title: Bayesian inference supports a location and neighbour-dependent model of DNA methylation propagation at the MGMT gene promoter in lung tumours.
abstract: We exploit model-based Bayesian inference methodologies to analyse lung tumour-derived methylation data from a CpG island in the O6-methylguanine-DNA methyltransferase (MGMT) promoter. Interest is in modelling the changes in methylation patterns in a CpG island in the first exon of the promoter during lung tumour development. We propose four competils of methylation state propagation based on two mechanisms. The first is the location-dependence mechanism in which the probability of a gain or loss of methylation at a CpG within the promoter depends upon its location in the CpG sequence. The second mechanism is that of neighbour-dependence in which gain or loss of methylation at a CpG depends upon the methylation status of the immediately preceding CpG. Our data comprises the methylation status at 12 CpGs near the 5' end of the CpG island in two lung tumour samples for both alleles of a nearby polymorphism. We use approximate Bayesian computation, a computationally intensive rejection-sampling algorithm to infer model parameters and compare models without the need to evaluate the likelihood function. We compare the four proposed models using two criteria: the approximate Bayes factors and the distribution of the Euclidean distance between the summary statistics of the observed and simulated datasets. Our model-based analysis demonstrates compelling evidence for both location and neighbour dependence in the process of aberrant DNA methylation of this MGMT promoter CpG island in lung tumours. We find equivocal evidence to support the hypothesis that the methylation patterns of the two alleles evolve independently.
authors.affiliation: School of Mathematics and Statistics, University of Sheffield, Sheffield S3 7RH, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bonello
authors.forename: James
authors.initials: J
authors.lastname: Sampson
authors.forename: John
authors.initials: J
authors.lastname: Burn
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Wilson
authors.forename: Gail
authors.initials: G
authors.lastname: McGrown
authors.forename: Geoff P
authors.initials: GP
authors.lastname: Margison
authors.forename: Mary
authors.initials: M
authors.lastname: Thorncroft
authors.forename: Philip
authors.initials: P
authors.lastname: Crossbie
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Povey
authors.forename: Mauro
authors.initials: M
authors.lastname: Santibanez-Koref
authors.forename: Kevin
authors.initials: K
authors.lastname: Walters
mesh_terms: D000483:Alleles; D001499:Bayes Theorem; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D030541:Databases, Genetic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics*; D008957:Models, Genetic; D015233:Models, Statistical; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: D019853:O(6)-Methylguanine-DNA Methyltransferase
keywords: Bayesian analysis; DNA methylation; Lung cancer; MGMT; Model selection