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Distinct germ line polymorphisms underlie glioma morphologic heterogeneity.

ABSTRACT: Two recent genome-wide association studies reported that single nucleotide polymorphisms (SNPs) in (or near) TERT (5p15), CCDC26 (8q24), CDKN2A/B (9p21), PHLDB1 (11q23), and RTEL1 (20q13) are associated with infiltrating glioma. From these reports, it was not clear whether the single nucleotide polymorphism associations predispose to glioma in general or whether they are specific to certain glioma grades or morphologic subtypes. To identify hypothesized associations between susceptibility loci and tumor subtype, we genotyped two case-control groups composed of the spectrum of infiltrating glioma subtypes and stratified the analyses by type. We report that specific germ line polymorphisms are associated with different glioma subtypes. CCDC26 (8q24) region polymorphisms are strongly associated with oligodendroglial tumor risk (rs4295627, odds ratio [OR] = 2.05, P = 8.3 × 10(-11)) but not glioblastoma risk. The opposite is true of RTEL (20q13) region polymorphisms, which are significantly associated with glioblastoma (rs2297440, OR = 0.56, P = 4.6 × 10(-10)) but not oligodendroglial tumor. The SNPs in or near CCDC26 (8q24) are associated with oligodendroglial tumors regardless of combined 1p and 19q deletion status; however, the association is greatest for those with combined deletion (rs4295627, OR = 2.77, P = 2.6 × 10(-9)). These observations generate hypotheses concerning the possible mechanisms by which specific SNPs (or alterations in linkage disequilibrium with such SNPs) are associated with glioma development.

SUBMITTER: Jenkins RB

PROVIDER: S-EPMC3062955 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Distinct germ line polymorphisms underlie glioma morphologic heterogeneity.

Jenkins Robert B RB Wrensch Margaret R MR Johnson Derek D Fridley Brooke L BL Decker Paul A PA Xiao Yuanyuan Y Kollmeyer Thomas M TM Rynearson Amanda L AL Fink Stephanie S Rice Terri T McCoy Lucie S LS Halder Chandralekha C Kosel Matthew L ML Giannini Caterina C Tihan Tarik T O'Neill Brian P BP Lachance Daniel H DH Yang Ping P Wiemels Joseph J Wiencke John K JK

Cancer genetics 20110101 1

Two recent genome-wide association studies reported that single nucleotide polymorphisms (SNPs) in (or near) TERT (5p15), CCDC26 (8q24), CDKN2A/B (9p21), PHLDB1 (11q23), and RTEL1 (20q13) are associated with infiltrating glioma. From these reports, it was not clear whether the single nucleotide polymorphism associations predispose to glioma in general or whether they are specific to certain glioma grades or morphologic subtypes. To identify hypothesized associations between susceptibility loci a ...[more]

PMID: 21356187

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Project description:BackgroundEpigenetic reprogramming is critical for genome regulation during germ line development. Genome-wide demethylation in mouse primordial germ cells (PGC) is a unique reprogramming event essential for erasing epigenetic memory and preventing the transmission of epimutations to the next generation. In addition to DNA demethylation, PGC are subject to a major reprogramming of histone marks, and many of these changes are concurrent with a cell cycle arrest in the G2 phase. There is limited information on how well conserved these events are in mammals. Here we report on the dynamic reprogramming of DNA methylation at CpGs of imprinted loci and DNA repeats, and the global changes in H3K27me3 and H3K9me2 in the developing germ line of the domestic pig.ResultsOur results show loss of DNA methylation in PGC colonizing the genital ridges. Analysis of IGF2-H19 regulatory region showed a gradual demethylation between E22-E42. In contrast, DMR2 of IGF2R was already demethylated in male PGC by E22. In females, IGF2R demethylation was delayed until E29-31, and was de novo methylated by E42. DNA repeats were gradually demethylated from E25 to E29-31, and became de novo methylated by E42. Analysis of histone marks showed strong H3K27me3 staining in migratory PGC between E15 and E21. In contrast, H3K9me2 signal was low in PGC by E15 and completely erased by E21. Cell cycle analysis of gonadal PGC (E22-31) showed a typical pattern of cycling cells, however, migrating PGC (E17) showed an increased proportion of cells in G2.ConclusionsOur study demonstrates that epigenetic reprogramming occurs in pig migratory and gonadal PGC, and establishes the window of time for the occurrence of these events. Reprogramming of histone H3K9me2 and H3K27me3 detected between E15-E21 precedes the dynamic DNA demethylation at imprinted loci and DNA repeats between E22-E42. Our findings demonstrate that major epigenetic reprogramming in the pig germ line follows the overall dynamics shown in mice, suggesting that epigenetic reprogramming of germ cells is conserved in mammals. A better understanding of the sequential reprogramming of PGC in the pig will facilitate the derivation of embryonic germ cells in this species.

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Distinct germ line polymorphisms underlie glioma morphologic heterogeneity.

Publications

Distinct germ line polymorphisms underlie glioma morphologic heterogeneity.

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