PRISM

PRISM infers the composition of epigenetically distinct tumor subclones from reduced representation bisulfite sequencing (RRBS) DNA methylation patterns to characterize tumor heterogeneity and global DNA methylation reprogramming.

Key Features:

• Methylation pattern-based inference: Utilizes subclonally reprogrammed methylation patterns and dichotomous methylation states (fully methylated vs. unmethylated) within short genomic regions to reveal constituent tumor populations.
• Reference-free analysis: Performs inference without reliance on a reference genome, using methylation pattern signals alone.
• RRBS and Bismark compatibility: Designed for RRBS data and requires mapping results from Bismark (BAM files) as input.
• HMM-based error correction: Incorporates an in silico proofreading step using a DNA methyltransferase 1-like hidden Markov model to correct erroneous methylation patterns.
• Beta-binomial mixture modeling: Models frequencies of dichotomous methylation patterns using a beta-binomial mixture model to obtain sufficient statistics for subclonal abundance.
• Expectation-maximization fitting: Fits the statistical model with an expectation-maximization algorithm to infer subclonal composition and evolutionary relationships.

Scientific Applications:

• Tumor subclone deconvolution: Infers relative abundances of epigenetically distinct subclones from RRBS-derived methylation patterns.
• Study of epigenetic reprogramming: Characterizes global DNA methylation reprogramming in cancers, including myeloid malignancies.
• Epigenetic heterogeneity and evolution: Reconstructs aspects of tumor heterogeneity and evolutionary history from methylation pattern data.

Methodology:

Inputs are BAM files of RRBS reads aligned by Bismark; methylation patterns are identified and corrected using a DNA methyltransferase 1-like hidden Markov model; frequencies of dichotomous methylation patterns in short regions are modeled with a beta-binomial mixture model; the model is fitted using an expectation-maximization algorithm to infer subclonal composition.