RESUMEN
NUT midline carcinoma is an aggressive neoplasm defined by chromosomal rearrangements of the nuclear protein in testis (NUT) gene (NUTM1). In this article, we present a strategy to detect this rare tumor through a standard DNA methylation array analysis even when occurring in unusual anatomic sites. We illustrate our approach through a case study in which we detected metastatic spread of a NUT midline carcinoma within a bone marrow biopsy that exhibited histological features of a blastoid, undifferentiated neoplasm. Our strategy builds on molecular data derived from The Cancer Genome Atlas and Gene Expression Omnibus as well as computational strategies adopted from the Brain Tumor Methylation Classifier. It is a combined approach that detects the unusual cell lineage of NUT midline carcinomas and makes diagnostic use of the entity-specific copy number alterations.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma/genética , Metilación de ADN , Perfilación de la Expresión Génica , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Transcriptoma , Anciano , Carcinoma/patología , Variaciones en el Número de Copia de ADN , Diagnóstico Diferencial , Resultado Fatal , Dosificación de Gen , Humanos , Aprendizaje Automático , Masculino , Valor Predictivo de las PruebasRESUMEN
Dead end (dnd) is a vertebrate-specific component of the germ plasm and germ-cell granules that is crucial for germ-cell development in zebrafish and mouse. Dnd counteracts the inhibitory function of miRNAs, thereby facilitating the expression of proteins such as Nanos and Tdrd7 in the germ cells. Here, we show that cis-acting elements within dnd mRNA and the RNA recognition motive (RRM) of the protein are essential for targeting protein expression to the germ cells and to the perinuclear granules, respectively. We demonstrate that as it executes its function, Dnd translocates between the germ-cell nucleus and germ-cell granules. This phenomenon is not observed in proteins mutated in the RRM motif, correlating with loss of function of Dnd. Based on molecular modeling, we identify the putative RNA binding domain of Dnd as a canonical RRM and propose that this domain is important for protein subcellular localization and function.