IGF2/H19 imprinting analysis of human germ cell tumors (GCTs) using the methylation-sensitive single-nucleotide primer extension method reflects the origin of GCTs in different stages of primordial germ cell development.
Previous studies have demonstrated biallelic expression of the imprinted genes H19 and IGF2 and loss of DNA methylation of the SNRPN gene, indicating a common precursor cell of human germ cell tumors (GCTs), namely, the primordial germ cell (PGC). In this study, we applied the methylation-sensitive single-nucleotide primer extension (MS-SNuPE) technique to the analysis of the IGF2/H19 imprinting control region (ICR) in 55 GCTs from representative clinical and histologic subgroups. Most GCTs showed low methylation at the IGF2/H19 ICR. All 8 ovarian GCTs, 9 of 10 testicular seminomas, 7 of 10 testicular nonseminomas (all in adolescents/adults), 6 of 9 testicular yolk sac tumors (YSTs), and 12 of 14 nongonadal GCTs (all in infants/children) were hypomethylated. The highest methylation was observed in three childhood YSTs (boys) and 2 of 4 spermatocytic seminomas. The latter are derived from more advanced stages of germ-cell development. The predominantly low methylation of most of the other GCTs correlates with studies that demonstrated erasure of the methylation imprint of the IGF2/H19 ICR during embryonal PGC migration and development. These findings suggest that the IGF2/H19 methylation status in GCTs might reflect preservation of the physiologic imprinting erasure in PGCs rather than a loss of imprinting in a sense that is accepted for somatic tumors. Furthermore, this study indicates that imprinting control mechanisms other than the proposed CTCF (CCCTC binding factor) boundary model regulate IGF2 expression during this stage of PGC development as well as in GCTs derived from PGC. (c) 2005 Wiley-Liss, Inc.
Clinic of Pediatric Oncology, Haematology and Immunology, Medical Center, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany.
Sonja
S
Sievers
Katayoun
K
Alemazkour
Susanne
S
Zahn
Elizabeth J
EJ
Perlman
Ad J M
AJ
Gillis
Leendert H J
LH
Looijenga
Ulrich
U
Göbel
Dominik T
DT
Schneider
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D000076246:CCCTC-Binding Factor; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D018450:Disease Progression; D005260:Female; D018392:Genomic Imprinting; D005854:Germ Cells / Q000254:growth & development / Q000378:metabolism; D018237:Germinoma / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D013736:Testicular Neoplasms / Q000235:genetics / Q000473:pathology
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D004268:DNA-Binding Proteins; C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D012097:Repressor Proteins; D007335:Insulin-Like Growth Factor II