An interdisciplinary research collaboration has taken a significant step towards understanding the mutational causes of cancers, a finding which may one day lead to personalised cancer treatment. The team from the University of Dundee, European Bioinformatics Institute (EMBL-EBI) and the Wellcome Sanger Institute used a type of worm called C. elegans as a model to study how cancer-causing genetic mutations arise when DNA is inaccurately replicated or when damaged DNA is not repaired.
Cancer is caused by the accumulation of mutations. A major challenge is to understand the mutagenic processes that silently and slowly convert normal cells into cancer ones. This is all the more crucial given that cancers of the same type generally arise by different mutagenic processes, including defects in DNA repair, but also exposure to UV light or tobacco smoke. Understanding the footprints of these mutational processes is an important first step to identify the true causes of a given cancer and to identify possible avenues to novel treatments.
Professor Anton Gartner, Principal Investigator in the Centre for Gene Regulation and Expression at Dundee, said, “Dr Bettina Meier in my team initiated this project by assessing the kinds of mutations that arise when C. elegans is defective for one specific DNA repair pathway. As it only takes three days to propagate these worms from one generation to the next, the process of studying how DNA is passed on is greatly expedited. DNA mismatch repair is propagated for many generations and this allowed us to deduce a distinct mutational pattern. The big question was if the same type of mutagenesis also occurred in human cancer cells.”
To address this, Dr Moritz Gerstung’s team at EMBL-EBI analysed human cancer samples. His PhD student Nadezda Volkova used the genetic information from 500 cancer genomes, focusing on colon and gastrointestinal cancers as both are often linked to mismatch repair deficiency. “Our analysis uncovered three distinct mutational signatures in human cancer that were associated with mutations in DNA mismatch repair genes,” said Dr Gerstung, Group Lead in computational cancer biology at EMBL-EBI. “The most common signature closely resembled the patterns found in C. elegans, indicating that the same mutational process operates in the model system. What’s more is that in some human cancers where mismatch repair is deficient, additional mutagenic processes are active, which we can now distinguish from the basic pattern of DNA replication errors found in both data sets.”
Having uncovered a conserved mutagenic mechanism, it is hoped the team’s work will lead to a better understanding of the cause of a particular persons’ cancer and result in the most appropriate treatment to be used. Professor Gartner added, “Knowing a mutational signature linked to DNA mismatch repair defects will be important for personalised cancer treatment in a sizable proportion of cancer patients, and not just for colon and gastrointestinal cancers. Knowing the mutational root cause leading to cancer development provides an Achilles Heel to specifically kill those cancer cells.”
The work was published today in Journal Genome Research.
Image (from top left, clockwise): Dr Bettina Meier, Nadezda Volkova, Professor Anton Gartner and Dr Moritz Gerstung.