes its way into the TEL-TRKC fusion protein. For these two genes to become fused, a large portion of  the interstitial part of 15q must be removed.  Krings only reported deletion of the proximal region of 15q.

A third complex ETV6-NTRK3 fusion involves a commonly deleted region of Chromosome 3

MASC5 is another complex fusion, this time with WDR53. The WDR53 gene is located on the very distal q arm of chromosome 3, 3q29 to be somewhat exact. This region is so much prone to deletion, there is a 3q29 deletion syndrome. No chromosome losses were reported in this tumor. Other interesting genes in the neighborhood include MUC4,  TNK2 (ACK1), and PAK2 ( p21 activated protein kinase).

One really has to ask how much of the pathology, if any,  in MASC5 is due to the ETV6-WDR53-NTRK3 gene fusion.   This fusion was detected by RNA sequencing but not DNA sequencing. RNA sequencing revealed the same fusion junctions in the other secretory carcinomas of the Krings study.

Ensembl location of WDR53 gene on the very distal q arm of chromosome 3. This region is very much prone to deletion and is called a 3q29 deletion syndrome.

Note that MUC4 is one of the IHC markers and is highly expressed in MASC5

A gain in chromsome 7, home of two IHC markers

On a companion IHC page we discussed use of EGFR and PIP/GCDFP-15 as markers. Chromosome 7 was only duplicated in MASC4. PIP IHC was not positive in any of the MASC tumors. Ironically, the other MASC tumors tended to have higher expression of EGFR.

Ensembl location of EGFR and PIP/GCDFP-15 which are used as markers on Chromosome 7.

These results question whether chromosome gain and loss data is really that useful. The information in databases like Cancer Index is more extensive for breast cancers than salivary gland cancers.

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 salivary gland secretory carcinoma.
  2. The database of chromosome gains and deletions associated with salivary gland cancers is not as extensive as that for cancers of the breast.

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 NTRK1NTRK2NTRK3ROS1, and ALK genes, resulting in solid tumors that can be treated with entrectinib, to support testing for the STARTRK-2 clinical trial.

Reference

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. PubMed