Retracing Cancer’s Life Story to the Cause of DNA Mutations

DNA mutations underlie many diseases, including cancer. Some sources of cancer-associated DNA mutations are well-known, like exposure to UV light and tobacco smoking. However, many remain a mystery. 

Dr. Ludmil Alexandrov is a professor of cellular and molecular medicine at the University of California, San Diego, and the lead of CAUSE—a team funded by Cancer Grand Challenges that aims to connect cancer-linked mutations to real-world exposures. 

Technology Networks spoke to Alexandrov to learn more about the mutational signatures linked to cancer, how team CAUSE plans to identify the exposures behind cancerous mutations, and what the work could mean for cancer prevention. 

Patterns of mutations can be traced to their source 

DNA mutations can arise from endogenous and exogenous sources, such as normal DNA damage and repair, aberrations to genome maintenance, and exposure to carcinogens.  

Different mutagenic processes create distinct patterns of genomic mutations, known as mutational signatures. 

“Every cancer genome represents a historical record of the mutagenic processes that have acted throughout a person's life,” explained Alexandrov. 

More than 80 single-base substitution mutational signatures have been identified across human cancers, some of which have been linked to their mutagenic processes. However, roughly half of all known mutational signatures lack a biological or environmental explanation. “The major gap is no longer in detecting mutational signatures—it is understanding what causes them,” said Alexandrov. 

“These unexplained signatures represent some of the largest unanswered questions in cancer biology.” — Dr. Ludmil Alexandrov 

Unexplained mutational signatures represent as-yet-unknown exposures that influence our risk of cancer, which could encompass microbial toxins, dietary factors, environmental exposures, endogenous metabolites, or a combination of these. 

Team CAUSE was established to uncover the molecular origins and mechanisms behind unexplained mutational signatures in cancer. 

“By connecting DNA damage to mutational signatures and then to specific environmental and endogenous exposures, we hope to uncover previously unknown causes of cancer.” — Dr. Ludmil Alexandrov 

“Rather than beginning with cancer genomes alone, we start with DNA damage itself,” explained Alexandrov. “Our goal is to systematically identify DNA adducts in human tissues, determine how they are repaired or misrepaired, define the mutational signatures they generate, and ultimately connect these signatures to real-world exposures and cancer risk.”  

Studying DNA adducts and their connection to mutational signatures and real-world exposures is a multidisciplinary effort. CAUSE brings together analytical chemistry, genomics, computational biology, experimental models, epidemiology, and clinical research. 

“That is what makes this project both challenging and exciting—it brings together chemistry, biology, genomics, and computational science to solve questions that none of these disciplines could answer on their own,” said Alexandrov. 

The challenge of identifying the cause of mutational signatures 

Historically, understanding the mechanisms and exposures underlying mutational signatures has been limited by technology. 

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“Until recently, we lacked the ability to comprehensively measure DNA damage directly in human tissues,” said Alexandrov. “Instead, we inferred the causes of mutations by looking only at the mutations themselves.”  

“While this approach has been remarkably successful in identifying mutational signatures, it is much less powerful for determining their underlying causes,” he continued. 

Additionally, DNA damage is transient. Sequencing a cancer genome reveals mutations that have accumulated over decades, so the original DNA damage and any trace of its cause are long gone.  

“Mutational signatures are the end product of a long biological process,” explained Alexandrov. “[Cancer genome sequencing provides] an indirect record that has been shaped by DNA repair, DNA replication, cell division, natural selection, and tumor evolution.” 

“Reconstructing events that may have occurred decades earlier from this molecular record is inherently difficult.” 

Many mutational processes leave subtle, and sometimes similar, patterns in the genome. “This makes them difficult to distinguish from one another, particularly when multiple processes have acted within the same cell over decades,” said Alexandrov. 

The same agent can cause different mutational patterns depending on the timing and duration of exposure and affected cell type, and different exposures can generate similar forms of DNA damage.  “The genome we sequence, therefore, reflects not only the mutagen itself, but also how the cell responded to that damage,” noted Alexandrov.  

Computational tools have played a major role in alleviating bottlenecks in extracting mutational signatures, leaving biological interpretation as an enduring challenge. 

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“A mutational signature is an observation—it tells us that a characteristic pattern of mutations has occurred, but not what caused it.” — Dr. Ludmil Alexandrov 

Rather than focusing on cancer mutations as a first port of call, CAUSE will work “backward” and start with DNA damage. Understanding how damage is repaired, how mutations form, and how different mutational signatures are generated will enable the team to establish causal links between specific exposures and mutations in human cancers. 

A mechanistic atlas of DNA adducts and mutational signatures 

One of CAUSE’s goals is to create the first mechanistic atlas of DNA adducts and their corresponding mutational signatures. 

“We need to connect three things that have usually been studied separately: the exposure, the DNA damage it creates, and the mutations that eventually appear in cancer genomes,” said Alexandrov. “CAUSE is designed to build that bridge systematically.” 

First, the team will directly measure DNA adducts using highly sensitive mass spectrometry. The adducts present in human tissues and experimental systems, their abundance, and how their abundance changes with different exposures will be cataloged. 

Next, they will study how these adducts are processed, as not every adduct becomes a mutation. “Some are repaired efficiently, some block replication, some are bypassed accurately, and some are miscopied into permanent mutations,” explained Alexandrov. In controlled models, the researchers will observe how specific adducts are repaired, tolerated, or converted into mutations. 

The team will then determine which mutational signatures are associated with specific damage processes. “By exposing experimental systems to specific agents or adduct-forming conditions, then sequencing the resulting genomes with very high accuracy, we can ask what mutational patterns are produced,” said Alexandrov. “These signatures can then be compared to the signatures observed in human cancers.” 

The data from these three steps will be integrated to link DNA damage and exposure history to mutational signatures and downstream pathways that are affected in cancer. 

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This atlas will enable researchers to identify the biological conditions and exposures that contribute to unexplained mutational signatures. 

“If successful, this atlas will give the field a new way to move from correlation to mechanism. It will not only help explain existing unexplained mutational signatures but also provide a framework for discovering previously unrecognized causes of cancer.” — Dr. Ludmil Alexandrov  

Moving beyond simply cataloging cancer mutational signatures and towards a mechanistic understanding of how they are generated could identify harmful environmental exposures, enabling novel approaches to cancer prevention. 

Impact across the cancer continuum 

A deeper understanding of the causes of mutational signatures could inform cancer prevention, diagnostic, and therapeutic strategies. 

“Understanding mutational signatures mechanistically changes them from descriptive markers into actionable biology.” — Dr. Ludmil Alexandrov 

“If we can connect an unexplained mutational signature to a specific environmental exposure, microbial metabolite, dietary factor, endogenous process, or occupational agent, then we can begin to reduce or eliminate that exposure,” explained Alexandrov. “This is where I think the greatest long-term opportunity lies.” 

Mutational signatures serve as a molecular “fingerprint” of prior exposure or DNA damage, which could be used as a screening tool to identify individuals at a greater risk of cancer. 

They can also illustrate vulnerabilities in cancer cells that could form novel therapeutic targets or inform precision medicine.  

“Some signatures already point to defects in DNA repair pathways, such as homologous recombination deficiency or mismatch repair deficiency, which can guide use of PARP inhibitors, platinum therapies, or immune checkpoint inhibitors,” explained Alexandrov. “As we decode more signatures mechanistically, we may uncover additional repair defects, metabolic dependencies, or immune features that can be therapeutically exploited.”