Team CAUSE with Juan Garaycoechea and Puck Knipscheer receives Cancer Grand Challenges grant

DNA is like an instruction manual for our cells, telling them how to grow and function. But over time, DNA is often damaged by harmful substances in the environment (like pollution, tobacco smoke, or UV rays from the sun) as well as by natural reactive molecules that are present inside our bodies. This damage can lead to changes in the DNA sequence (known as mutations), that can sometimes lead to cancer. These mutations are not completely random but have unique patterns, known as mutational signatures. These signatures act like forensic clues, helping scientists figure out what caused the DNA damage.

The challenge: unexplained mutational signatures

Researchers have linked some mutational signatures to clear causes, like tobacco smoke. But many others remain unexplained, even though they account for a large share of cancer-driving mutations. Advances in whole-genome sequencing have accelerated this research. “Over the past 15 years, researchers have sequenced thousands of cancer genomes. They have identified at least 183 distinct mutational signatures. But we still do not know what causes most of them,” says Garaycoechea.

“Take Signature 5,” says Knipscheer. “It occurs widespread in many cancer types and causes more cancer-driving mutations than smoking and UV radiation combined, yet we don’t know which DNA-damaging insults cause it. That shows how much we still need to learn.” This knowledge is important to better understand what can trigger cancer, and how to prevent it.

Linking damage to mutation

The CAUSE (Connecting DNA Adducts, Unexplained Mutational Signatures and Cancer Etiologies) team focuses on a fundamental gap in knowledge: how does chemical DNA damage lead to a permanent mutation? The team will connect three levels of biology: the DNA-damaging agent, the DNA damage it creates, and the resulting mutational signature. By systematically identifying and characterizing DNA damage, or more specifically the chemistry of so-called DNA adducts, the team aims to trace each mutational signature back to its origin.

“DNA adducts are pieces of DNA bound to a cancer-causing chemical. They can arise from internal metabolic processes, such as oxidative damage, but also from unknown environmental mutagens,” says Garaycoechea. Some chemicals used in chemotherapy also cause DNA adducts. Especially in children treated with chemotherapy, this often leads to secondary cancers later in life. “With this project we may find ways to reduce the mutagenic effects of chemotherapy while keeping it effective,” Knipscheer explains.

DNA repair and mutation patterns

The Garaychoechea group and Knipscheer group will play distinct key roles within the CAUSE team. With her group, Knipscheer will introduce chemically defined DNA adducts into a controlled experimental system. They will study how biochemical mechanisms deal with DNA damage. “By analyzing one chemically defined DNA adduct at a time, we can determine which DNA repair pathways and polymerases convert damage into mutations,” explains Knipscheer.

The Garaycoechea group will examine how DNA damage shapes mutation patterns in cells and animal models. “We work with systems where mutations accumulate, but we don’t know what causes them,” Garaycoechea explains. “We will investigate which tissues accumulate mutations and look for the adducts building up in those tissues.”

Toward prevention and better treatment

Ultimately, the CAUSE team aims to understand the origin of mutational signatures by systematically characterizing DNA adducts and exploring their underlying mutagenic mechanisms – including endogenous processes, geography-linked exposures and chemotherapy-induced damage – to provide actionable insights for cancer prevention and treatment.

“If we understand how DNA modifications lead to mutations, we might be able to intervene,” says Knipscheer. “We could identify unknown environmental mutagens that people can potentially avoid or reduce harmful side effects of chemotherapy.” Garaycoechea adds: “We don’t expect to cure cancer in five years. But we hope to identify lifestyle or dietary changes that lower cancer risk.”

More information at: New Teams Announcement | Cancer Grand Challenges