Genomes carry a record of everything that has happened to a cell - not as memories, but as chemistry, written into the mutations that accumulate over time. This is true for all cells, including healthy ones. Over the past fifteen years, however, scientists have sequenced thousands of tumours, providing especially rich data, and identified recurring patterns of mutations, known as mutational signatures. Some are well understood: smoking leaves a clear imprint in lung tumours, UV light shapes melanoma. But many signatures still have no known cause.

On Wednesday 4 March 2026, Cancer Grand Challenges announced five new international research teams selected from hundreds of proposals worldwide, representing a total investment of $125 million in bold, high-risk science. One of these teams is CAUSE, created to address one of the most persistent gaps in cancer research: linking mutational patterns in cancer genomes to the chemical processes and DNA lesions that produced them.

For Oncode Investigator Puck Knipscheer (PI at Hubrecht Institute and professor at LUMC) who is part of CAUSE, this question is both fundamental and energising. Not because it promises quick answers, but because it exposes a central paradox: we can recognise mutational patterns with great precision, yet we often do not know what causes them. CAUSE brings together the expertise needed to close that gap. “For me it’s also working in this amazing group of people,” Knipscheer says:

The message by the ice rink

Knipscheer learned the news in a moment that could not have been more ordinary. It was the first day of the school holiday. Her daughter was skating on a small rink. Knipscheer stood nearby with a warm drink in hand, when a whatsapp arrived.

The message came through their team lead, based in San Diego, who had heard the outcome earlier that day and sent it on once his morning began. The decision was already there in writing.

It was an unexpected email to read in that moment, but an important one. For Knipscheer, it marked more than personal recognition. “For my group, this means we can pursue a new research direction, closely connected to what we already do, yet genuinely new,” she says. “It allows us to work with outstanding scientists across many different fields, which will likely give a strong boost to our broader research as well. That’s hugely important  and exciting to me, and it’s why I’m so enthusiastic about this project.”

A black box in plain sight

CAUSE begins with a paradox at the heart of modern cancer research. We can read cancer genomes with stunning precision. We can classify mutations into signatures distinct patterns that hint at how damage occurred. And yet, for many of the signatures most commonly seen, we still cannot say what caused them.

Knipscheer calls it the “black box”: the missing chain between a damaging agent and the mutational fingerprint left behind. The field has become excellent at recognising the fingerprint [PK3.1]. But in many important cases, the damaging agent itself - along with the precise DNA lesion it creates and the mechanism by which that lesion becomes a mutation - remains unknown. Many of these genomic signatures were first identified by Ludmil Alexandrov – the lead of CAUSE - during his PhD. CAUSE is built to uncover the processes that produced them.

The big scientific question is deceptively simple: what kinds of DNA damage lead to which signatures and what causes that damage in the first place?

Some signatures likely come from external exposures and cluster in certain populations or regions. Others may come from endogenous processes, driven by normal cell metabolism. The problem is that much of this remains inference.

“We have these signatures, these fingerprints, and for many of them we still don’t know how they arise,” Knipscheer says. “But for cancer, that’s a major gap. Because we don’t know the underlying DNA damage that caused them.”

What CAUSE is really trying to connect

The team’s approach follows the biology in sequence.

First: something modifies DNA. It can be a chemical from the environment, or something generated inside the cell. That event leaves behind DNA damage and often, more specifically, DNA adducts, small chemical changes to DNA bases.

Second: the cell responds. Repair pathways try to remove damage. DNA polymerases try to copy past it. Sometimes that process is accurate. Sometimes it is not. When errors become fixed in the DNA sequence, the result is mutation.

Third: across time and many cells, those mutations accumulate and form recognisable signatures. And a handful of those mutations will rewire normal cells into cancer cells. 

Knipscheer is careful with terminology, because it maps onto what CAUSE can detect. “All adducts are DNA damage, but not all DNA damage is DNA adducts,” she explains. A DNA break is damage, but not an adduct. CAUSE is particularly interested in the chemical modifications on bases, because they carry information about the origin of the insult and are closely linked to mutational signatures.

She also emphasises a second distinction that sits at the core of the proposal: the chemical that modifies DNA is not always the same as the adduct that ends up on DNA. Cigarette smoke can cause a certain adduct, but the adduct is the result of chemical reactions, not simply a mirror of what is present in smoke itself. That step, agent to adduct, is often unknown. The next step, adduct to signature, often involves repair and polymerases, and is frequently unknown as well.

The CAUSE team is built to understand both.

