CAUSE - Connecting DNA Adducts, Unexplained Mutational Signatures, and Cancer Etiologies
openNCI - National Cancer Institute
RESEARCH ABSTRACT
Cancer Grand Challenges
Connecting DNA Adducts, Unexplained Mutational Signatures, and Cancer Etiologies (CAUSE)
Host Institution: University of California, San Diego
Background: Genome sequencing of thousands of cancers has identified over 100 distinct mutational
signatures—recurring patterns of somatic mutations that reflect mutagenic processes. While some
have known causes, most—including key cancer-driving signatures—remain unexplained. These
include endogenous ubiquitous age-associated signatures (e.g., SBS5), tissue-specific processes
(e.g., SBS40), and geography-associated patterns likely linked to unknown environmental exposures
(e.g., SBS12, SBS89). Biochemically, most somatic mutations arise from misrepair or replication across
damaged DNA (i.e., DNA adducts). Cells experience tens of thousands of DNA adducts daily—from
both endogenous metabolism and environmental exposures. While most are accurately repaired, some
persist leading to permanent changes in the DNA sequence (i.e., somatic mutations). As a result,
cancer genomes preserve a durable, but mechanistically obscured, record of genotoxic damage.
Understanding the origins of unexplained mutational signatures requires identifying the initiating DNA
adducts and dissecting how their formation, persistence, and processing shape mutational patterns.
Aims: The Connecting Adducts, Unexplained Signatures, and Cancer Etiologies (CAUSE) project aims
to mechanistically understand unexplained mutational signatures by systematically identifying specific
DNA adducts and linking them to the mutations they generate. CAUSE will build a high-throughput
discovery platform that integrates chemistry, biology, genomics and cutting-edge technologies. The
project will focus on three mutagenic contexts: (1) endogenous processes underlying signatures like
SBS5 and SBS40, (2) likely environmental exposures driving tissue- and geography-specific patterns
like SBS12 and SBS89, and (3) chemotherapy-induced DNA adducts, which will be used as a controlled
benchmark. The proposed approaches are broadly applicable and will help uncover the origins of many
unexplained mutational signatures while advancing next-generation mutagenesis technologies such as
a reimagined Ames test.
Methods: CAUSE will integrate human tissue analysis with diverse experimental systems—including
in vitro assays, cell lines, and mouse models—across seven coordinated modules: (1) mass
spectrometry to detect diverse DNA adducts; (2) structural characterization via chemical synthesis and
microcrystal electron diffraction; (3) genome-wide lesion mapping using Endo-seq, long-read
sequencing, and polymerase-stalling enrichment; (4) single-molecule reporter assays of misrepair in
defined repair contexts; (5) biochemical perturbations in Xenopus cell-free systems to dissect repair
mechanisms; (6) genetic perturbations in animal models to dissect damage and repair pathways; and
(7) interpretable AI to model how lesion features and repair status predict mutational outcomes.
Impact: CAUSE will generate the first mechanistic atlas linking DNA adducts to mutational signatures.
This foundational resource will enable causal attribution, clarify age- and exposure-related
mutagenesis, and shift mutational signature research from observational to actionable—transforming
cancer prevention, diagnosis, and care.
Up to $1.1M
health research