Characterization of translocations in mesenchymal hamartoma and undifferentiated embryonal sarcoma of the liver

BackgroundMesenchymal hamartoma of the liver (MHL) is an uncommon benign primary liver tumor that typically occurs in the pediatric population, although cases have been described in adults. MHL is sometimes associated with the highly malignant undifferentiated embryonal sarcoma (UES), and the synchronous or metachronous occurrence of MHL and UES suggests they share a common genetic link. Although the exact mechanism of tumorigenesis has not been identified, MHL cases harbor recurring chromosomal rearrangements involving 19q13.DesignIn order to provide more details on the genetic events of MHL tumorigenesis, capture-based next generation sequencing (NGS) targeted to loci recently shown to be involved in a translocation in a case of UES arising in MHL (specifically, the MALAT1 gene on chromosome 11 and a gene poor region termed MHLB1 on chromosome 19) was performed on formalin fixed paraffin embedded tissue from seven cases of MHL.ResultsChromosome rearrangements involving the MHLB1 locus were identified in three of the seven cases, including the translocation t(11,19)(q13.1;q13.42) involving the MALAT1 gene; the translocation t(2,19)(q31.1;q13.42) involving AK023515, an uncharacterized noncoding gene; and the inversion inv(19,19)(q13.42;q13.43) involving the PEG3 gene encoding a Kruppel-type zinc-finger protein. Rearrangements were exclusively identified in pediatric tumors. In each case, the presence of the rearrangement was confirmed by PCR and interphase FISH. Interphase FISH also demonstrated that the arrangements occur within the spindle cell component but not within the epithelial components of the tumor.ConclusionsSince the MHLB1 locus contains a CpG-rich region whose methylation regulates C19MC miRNA genes, rearrangements that disrupt this region may contribute to MHL development through alteration of miRNA expression. The demonstration that the loose stromal cells harbor the rearrangements indicates that (some cases of) MHL are a neoplastic process due to a somatic genetic change and not a germline abnormality.