Why now: technology has caught up with ambition

The project is enabled by recent technological advances. Mass spectrometry has become sensitive enough to detect a single DNA adduct across the entire genome. At the same time, sequencing technologies can now map extremely rare mutations. Together, these tools make it possible to align chemical lesions with mutational patterns at unprecedented resolution. Just as important is the integration of previously fragmented fields, chemistry, sequencing, DNA repair and modelling, into a single collaborative pipeline.

Puck Knipscheer’s role: from damage to mutation

Within that pipeline, Knipscheer’s contribution is distinct. Her work package is centered on a mechanistic question: how does a specific type of DNA damage get converted into a mutation?

Her lab works with highly defined DNA lesions, that precision is the strength. If you expose DNA to a damaging chemical, you often create a mixture of lesions, and it becomes difficult to say which lesion caused which mutation. In Knipscheer’s system, lesions can be isolated and defined. Some are commercially available; others need to be made chemically by an excellent chemist who is part of the team.

This allows her team to dissect which repair pathways act on a lesion, how polymerases behave when copying past it, and which mutation outcomes arise in which contexts. She describes it as an approach that is rigorous and, at least initially, pragmatic. There are known damaging agents used in chemotherapy, for example, where the exact adducts, the ratio's at which they form, and the repair pathways involved are still not fully understood. 

Later in the project, the ambition grows: to take newly identified adducts, discovered in human samples, and test them in defined systems, linking them back to signatures.

“We definitely need to know what we add to our system,” she says. “And then we hope to figure out how known damaging agents or newly identified ones are converted into mutations, and what pathways play a role.”

The collaboration: present, real, and necessary

Although Knipscheer sits in a mechanistic corner of the project, she is clear that CAUSE only works if the inputs keep flowing from other parts of the team. “We can start without that input,” she says, “but the most exciting things will come from having that input.”

This is where Juan comes in naturally. Based at the Hubrecht Institute and one of the initiators of CAUSE, he works on mutational signatures in biological systems and helps generate the model contexts where adducts can be searched for in the first place. In some cases, his systems can suggest what kind of modification might be responsible. In others, they create the puzzle: mutations appear, a signature emerges, but the chemistry is missing.

Knipscheer describes him as being “a bit in the middle of it all,” because his model systems can generate samples where adducts accumulate and can be analysed with mass spectrometry, while also connecting those observations to what happens in tissues over time.

Patient advocates and Oncode Institute

CAUSE is a fundamental team, and that makes patient involvement both challenging and important. For a project focused on endogenous damage and mutation mechanisms, the “why does this matter?” question needs careful translation.

The CAUSE team includes several patient advocates. Among them Sako Severijn, a patient advocate within Oncode Institute’s Patient Perspective Program, who has been closely involved from early on. He has a cancer history and a strong interest in DNA mutations, and he has experience so the team can also learn from him. Knipscheer sees this as part of the Oncode Institute mission in practice: connecting deep mechanism to human relevance, without turning discovery science into oversimplified promises.

What success could look like

Knipscheer is careful not to overpromise. But she is clear about what progress would mean.

At the patient level, she sees two directions. The first is prevention: if the team can learn to interfere with processes that cause mutations whether by identifying avoidable exposures or understanding modifiable mechanisms, it could, in the long run, reduce mutation accumulation and therefore cancer risk. The second is therapy. DNA damage is used deliberately in cancer treatment. If CAUSE can clarify which therapy-induced lesions are most mutagenic, and how to reduce that mutagenicity while maintaining tumour-killing effects, it may eventually help lower the risk of secondary cancers, especially in childhood cancer survivors.

Scientifically, success might be more concrete. If the team can solve the origin of even one major mutational signature, linking it to a specific DNA lesion and its source, that would already be a field-changing step. And the long-term dream is elegant: sequence a tumour, read its mutational pattern, and trace back not just what went wrong, but what processes and exposures wrote the pattern in the first place.

Asked what the awarded grant means to her personally, Knipscheer hesitate a bit, she describes a mix of pride and gratitude: being invited to join the team in the first place. “That was already a huge step,” she says. Securing the grant together only strengthened that sense of recognition. But Knipscheer emphasizes: “This was a true team effort.  We worked incredibly hard for it: together.”

The support behind CAUSE

CAUSE unites clinicians, advocates and scientists from six institutions across three countries, integrating expertise in chemistry, prevention, AI, public health and region-specific environmental exposures. The team is supported through Cancer Grand Challenges by Cancer Research UK, the National Cancer Institute and KWF Dutch Cancer Society.