Modeling DNA Methylation in a Population of Cancer Cells
-
Kimberly D. Siegmund
Little is known about how human cancers grow because direct observations are impractical. Cancers are clonal populations and the billions of cancer cells present in a visible tumor are progeny of a single transformed cell. Therefore, human cancers can be represented by somatic cell ancestral trees that start from a single transformed cell and end with billions of present day cancer cells. We use a genealogical approach to infer tumor growth from somatic trees, employing haplotype DNA methylation pattern variation, or differences between specific CpG sites or "tags," in the cancer genome. DNA methylation is an epigenetic mark that is copied, with error, during genome replication. At our tags, neutral copy errors in DNA methylation appear to occur at random, and much more frequently than sequence copy errors. To reconstruct a cancer tree, we sample and compare human colorectal genomes within small geographic regions (a cancer fragment), between fragments on the same side of the tumor, and between fragments from opposite tumor halves. The combined information on both physical distance and epigenetic distance informs our model for tumor ancestry. We use approximate Bayesian computation, a simulation-based method, to model tumor growth under a variety of evolutionary scenarios, estimating parameters that fit observed DNA methylation patterns. We conclude that methylation patterns sampled from human cancers are consistent with replication errors and certain simple cancer growth models. The inferred cancer trees are consistent with Gompertzian growth, a well-known cancer growth pattern.
©2011 Walter de Gruyter GmbH & Co. KG, Berlin/Boston
Articles in the same Issue
- Article
- Self-Organizing Maps with Statistical Phase Synchronization (SOMPS) for Analyzing Cell Cycle-Specific Gene Expression Data
- Coalescent Time Distributions in Trees of Arbitrary Size
- Quantifying the Association between Gene Expressions and DNA-Markers by Penalized Canonical Correlation Analysis
- Nonparametric Functional Mapping of Quantitative Trait Loci Underlying Programmed Cell Death
- Accommodating Uncertainty in a Tree Set for Function Estimation
- Drifting Markov Models with Polynomial Drift and Applications to DNA Sequences
- Comparing the Characteristics of Gene Expression Profiles Derived by Univariate and Multivariate Classification Methods
- Calculating Confidence Intervals for Prediction Error in Microarray Classification Using Resampling
- Structure Learning in Nested Effects Models
- Correcting the Estimated Level of Differential Expression for Gene Selection Bias: Application to a Microarray Study
- Adapting Prediction Error Estimates for Biased Complexity Selection in High-Dimensional Bootstrap Samples
- Adaptive Choice of the Number of Bootstrap Samples in Large Scale Multiple Testing
- Re-Cracking the Nucleosome Positioning Code
- Semi-Parametric Differential Expression Analysis via Partial Mixture Estimation
- A SNP Streak Model for the Identification of Genetic Regions Identical-by-descent
- Detecting Two-Locus Gene-Gene Effects Using Monotonisation of the Penetrance Matrix
- Modeling DNA Methylation in a Population of Cancer Cells
- Phenotyping Genetic Diseases Using an Extension of µ-Scores for Multivariate Data
- The Estimator of the Optimal Measure of Allelic Association: Mean, Variance and Probability Distribution When the Sample Size Tends to Infinity
- Predicting Protein Concentrations with ELISA Microarray Assays, Monotonic Splines and Monte Carlo Simulation
- A Comparison of Normalization Techniques for MicroRNA Microarray Data
- Collapsing SNP Genotypes in Case-Control Genome-Wide Association Studies Increases the Type I Error Rate and Power
- Estimating Number of Clusters Based on a General Similarity Matrix with Application to Microarray Data
- Data Distribution of Short Oligonucleotide Expression Arrays and Its Application to the Construction of a Generalized Intellectual Framework
