Premium
Meiosis error and subsequent genetic and epigenetic alterations invoke the malignant transformation of germ cell tumor
Author(s) -
Ichikawa Mizuho,
Arai Yasuhito,
Haruta Masayuki,
Furukawa Shinsuke,
Ariga Tadashi,
Kajii Tadashi,
Kaneko Yasuhiko
Publication year - 2013
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.22027
Subject(s) - biology , genomic imprinting , genetics , epigenetics , loss of heterozygosity , meiosis , reprogramming , dna methylation , gene , allele , gene expression
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. © 2012 Wiley Periodicals, Inc.