BACKGROUND: Although much is known about molecular and chromosomal characteristics that distinguish glioma histological subtypes, DNA methylation patterns of gliomas and their association with other tumor features such as mutation of isocitrate dehydrogenase (IDH) genes have only recently begun to be investigated. METHODS: DNA methylation of glioblastomas, astrocytomas, oligodendrogliomas, oligoastrocytomas, ependymomas, and pilocytic astrocytomas (n = 131) from the Brain Tumor Research Center at the University of California San Francisco, as well as nontumor brain tissues (n = 7), was assessed with the Illumina GoldenGate methylation array. Methylation data were subjected to recursively partitioned mixture modeling (RPMM) to derive methylation classes. Differential DNA methylation between tumor and nontumor was also assessed. The association between methylation class and IDH mutation (IDH1 and IDH2) was tested using univariate and multivariable analysis for tumors (n = 95) with available substrate for sequencing. Survival of glioma patients carrying mutant IDH (n = 57) was compared with patients carrying wild-type IDH (n = 38) using a multivariable Cox proportional hazards model and Kaplan-Meier analysis. All statistical tests were two-sided. RESULTS: We observed a statistically significant association between RPMM methylation class and glioma histological subtype (P < 2.2 × 10(-16)). Compared with nontumor brain tissues, across glioma tumor histological subtypes, the differential methylation ratios of CpG loci were statistically significantly different (permutation P < .0001). Methylation class was strongly associated with IDH mutation in gliomas (P = 3.0 × 10(-16)). Compared with glioma patients whose tumors harbored wild-type IDH, patients whose tumors harbored mutant IDH showed statistically significantly improved survival (hazard ratio of death = 0.27, 95% confidence interval = 0.10 to 0.72). CONCLUSION: The homogeneity of methylation classes for gliomas with IDH mutation, despite their histological diversity, suggests that IDH mutation is associated with a distinct DNA methylation phenotype and an altered metabolic profile in glioma.
BACKGROUND: Although much is known about molecular and chromosomal characteristics that distinguish glioma histological subtypes, DNA methylation patterns of gliomas and their association with other tumor features such as mutation of isocitrate dehydrogenase (IDH) genes have only recently begun to be investigated. METHODS: DNA methylation of glioblastomas, astrocytomas, oligodendrogliomas, oligoastrocytomas, ependymomas, and pilocytic astrocytomas (n = 131) from the Brain Tumor Research Center at the University of California San Francisco, as well as nontumor brain tissues (n = 7), was assessed with the Illumina GoldenGate methylation array. Methylation data were subjected to recursively partitioned mixture modeling (RPMM) to derive methylation classes. Differential DNA methylation between tumor and nontumor was also assessed. The association between methylation class and IDH mutation (IDH1 and IDH2) was tested using univariate and multivariable analysis for tumors (n = 95) with available substrate for sequencing. Survival of gliomapatients carrying mutant IDH (n = 57) was compared with patients carrying wild-type IDH (n = 38) using a multivariable Cox proportional hazards model and Kaplan-Meier analysis. All statistical tests were two-sided. RESULTS: We observed a statistically significant association between RPMM methylation class and glioma histological subtype (P < 2.2 × 10(-16)). Compared with nontumor brain tissues, across glioma tumor histological subtypes, the differential methylation ratios of CpG loci were statistically significantly different (permutation P < .0001). Methylation class was strongly associated with IDH mutation in gliomas (P = 3.0 × 10(-16)). Compared with gliomapatients whose tumors harbored wild-type IDH, patients whose tumors harbored mutant IDH showed statistically significantly improved survival (hazard ratio of death = 0.27, 95% confidence interval = 0.10 to 0.72). CONCLUSION: The homogeneity of methylation classes for gliomas with IDH mutation, despite their histological diversity, suggests that IDH mutation is associated with a distinct DNA methylation phenotype and an altered metabolic profile in glioma.
Authors: Katleen De Preter; Frank Speleman; Valérie Combaret; John Lunec; Geneviève Laureys; Bert H J Eussen; Nadine Francotte; Julian Board; Andy D J Pearson; Anne De Paepe; Nadine Van Roy; Jo Vandesompele Journal: Mod Pathol Date: 2002-02 Impact factor: 7.842
Authors: A J Wong; S H Bigner; D D Bigner; K W Kinzler; S R Hamilton; B Vogelstein Journal: Proc Natl Acad Sci U S A Date: 1987-10 Impact factor: 11.205
Authors: Annalisa R Stone; William Bobo; Daniel J Brat; Nara S Devi; Erwin G Van Meir; Paula M Vertino Journal: Am J Pathol Date: 2004-10 Impact factor: 4.307
Authors: Dan Wang; Li Yan; Qiang Hu; Lara E Sucheston; Michael J Higgins; Christine B Ambrosone; Candace S Johnson; Dominic J Smiraglia; Song Liu Journal: Bioinformatics Date: 2012-01-16 Impact factor: 6.937
Authors: Scott M Langevin; Devin C Koestler; Brock C Christensen; Rondi A Butler; John K Wiencke; Heather H Nelson; E Andres Houseman; Carmen J Marsit; Karl T Kelsey Journal: Epigenetics Date: 2012-03 Impact factor: 4.528
Authors: K L Rankeillor; D A Cairns; C Loughrey; S C Short; P Chumas; A Ismail; A Chakrabarty; S E Lawler; P Roberts Journal: J Neurooncol Date: 2014-02-20 Impact factor: 4.130