Activation of the chromosome 19q microRNA cluster in sporadic and androgenetic-biparental mosaicism-associated hepatic mesenchymal hamartoma

Pediatr Dev Pathol. 2014 Mar-Apr;17(2):75-84. doi: 10.2350/13-12-1415-OA.1. Epub 2014 Feb 20.

Abstract

Recurrent genetic alterations found in hepatic mesenchymal hamartoma include either androgenetic-biparental mosaicism or chromosomal rearrangements involving chromosome 19q13.4, in the vicinity of the chromosome 19q microRNA cluster (C19MC). Abnormal activation of C19MC, which is subject to paternal imprinting and is normally expressed only in placenta, could account for both genetic associations because androgenetic cells carry only paternal chromosomes. In this study, a 4.2-Mb deletion involving the 5'-end of C19MC was detected in a sporadic mesenchymal hamartoma by chromosomal microarray. Fluorescence in situ hybridization studies showed that the deletion localized to mesenchymal cells in the stroma of the hamartoma. Quantitative real-time polymerase chain reaction analysis of this tumor, 9 other sporadic hepatic mesenchymal hamartomas, and 3 hamartomas associated with androgenetic-biparental mosaicism demonstrated C19MC microRNA expression in all but 2 sporadic cases, with no significant expression in control liver. The findings support a pathogenetic model for mesenchymal hamartoma as a consequence of "ectopic" activation of C19MC in hepatic stroma, due to either chromosomal rearrangements or paternal uniparental disomy.

Keywords: androgenetic; imprinting; mesenchymal hamartoma; microRNA; uniparental disomy.

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Chromosome Aberrations
  • Chromosomes, Human, Pair 19 / genetics*
  • Chromosomes, Human, Pair 19 / metabolism
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing / methods
  • Hamartoma / genetics*
  • Hamartoma / metabolism
  • Hamartoma / pathology
  • Humans
  • Infant
  • Liver Diseases / genetics*
  • Liver Diseases / metabolism
  • Liver Diseases / pathology
  • Male
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Mosaicism*
  • Multigene Family
  • Placenta / metabolism
  • Placenta / pathology
  • Pregnancy

Substances

  • MicroRNAs