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Meiosis error and subsequent genetic and epigenetic alterations invoke the malignant transformation of germ cell tumor.

Abstract
Germ cell tumors (GCTs) are thought to arise from primordial germ cells (PGCs) that undergo epigenetic reprogramming. To explore the mechanisms of GCT formation, we analyzed single-nucleotide polymorphism array comparative genomic hybridization patterns and the methylation status of 15 tumor suppressor genes (TSGs) and differentially methylated regions (DMRs) of two imprinted genes, H19 and SNRPN, in 28 children with GCTs. Three GCTs with 25-26 segmental uniparental disomies (UPDs), heterozygous centromeric regions, and a highly methylated SNRPN DMR may have occurred through meiosis I error. Three other GCTs with whole UPD and homozygous centromeric regions of all chromosomes may have occurred through endoreduplication of a haploid set in an ovum or testis. The other 22 GCTs had heterozygous centromeric regions of all chromosomes and no or a small number of segmental or whole UPDs and may have developed from premeiotic PGCs before imprint erasure or a reestablishment of imprinting. Gain and amplification of 3p24-p22 and 20q13-q13, and loss and UPD of 1p36-p35, 4q21-q21, 5q11-q13, and 6q26-qter were found in five or more tumors. 1p36-p35 loss was frequent, and found in 19 tumors; RUNX3 residing at 1p36 was methylated in the promoter regions of 16 tumors. Two yolk sac tumors with many segmental UPDs or whole UPD of all chromosomes had gain of 20q13-q13 and loss of 1p36-p35, and seven or eight methylated TSGs. These genetic and epigenetic alterations may have caused malignant transformation because they were rarely found in teratomas with segmental or whole UPDs.
AuthorsMizuho Ichikawa, Yasuhito Arai, Masayuki Haruta, Shinsuke Furukawa, Tadashi Ariga, Tadashi Kajii, Yasuhiko Kaneko
JournalGenes, chromosomes & cancer (Genes Chromosomes Cancer) Vol. 52 Issue 3 Pg. 274-86 (Mar 2013) ISSN: 1098-2264 [Electronic] United States
PMID23225212 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Wiley Periodicals, Inc.
Chemical References
  • Core Binding Factor Alpha 3 Subunit
  • Histones
  • snRNP Core Proteins
Topics
  • Adolescent
  • Cell Transformation, Neoplastic (genetics)
  • Child
  • Child, Preschool
  • Chromosome Aberrations
  • Core Binding Factor Alpha 3 Subunit (genetics)
  • DNA Methylation
  • Epigenesis, Genetic
  • Female
  • Genomic Imprinting
  • Histones (metabolism)
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Meiosis (genetics)
  • Methylation
  • Mutation
  • Neoplasms, Germ Cell and Embryonal (genetics, metabolism, pathology)
  • Polymorphism, Single Nucleotide
  • Uniparental Disomy
  • snRNP Core Proteins (metabolism)

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