title: NUT Midline Carcinoma: Morphoproteomic Characterization with Genomic and Therapeutic Correlates.
abstract: NUT midline carcinoma is a rare entity arising primarily in the midline of teenagers and young adults. Genomically, it is associated with a translocation involving a nuclear protein in testis (NUT) gene with other genes, most commonly, the BRD4 gene. The resultant is a partial or near total block in differentiation of tumor cells into mature squamous elements. Such tumors are resistant to conventional therapy with a reported mean survival at less than 1 year. In this study, we investigated two cases with genomic confirmation as NUT midline carcinoma by morphoproteomic analysis using immunohistochemical antibodies. Our results showed overexpression, largely in the undifferentiated cells of the tumors of: 1) Stemness marker, SRY (sex determining region Y)-box 2 (Sox2); 2) Constitutive activation of the mTORC2 pathway with expression of total insulin-like growth factor-1 receptor (IGF-1R[Tyr1165/1166]), and nuclear p-mTOR (Ser 2448) and p-Akt (Ser 473); and 3) c-Myc, silent mating type information regulation 2 homolog 1 (Sirt1) and histone methyltransferase enhancer of Zeste, Drosophila, homolog 2 (EZH2) as molecular impediments to differentiation. These data were analyzed through the use of QIAGEN's Ingenuity(®) Pathway Analysis (IPA(®), QIAGEN Redwood City, www.qiagen.com/ingenuity). The results established the interconnection of these pathways and molecules, and identified several pharmacogenomic agents--melatonin, metformin, vorinostat, curcumin, and sulforaphane--that have the potential to remove the block in differentiation and lead to the establishment of a more benign form of NUT midline carcinoma.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Texas Health Science Center - Medical School at Houston, Texas, USA.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Texas Health Science Center - Medical School at Houston, Texas, USA.
authors.forename: Mary F
authors.initials: MF
authors.lastname: McGuire
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Texas Health Science Center - Medical School at Houston, Texas, USA.
authors.forename: Songlin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Texas Health Science Center - Medical School at Houston, Texas, USA Robert.Brown@uth.tmc.edu.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Brown
mesh_terms: D000293:Adolescent; D000328:Adult; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D017879:Isothiocyanates / Q000494:pharmacology; D008297:Male; D008479:Mediastinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D008687:Metformin / Q000494:pharmacology; D058990:Molecular Targeted Therapy / Q000379:methods; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D013454:Sulfoxides; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D017879:Isothiocyanates; C000630260:NUTM1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D013454:Sulfoxides; D008687:Metformin; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; C016766:sulforaphane
keywords: EZH2; NUT midline carcinoma; Sirt1; biomedical analytics; c-Myc; mTORC2 pathway; morphoproteomic