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Mammary Analogue Secretory Carcinoma (MASC) Tumors
Mammary analogue secretory carcinoma (MASC) of the salivary gland was first described by Skálová in 2010 [1]. A chromosome translocation was found to be identical to the t(12;15) (p13;q25)found in secretory carcinoma of the breast. This fusion is between the ETV6 and NTRK3 genes https://en.wikipedia.org/wiki/ETV6-NTRK3_gene_fusion.

The fusion gene product contains the N-terminus of the transcription faction TEL that is responsible for dimerization/ polymerization https://en.wikipedia.org/wiki/ETV6. The C-terminus of the protein product of the gene fusion contains the C-terminus of the receptor tyrosine kinase TrkC https://en.wikipedia.org/wiki/Tropomyosin_receptor_kinase_C. It should be noted that the fusion protein lacks regulation by growth factors. Since it's discovery, much of the literature concerning MASC has addressed the challenge of differentiating it from similar appear cancers such as acinic cell carcinoma (https://en.wikipedia.org/wiki/Acinic_cell_carcinoma AciCC), low grade cribriform cystadenocarcinoma ( https://en.wikipedia.org/wiki/Low-grade_cribriform_cystadenocarcinoma, LGCCC), and adenocarcinoma not otherwise specified (AcNOS). Means of identifying and differentiating MASC rely on histology, protein markers, and genetic markers.

Skálová et al 2010 and 2015 [1,2]

Protein Expression Presence of •	S100, a family of calcium binding proteins. Many of the antibodies used in MASC studies are specific to the S100B isoform. https://en.wikipedia.org/wiki/S100B •	mammaglobin, https://en.wikipedia.org/wiki/Mammaglobin, a breast cancer marker •	cytokeratin CK7, https://en.wikipedia.org/wiki/Keratin_7, an intermediate filament found in epithelial cells. •	GATA-3, https://en.wikipedia.org/wiki/GATA3, a transcription factor that is a breast cancer biomarker. •	SOX-10, https://en.wikipedia.org/wiki/SOX10, a transcription factor important in neural crest origin cells and in development of the peripheral nervous system. •	STAT5a https://en.wikipedia.org/wiki/STAT5A, a transcription factor Absence of •	p63 https://en.wikipedia.org/wiki/TP63, a transcription factor in the same family as p53 •	DOG1 Discovered On Gastrointestinal Stromal Tumors Protein) otherwise known as Anoctamin-1,  https://en.wikipedia.org/wiki/ANO1, a voltage sensitive calcium activated chloride channel.

Histology

•	lobulated growth pattern •	microcystic https://en.wikipedia.org/wiki/Cyst and glandular spaces •	eosinophilic secretions, i.e. stains strongly for eosin Y https://en.wikipedia.org/wiki/Eosin_Y •	positive for periodic acid-Schiff https://en.wikipedia.org/wiki/Periodic_acid–Schiff_stain, often after diastase digestion https://en.wikipedia.org/wiki/Diastase. •	Vesicular oval nuclei with a single small but prominent nucleolus •	 absence of basophilic https://en.wikipedia.org/wiki/Haematoxylin or zymogen granules https://en.wikipedia.org/wiki/Zymogengranules found in AciCC

Molecular Biology •	Chromosome break at the ETV6 loci using FISH, https://en.wikipedia.org/wiki/Fluorescence_in_situ_hybridization •	reverse transcript PCR for the junction between the transcript of the ETV6-NTRK3 gene fusion. •	Murphy and coworkers [3] developed a different two step for identifying the molecular component of MASC. In this two step process a tissue section is (1a) screened with pan-receptor tyrosine kinase antibody (1b) screened with specific receptor tyrosine kinase antibodies known to drive cancers, e.g. TrkC (2) Based on the results of immunohistochemistry, next generation sequencing is used to identify the fusion partner. This assay as come to be called the Trailblaze Pharos assay [4] and is part of an ongoing clinical trial [5].

In a 2016 report, Skálová and coworkers investigated the discrepancy between positive FISH results and negative reverse transcriptase PCR for the fusion transcript [2]. Using reverse transcriptase PCR https://en.wikipedia.org/wiki/Reverse_transcription_polymerase_chain_reaction and a more rigorous nested primer system they found evidence for splice variants of the ETV6-NTRK3 fusion gene. They also presented evidence of a different splice variants led to more aggressive forms of MASC [2].

1.  Skálová A, Vanecek T, Sima R, Laco J, Weinreb I, Perez-Ordonez B, Starek I, Geierova M, Simpson RH, Passador-Santos F, Ryska A, Leivo I, Kinkor Z, Michal M.(2010)Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol.34(5):599-608. PMID: 20410810  DOI:  10.1097/PAS.0b013e3181d9efcc

2. Skálová A, Vanecek T, Simpson RH, Laco J, Majewska H, Baneckova M, Steiner P, Michal M.(2016) Mammary Analogue Secretory Carcinoma of Salivary Glands: Molecular Analysis of 25 ETV6 Gene Rearranged Tumors With Lack of Detection of Classical ETV6-NTRK3 Fusion Transcript by Standard RT-PCR: Report of 4 Cases Harboring ETV6-X Gene Fusion. Am J Surg Pathol. 40(1):3-13. PMID: 26492182  DOI: 10.1097/PAS.0000000000000537

3. Murphy DA, Ely HA, Shoemaker R, Boomer A, Culver BP, Hoskins I, Haimes JD, Walters RD, Fernandez D, Stahl JA, Lee J, Kim KM, Lamoureux J, Christiansen J.(2016)Detecting Gene Rearrangements in Patient Populations Through a 2-Step Diagnostic Test Comprised of Rapid IHC Enrichment Followed by Sensitive Next-Generation Sequencing.Appl Immunohistochem Mol Morphol. [Epub ahead of print PMID: 27028240  DOI: 10.1097/PAI.0000000000000360

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(t) Josve05a  (c) 04:46, 9 August 2017 (UTC)