Colon cancer: Scientists find new predisposition mechanism

New research finds a novel mechanism that interferes with our DNA's ability to repair itself, genetically predisposing some people to colon cancer.

The new study was published in the journal Nature Chemistry, and the first author of the paper is Kevin J. McDonnell , from the Norris Comprehensive Cancer Center, based at the University of Southern California in Los Angeles.

Study co-author Jacqueline Barton — the John G. Kirkwood and Arthur A. Noyes Professor of Chemistry at the California Institute of Technology in Pasadena — was the first researcher who, over 2 decades ago, identified a DNA process called "DNA charge transport."

DNA charge transport refers to the process in which electrons move through our DNA's double helix, sending signals to so-called DNA repair proteins and "telling" them to start fixing damage found along the way.

In the new study, the researchers show how a genetic variant commonly found in colon cancer disrupts this DNA charge transport process.

The findings may have important implications for colon cancer prevention, explain the scientists.

New mechanism of cancer predisposition

McDonnell  and his colleagues focused on a mutation in a gene called MUTYH. Normally, MUTYH provides instructions for creating a DNA repair protein.

Genetic mutations in MUTYH, however, affect the DNA's ability to repair its own errors. MUTYH mutations have also been associated with polyposis, or the formation of polyps in the colon that may later lead to cancer.

In this study, the researchers focused on a MUTYH mutation called C306W, which affects MUTYH's ability to retain and keep a tiny cluster of iron and sulfur atoms together inside the protein.

Several electrochemical experiments in the study revealed that the C306W mutation makes the iron-sulfur cluster degrade when it comes into contact with oxygen. Iron-sulfur clusters are key for DNA repair, so this degradation prevents the MUTYH protein from doing its DNA-fixing job.

The iron-sulfur clusters are crucial for DNA repair because they provide the electrons that proteins need in order to "cling on" to the DNA's double helix and "scan" for damage.

"We have found that a mutation [C306W] to a DNA repair protein associated with cancer [MUTYH] can disrupt electron transport through DNA," explains Prof. Barton.

In the paper, McDonnell  and colleagues conclude, "[W]e have documented and provided an explanation for a novel mechanism of colonic polyposis and cancer predisposition linked to electrochemical compromise of the MUTYH [iron-sulfur] cluster."

Phillip Bartels, a postdoctoral researcher in chemistry and one of three co-lead authors of the study, comments on the findings. He explains, "This is only the tip of the iceberg [...] There may be other mutations in cancer patients besides C306W that similarly disrupt this charge transport process."

Prof. Barton is hopeful that the new study paves the way for novel prevention strategies against colon cancer.

"The work provides a strategy for thinking about how to possibly stabilize these repair proteins and restore their ability to carry out long-range signaling through DNA, so that the repair proteins can find and fix the mutations in DNA before they lead to cancer."

Prof. Jacqueline Barton