Damage to stem-cell DNA may explain link between alcohol and cancer

A new study in mice suggests alcohol causes stem-cell mutations in the absence of a critical enzyme.

When the body breaks down alcohol, it briefly converts it into a chemical called acetaldehyde. For most people, acetaldehyde is only a temporary by-product of alcohol, before it is oxidized by the enzyme aldehyde dehydrogenase 2 (ALDH2). However, an estimated 540 million people in Asia have a mutated ALDH2 gene that stops them from breaking acetaldehyde down. This could potentially increase the risk of cancer in this population, as acetaldehyde accumulation can damage the DNA.

A new study in mice sheds light on this process, and the potential link between alcohol consumption and increased cancer risk. We talk to one the study’s authors, Ketan Patel from the MRC Laboratory of Molecular Biology in Cambridge, about the work.

ResearchGate: What motivated this study?

Ketan Patel: We were interested in what natural factors damage the DNA of blood stem cells and how this damage is repaired. In the human illness fanconi anaemia a DNA repair system fails and causes the blood stem cells to die which leads to a loss of blood production. Individuals with this illness also develop blood cancers. We wanted to know what exactly this DNA repair system fixed in these very important cells. We discovered that one of the factors that damage the DNA in these cells is a byproduct of alcohol metabolism, the chemical acetaldehyde.

RG: How does alcohol increases cancer risk?

Patel: Our research suggests that alcohol causes cancer because, when the body breaks it down, it briefly converts it into acetaldehyde, which damages DNA if allowed to accumulate. Damaging DNA leads to DNA scars (mutations) and these mutations can then alter the genes that instruct a cell to become cancerous. Because alcohol seems to damage stem cells (at least in the blood) these changes can then be transmitted to many cells that are then subsequently created from a single stem cell.

RG: How did you discover this?

Patel: We used genetically engineered mice that lack protection against acetaldehyde. This protection system has two tiers; the first line of defense is to process acetaldehyde with an enzyme called ALDH2, and the second line of defense is the DNA repair pathway that fixes the DNA damaged by acetaldehyde. When we genetically remove both protection mechanisms in mice, they become hugely prone to alcohol induced DNA damage. Our more detailed analysis of these mice shows that some of this DNA damage occurs in blood stem cells, causing most of the stem cells to die. The few that survive carry DNA scars or mutations that they then pass on to many blood cells.

RG: What would you like the public to take away from your study?

Patel: This work informs us of how alcohol causes damage to an important class of cells (stem cells) and how this could lead to cancer. In addition, the work predicts that the huge number of people in Asia who lack their first line of protection enzyme are unusually prone to alcohol induced DNA damage and hence possibly cancer. Such individuals (Asian alcohol flushers) are utterly reliant on their DNA repair system.

RG: What's questions are you looking to tackle next?

Patel: How precisely does acetaldehyde damage DNA and how does the repair system fix this? Does this matter for other stem cells? Can this concept be in fact exploited therapeutically?

Featured image courtesy of Santy Gimeno.