Gurevich, N. Q. | bioRxiv Science

bioRxiv2026

Characterizing Multimodal Mutational Processes in Cancer Using MOTET

Mutational signatures are characteristic patterns of somatic alterations in cancer genomes. A single aberrant mechanism can simultaneously generate coordinated patterns of alterations across multiple mutation modalities, including single-base substitutions (SBSs), doublet-base substitutions (DBSs), and small insertions and deletions (IDs). However, these signatures are typically inferred separately and linked post hoc, obscuring their shared underlying mechanisms. To resolve this, we formally define a Mutational Process (MP) as a unified latent activity that induces coupled mutational signatures across these modalities. We developed MOTET, a Bayesian framework that jointly infers multimodal MPs. Applied to 2,583 whole genomes from the PCAWG cohort, MOTET recovers known MPs more accurately than standard post hoc correlation methods. MOTET also identifies a process linking an SBS37-related signature with a TG>CA-dominated DBS component and resolves canonical SBS12-like activity into two separate MPs with distinct tissue distributions. These results establish a paradigm for formally defining catalogs of MPs and demonstrate that integrating across modalities enhances the ability to discover new mutational patterns.

bioinformatics↗

bioRxiv2026

Defining mutational signatures of lung cancer-associated carcinogens through in vitro exposure of human airway epithelial cells

While distinct environmental exposures imprint unique mutational signatures on cancer genomes, the specific causal patterns for many known carcinogens remain uncharacterized in relevant human tissues. To address this gap, we developed a novel, physiologically relevant system that uses a combination of airway epithelial cells and whole genome sequencing to characterize mutational patterns induced by genotoxic carcinogens associated with lung cancer. After validating the platforms accuracy by successfully recapturing the known signature for Benzo(a)pyrene (BaP), we used this system to gain detailed insights into the types of mutations that occur with exposure to N-nitrosotris-(2-chloroethyl) urea (NTCU) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), genotoxic compounds that induce lung squamous cell carcinoma and lung adenocarcinoma in mouse models, respectively. Cells exposed to NTCU had significantly more somatic SNVs compared to control samples. An average of 82.3% of mutations in NTCU samples were attributed to a novel mutational signature distinct from those in the COSMIC database but highly correlated with recent in vivo mouse models. In contrast, NNK exposure did not demonstrate a distinct mutational pattern above background at both high and low concentrations. Ultimately, this in vitro system provides a robust platform to define causal links between environmental exposures and mutational patterns in lung cancer mutagenesis. Statement of SignificanceIn vitro exposure of N-nitrosotris-(2-chloroethyl) urea to airway epithelial cells revealed a distinct mutational signature.

bioinformatics↗