Project description:Purpose: Melanotic neuroectodermal tumor of infancy (MNTI) is exceptionally rare and occurs predominantly in the head and neck (92.8% cases). A 2-month-old female patient presented with a mass arising in the fibula which was excised at our surgical center. This is only the eighth case of MNTI affecting an extremity, and the first reported in the fibula. To understand better the etiology of this MNTI, we used high-throughput sequencing technology to carry out an exhaustive genomic, transcriptomic and epigenetic characterization on the excised primary tumor and a derived cell line. Methods: RNA was extracted from the flash frozen tumor and paired-end RNA-Seq was performed to identify potential oncogenic fusion genes and to quantify gene expression in the MNTI transcriptome. Genomic DNA was extracted from the tumor and from a sample of the patient's blood and whole-exome sequencing was done to detect somatic and germline variants. Copy number variation in the MNTI was determined by comparative genomic hybridization (CGH) of DNA from the tumor and blood to a SNP array. A cell line was derived from the tumor and was tested for sensitivity to a panel of compounds targeting epigenetic regulators. Results: Whole-exome analysis indicated no somatic, non-synonymous coding mutations within the tumor, but a heterozygous, unique germline, loss of function mutation in CDKN2A (p16INK4A, D74A). SNP-array CGH revealed the tumor to be euploid, with no detectable gene copy number variants. Multiple chromosomal translocations were identified by RNA-Seq, and fusion genes included RPLP1-C19MC, potentially deregulating the C19MC cluster, an imprinted locus containing microRNA genes reactivated by gene fusion in embryonal tumors with multilayered rosettes. Since the presumed cell of origin of MNTI is from the neural crest, we also compared gene expression with a dataset from human neural crest cells (GEO acession: GSE28875) and identified 185 genes with significantly different expression. Consistent with the melanotic phenotype of the tumor, elevated expression of tyrosinase was observed. Other highly expressed genes encoded muscle proteins and modulators of the extracellular matrix. The derived MNTI cell line was sensitive to inhibitors of lysine demethylase, but not to compounds targeting other epigenetic regulators. Conclusions: In the absence of somatic copy number variations or mutations, the fully transformed phenotype of the MNTI may have arisen in infancy because of the combined effects of a germline CDKN2A mutation, tumor promoting somatic fusion genes and epigenetic deregulation. Very little is known about the etiology of MNTI and this report advances knowledge of these rare tumors by providing the first comprehensive genomic, transcriptomic and epigenetic characterization of a case.

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A germline mutation of CDKN2A and a novel RPLP1-C19MC fusion detected in a rare melanotic neuroectodermal tumor of infancy: a case report

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