SNRPN methylation patterns in germ cell tumors as a reflection of primordial germ cell development

Studies examining altered imprinted gene expression in cancer compare the observed expression pattern to the normal expression pattern for a given tissue of origin, usually the somatic expression pattern for the imprinted gene. Germ cell tumors (GCTs), however, require a developmental stage‐dependent comparison. To explore using methylation as an indicator of germ cell development, we determined the pattern of methylation at the 5′ untranslated region of SNRPN in 89 GCTs from both children and adults. Fifty‐one of 84 tumors (60.7%) (12/30 (40%) of cultured pediatric GCTs, 23/36 (63.9%) of frozen adult GCTs, and 16/23 (69.5%) of frozen pediatric GCTs, with five samples having results from both cultured and uncultured material) demonstrated a nonsomatic methylation pattern after dual digestion with XbaI, NotI, and Southern blot analysis. In contrast, only 2 of 18 (11%) control samples (16 non‐GCTs and 2 normal ovaries) exhibited a nonsomatic pattern. In both cases, the result was shown to be due to copy number differences between maternal and paternal homologs, unlike the GCTs in which there was no evidence of an uneven homolog number. A comparison of the data for only the gonadal GCTs and the control data showed a highly significant difference in the proportion of tumors with methylation alterations at this locus (P = 0.0000539). Since there is no published evidence of the involvement of SNRPN methylation changes in the development of malignancy, the data suggest that the methylation pattern of SNRPN in GCTs reflects that of the primordial germ cell giving rise to the tumor. © 2001 Wiley‐Liss, Inc.

[1]  S. Latt,et al.  Clinical heterogeneity associated with deletions in the long arm of chromosome 15: report of 3 new cases and their possible genetic significance. , 1987, American journal of medical genetics.

[2]  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.

[3]  J. Rowley,et al.  Clonal, nonconstitutional rearrangements of the MLL gene in infant twins with acute lymphoblastic leukemia: in utero chromosome rearrangement of 11q23. , 1994, Blood.

[4]  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.

[5]  O. Haas,et al.  Presence of clone-specific antigen receptor gene rearrangements at birth indicates an in utero origin of diverse types of early childhood acute lymphoblastic leukemia. , 2000, Blood.

[6]  G. Rovera,et al.  Predominance of fetal type DJH joining in young children with B precursor lymphoblastic leukemia as evidence for an in utero transforming event , 1992, The Journal of experimental medicine.

[7]  A. Hochberg,et al.  Unique expression patterns of H19 in human testicular cancers of different etiology , 1997, Oncogene.

[8]  N. Niikawa,et al.  Methylation imprinting of H19 and SNRPN genes in human benign ovarian teratomas. , 1999, American journal of human genetics.

[9]  D. Ledbetter,et al.  Analysis of parent of origin specific DNA methylation at SNRPN and PW71 in tissues: implication for prenatal diagnosis. , 1996, Journal of medical genetics.

[10]  A. Reeve,et al.  Equivalent Parental Distribution of Frequently Lost Alleles and Biallelic Expression of the H19 Gene in Human Testicular Germ Cell Tumors , 1996, Japanese journal of cancer research : Gann.

[11]  J. Mann,et al.  Allele-specific expression and total expression levels of imprinted genes during early mouse development: implications for imprinting mechanisms. , 1995, Genes & development.

[12]  A. Yachie,et al.  Coexistence of lymphoblastic and monoblastic populations with identical mixed lineage leukemia gene rearrangements and shared immunoglobulin heavy chain rearrangements in leukemia developed in utero. , 2000, Journal of pediatric hematology/oncology.

[13]  L. Meisner,et al.  Identical Cytogenetic Clones and Clonal Evolution in Pediatric Monozygotic Twins With Acute Myeloid Leukemia: Presymptomatic Disease Detection by Interphase Fluorescence In Situ Hybridization and Review of the Literature , 1998, Journal of pediatric hematology/oncology.

[14]  T. Miki,et al.  Altered imprinting of the H19 and insulin-like growth factor II genes in testicular tumors. , 1997, The Journal of urology.

[15]  S. Leff,et al.  Maternal imprinting of human SNRPN, a gene deleted in Prader–Willi syndrome , 1994, Nature Genetics.

[16]  A. Riggs,et al.  Structure of the imprinted mouse Snrpn gene and establishment of its parental-specific methylation pattern. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[17]  B. Popovich,et al.  The impact of imprinting: Prader-Willi syndrome resulting from chromosome translocation, recombination, and nondisjunction. , 1996, American journal of human genetics.

[18]  Imprinted expression of SNRPN in human preimplantation embryos. , 1998, American journal of human genetics.

[19]  Uta Francke,et al.  Maternal imprinting of the mouse Snrpn gene and conserved linkage homology with the human Prader–Willi syndrome region , 1992, Nature Genetics.

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

[21]  J. Zonana,et al.  Comparison of the 15q deletions in Prader-Willi and Angelman syndromes: specific regions, extent of deletions, parental origin, and clinical consequences. , 1990, American journal of medical genetics.

[22]  M. Greaves,et al.  Monoclonal origin of concordant T-cell malignancy in identical twins. , 1997, Blood.

[23]  M. Greaves,et al.  Fetal origins of the TEL-AML1 fusion gene in identical twins with leukemia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  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.

[25]  J. Knoll,et al.  Genetic imprinting suggested by maternal heterodisomy in non-deletion Prader-Willi syndrome , 1989, Nature.

[26]  J. Rowley,et al.  Clonal, nonconstitutional rearrangements of the MLL gene in infant twins with acute lymphoblastic leukemia: in utero chromosome rearrangement of 11q23 , 1994 .

[27]  J. Walter,et al.  Maternal methylation imprints on human chromosome 15 are established during or after fertilization , 2001, Nature Genetics.

[28]  S. Olson,et al.  Human chromosome variation: the discriminatory power of Q-band heteromorphism (variant) analysis in distinguishing between individuals, with specific application to cases of questionable paternity. , 1986, American journal of human genetics.

[29]  S. Latt,et al.  Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion. , 1989, American journal of medical genetics.

[30]  D. Ledbetter,et al.  Is Angelman syndrome an alternate result of del(15)(q11q13)? , 1987, American journal of medical genetics.

[31]  M. Greaves,et al.  Protracted and variable latency of acute lymphoblastic leukemia after TEL-AML1 gene fusion in utero. , 1999, Blood.

[32]  M. Greaves,et al.  Prenatal origin of acute lymphoblastic leukaemia in children , 1999, The Lancet.

[33]  M. Greaves,et al.  In utero rearrangements in the trithorax-related oncogene in infant leukaemias , 1993, Nature.

[34]  M. Greaves,et al.  Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  T. Brady,et al.  Cytogenetic darkroom magic: now you see them, now you don't. , 1976, American journal of human genetics.

[36]  K. Bussey,et al.  Chromosomes 1 and 12 abnormalities in pediatric germ cell tumors by interphase fluorescence in situ hybridization. , 2001, Cancer Genetics and Cytogenetics.

[37]  D. J. Driscoll,et al.  Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene. , 1996, American journal of human genetics.