Bayesian Probit Multi-Study Non-negative Matrix Factorization for Mutational Signatures

TL;DR

This paper introduces a Bayesian multi-study NMF method for analyzing mutational signatures across different cancer types, enabling more precise, interpretable, and tissue-specific insights into tumor mutational processes.

Contribution

The paper presents a novel Bayesian multi-study NMF model that incorporates sparsity and covariate dependence to improve mutational signature estimation across multiple cancer types.

Findings

Accurately estimates mutational signatures in diverse cancer datasets.

Identifies tissue-specific and individual mutational signature patterns.

Provides an interpretable framework for patient subtyping based on mutational profiles.

Abstract

Mutational signatures are patterns of somatic mutations in tumor genomes that provide insights into underlying mutagenic processes and cancer origin. Developing reliable methods for their estimation is of growing importance in cancer biology. Somatic mutation data are often collected for different cancer types, highlighting the need for multi-study approaches that enable joint analysis in a principled and integrative manner. Despite significant advancements, statistical models tailored for analyzing the genomes of multiple cancer types remain underexplored. In this work, we introduce a Bayesian Multi-Study Non-negative Matrix Factorization (NMF) approach that uses mixture modeling to incorporate sparsity in the exposure weights of each subject to mutational signatures, allowing for individual tumor profiles to be represented by a subset rather than all signatures, and making this subset depend on covariates. This allows for a) more precise ability to identify meaningful contributions of mutational signatures at the individual level; b) estimation of the prevalence of activity of signatures within a cancer type, defined by the proportion of tumor profiles where a certain signature is present; and c) de-novo identification of interpretable patient subtypes based on the mutational signatures present within their mutational profile. We apply our approach to the mutational profiles of tumors from seven different cancer types, demonstrating its ability to accurately estimate mutational signatures while uncovering both individual and tissue-specific differences. An R package implementing our method is available at https://github.com/blhansen/BAPmultiNMF.