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

Abstract

BackgroundMelanotic neuroectodermal tumor of infancy (MNTI) is exceptionally rare and occurs predominantly in the head and neck (92.8 % cases). The patient reported here is only the eighth case of MNTI presenting in an extremity, and the first reported in the fibula.Case presentationA 2-month-old female presented with a mass arising in the fibula. Exhaustive genomic, transcriptomic, epigenetic and pathological characterization was performed on the excised primary tumor and a derived cell line. Whole-exome analysis of genomic DNA from both the tumor and blood 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 on DNA samples 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 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. A derived MNTI cell line was sensitive to inhibitors of lysine demethylase, but not to compounds targeting other epigenetic regulators.ConclusionsIn 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2669-3) contains supplementary material, which is available to authorized users.

RPLP1 promotes tumor metastasis and is associated with a poor prognosis in triple-negative breast cancer patients

“…During flavivirus infection, RPLP1 and RPLP2 are important factors for virus translation and may represent a regulatory step for the translation of specific cellular mRNAs [ 15 ]. An increasing number of studies show RPLP1 plays essential roles in cancer development [ 16 ]. In colon cancer, RPLP1 expression was fivefold up-regulated in cancerous versus normal tissues [ 12 ].…”

Detection of recurrent, rare, and novel gene fusions in patients with acute leukemia using next‐generation sequencing approaches

“…LMO1 is a transcription factor without DNA binding domains, and RIC3 was reported to fuse with the TCR gene in a T‐cell ALL patient . In addition, LMO1‐RIC3 was reported in a patient with melanotic neuroectodermal tumor; however, the role in tumorigenesis is unknown.…”

Melanotic neuroectodermal tumour of infancy: An enigmatic tumour with unique cytomorphological features

“…Molecular abnormalities such as MYC amplification, deletion of 1p (found in neuroblastoma), t (11;22) (q24;q12), t (11;22) (p13;q12) (found in Ewing sarcoma) identified in paediatric small round cells tumours have not been detected in MNTI . Barnes et al detected heterozygous CDKN2A mutation (p16INK4A, D74A) allele, on whole genome sequencing. SNP‐array CGH revealed the tumour to be euploid.…”