- Approximately Sufficient Statistics and Bayesian Computation
- A Composite-Conditional-Likelihood Approach for Gene Mapping Based on Linkage Disequilibrium in Windows of Marker Loci
- Statistical Methods in Integrative Analysis for Gene Regulatory Modules
- Reducing Spatial Flaws in Oligonucleotide Arrays by Using Neighborhood Information
- Pattern Classification of Phylogeny Signals
- A Unification of Multivariate Methods for Meta-Analysis of Genetic Association Studies
- Importance Sampling for the Infinite Sites Model
- Supervised Distance Matrices
- Addressing the Shortcomings of Three Recent Bayesian Methods for Detecting Interspecific Recombination in DNA Sequence Alignments
- A Sparse PLS for Variable Selection when Integrating Omics Data
- Software Communication
- TRAB: Testing Whether Mutation Frequencies Are Above an Unknown Background
Articles in the same Issue
- Article
- Self-Organizing Maps with Statistical Phase Synchronization (SOMPS) for Analyzing Cell Cycle-Specific Gene Expression Data
- Coalescent Time Distributions in Trees of Arbitrary Size
- Quantifying the Association between Gene Expressions and DNA-Markers by Penalized Canonical Correlation Analysis
- Nonparametric Functional Mapping of Quantitative Trait Loci Underlying Programmed Cell Death
- Accommodating Uncertainty in a Tree Set for Function Estimation
- Drifting Markov Models with Polynomial Drift and Applications to DNA Sequences
- Comparing the Characteristics of Gene Expression Profiles Derived by Univariate and Multivariate Classification Methods
- Calculating Confidence Intervals for Prediction Error in Microarray Classification Using Resampling
- Structure Learning in Nested Effects Models
- Correcting the Estimated Level of Differential Expression for Gene Selection Bias: Application to a Microarray Study
- Adapting Prediction Error Estimates for Biased Complexity Selection in High-Dimensional Bootstrap Samples
- Adaptive Choice of the Number of Bootstrap Samples in Large Scale Multiple Testing
- Re-Cracking the Nucleosome Positioning Code
- Semi-Parametric Differential Expression Analysis via Partial Mixture Estimation
- A SNP Streak Model for the Identification of Genetic Regions Identical-by-descent
- Detecting Two-Locus Gene-Gene Effects Using Monotonisation of the Penetrance Matrix
- Modeling DNA Methylation in a Population of Cancer Cells
- Phenotyping Genetic Diseases Using an Extension of µ-Scores for Multivariate Data
- The Estimator of the Optimal Measure of Allelic Association: Mean, Variance and Probability Distribution When the Sample Size Tends to Infinity
- Predicting Protein Concentrations with ELISA Microarray Assays, Monotonic Splines and Monte Carlo Simulation
- A Comparison of Normalization Techniques for MicroRNA Microarray Data
- Collapsing SNP Genotypes in Case-Control Genome-Wide Association Studies Increases the Type I Error Rate and Power
- Estimating Number of Clusters Based on a General Similarity Matrix with Application to Microarray Data
- Data Distribution of Short Oligonucleotide Expression Arrays and Its Application to the Construction of a Generalized Intellectual Framework
- Approximately Sufficient Statistics and Bayesian Computation
- A Composite-Conditional-Likelihood Approach for Gene Mapping Based on Linkage Disequilibrium in Windows of Marker Loci
- Statistical Methods in Integrative Analysis for Gene Regulatory Modules
- Reducing Spatial Flaws in Oligonucleotide Arrays by Using Neighborhood Information
- Pattern Classification of Phylogeny Signals
- A Unification of Multivariate Methods for Meta-Analysis of Genetic Association Studies
- Importance Sampling for the Infinite Sites Model
- Supervised Distance Matrices
- Addressing the Shortcomings of Three Recent Bayesian Methods for Detecting Interspecific Recombination in DNA Sequence Alignments
- A Sparse PLS for Variable Selection when Integrating Omics Data
- Software Communication
- TRAB: Testing Whether Mutation Frequencies Are Above an Unknown Background
