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. © 2005 Wiley‐Liss, Inc.

[1]  B. No̸rgaard-Pedersen,et al.  The histogenetic-embryologic basis for reappearance of alpha-fetoprotein in endodermal sinus tumors (yolk sac tumors) and teratomas. , 2009, Acta pathologica et microbiologica Scandinavica. Section A, Pathology.

[2]  L. Looijenga,et al.  Testicular germ-cell tumours in a broader perspective , 2005, Nature Reviews Cancer.

[3]  Andrew P Feinberg,et al.  The epigenetics of cancer etiology. , 2004, Seminars in cancer biology.

[4]  G. Pfeifer,et al.  Parent-of-Origin-Specific Binding of Nuclear Hormone Receptor Complexes in the H19-Igf2 Imprinting Control Region , 2004, Molecular and Cellular Biology.

[5]  Shi Tang,et al.  Role of CTCF Binding Sites in the Igf2/H19 Imprinting Control Region , 2004, Molecular and Cellular Biology.

[6]  D. Harms,et al.  Epidemiologic analysis of 1,442 children and adolescents registered in the German germ cell tumor protocols , 2004, Pediatric Blood & Cancer.

[7]  Y. Yamazaki,et al.  Reprogramming of primordial germ cells begins before migration into the genital ridge, making these cells inadequate donors for reproductive cloning , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[8]  P. Grundy,et al.  Genetic and Genetic Expression Analyses of Clear Cell Sarcoma of the Kidney , 2003, Laboratory Investigation.

[9]  J. Kononen,et al.  POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors. , 2003, Cancer research.

[10]  A. Feinberg,et al.  Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. , 2002, Cancer research.

[11]  L. Looijenga,et al.  Pathobiology of testicular germ cell tumors: views and news. , 2002, Analytical and quantitative cytology and histology.

[12]  Victor V Lobanenkov,et al.  The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer. , 2002, Seminars in cancer biology.

[13]  M. Surani,et al.  Epigenetic reprogramming in mouse primordial germ cells , 2002, Mechanisms of Development.

[14]  A. Feinberg,et al.  Monoallelic expression and methylation of imprinted genes in human and mouse embryonic germ cell lineages , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Peter A. Jones,et al.  Quantitative methylation analysis using methylation-sensitive single-nucleotide primer extension (Ms-SNuPE). , 2002, Methods.

[16]  J. J. Breen,et al.  BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the soma , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Fritsch,et al.  Genetic analysis of mediastinal nonseminomatous germ cell tumors in children and adolescents , 2002, Genes, chromosomes & cancer.

[18]  K. Bussey,et al.  SNRPN methylation patterns in germ cell tumors as a reflection of primordial germ cell development , 2001, Genes, chromosomes & cancer.

[19]  A. Feinberg,et al.  Loss of imprinting of insulin-like growth factor-II (IGF2) gene in distinguishing specific biologic subtypes of Wilms tumor. , 2001, Journal of the National Cancer Institute.

[20]  D. Takai,et al.  Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer. , 2001, Human molecular genetics.

[21]  S. Lauer,et al.  Multipoint imprinting analysis indicates a common precursor cell for gonadal and nongonadal pediatric germ cell tumors. , 2001, Cancer research.

[22]  M. Fritsch,et al.  Genetic analysis of childhood germ cell tumors with comparative genomic hybridization. , 2001, Klinische Padiatrie.

[23]  L. Looijenga,et al.  Reactivity of Germ Cell Maturation Stage-Specific Markers in Spermatocytic Seminoma: Diagnostic and Etiological Implications , 2001, Laboratory Investigation.

[24]  A. Feinberg,et al.  Loss of imprinting of insulin-like growth factor-II in Wilms' tumor commonly involves altered methylation but not mutations of CTCF or its binding site. , 2001, Cancer research.

[25]  M. Bartolomei,et al.  The H19 methylation imprint is erased and re-established differentially on the parental alleles during male germ cell development. , 2000, Human molecular genetics.

[26]  L. Cuisset,et al.  Establishment of the paternal methylation imprint of the human H19 and MEST/PEG1 genes during spermatogenesis. , 2000, Human molecular genetics.

[27]  L. Looijenga,et al.  Comparative Genomic and In Situ Hybridization of Germ Cell Tumors of the Infantile Testis , 2000, Laboratory Investigation.

[28]  D. Harms,et al.  Germ-cell tumors in childhood and adolescence , 2000 .

[29]  Jie Hu,et al.  Genetic analysis of childhood endodermal sinus tumors by comparative genomic hybridization. , 2000, Journal of pediatric hematology/oncology.

[30]  A. Reeve,et al.  Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation , 1999, Oncogene.

[31]  A. Feinberg.  Imprinting of a genomic domain of 11p15 and loss of imprinting in cancer: an introduction. , 1999, Cancer research.

[32]  J. Perentesis,et al.  Genomic imprinting of H19 and insulin‐like growth factor‐2 in pediatric germ cell tumors , 1999, Cancer.

[33]  H. Tanke,et al.  Chromosomal constitution of human spermatocytic seminomas: Comparative genomic hybridization supported by conventional and interphase cytogenetics , 1997, Genes, chromosomes & cancer.

[34]  P. Jones,et al.  Rapid quantitation of methylation differences at specific sites using methylation-sensitive single nucleotide primer extension (Ms-SNuPE). , 1997, Nucleic acids research.

[35]  L. Looijenga,et al.  No recurrent structural abnormalities apart from i(12p) in primary germ cell tumors of the adult testis , 1995, Genes, chromosomes & cancer.

[36]  J. Mann,et al.  Biallelic expression of imprinted genes in the mouse germ line: implications for erasure, establishment, and mechanisms of genomic imprinting. , 1995, Genes & development.

[37]  A. Feinberg,et al.  Loss of imprinting in hepatoblastoma. , 1995, Cancer research.

[38]  M. Bartolomei,et al.  A paternal–specific methylation imprint marks the alleles of the mouse H19 gene , 1995, Nature Genetics.

[39]  E. Mariman,et al.  Biallelic expression of the H19 and IGF2 genes in human testicular germ cell tumors. , 1994, Journal of the National Cancer Institute.

[40]  A. Feinberg,et al.  Relaxation of imprinted genes in human cancer , 1993, Nature.

[41]  L. E. McDonald,et al.  A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[42]  J. Richie.  Chromosome abnormalities of eighty-one pediatric germ cell tumors: sex-, age-, site,- and histopathology-related differences--a Children's Cancer Group Study. , 2002, The Journal of urology.

[43]  C. Griffin,et al.  Cytogenetic analysis of childhood endodermal sinus tumors: a Pediatric Oncology Group study. , 1994, Pediatric pathology.

[44]  O. Cummings,et al.  Spermatocytic seminoma: an immunohistochemical study. , 1994, Human pathology.