Alcohol Boosts Cancer Risk by Damaging Stem Cell DNA

Alcohol consumption is known to raise the risk of certain cancers, but exactly how alcohol causes cells to stagger toward malignant fates is often unclear. To find ways of keeping cells on the straight and narrow, scientists based at MRC Laboratory of Molecular Biology, Cambridge, used mice to show how alcohol exposure leads to permanent genetic damage. In particular, the scientists found that acetaldehyde, an endogenous and alcohol-derived metabolite, can break and damage DNA within blood stem cells.

Although alcohol isn't thought to cause blood cancers, blood stem cells offer a valuable way for scientists to investigate what's happening to the DNA inside. For example, by showing how alcohol consumption can lead to rearranged chromosomes and permanently altered DNA sequences within blood stem cells, the MRC scientists uncovered mechanisms that could be relevant in other kinds of stem cells, including stem cells in tissues where cancer is known to raise the risk of cancer. These tissues the breast, liver, and bowel.

“Some cancers develop due to DNA damage in stem cells,” said Ketan Patel, Ph.D., a professor at the MRC Laboratory of Molecular Biology. “While some damage occurs by chance, our findings suggest that drinking alcohol can increase the risk of this damage.”

Prof. Patel is the senior author of a new study (“Alcohol and Endogenous Aldehydes Damage Chromosomes and Mutate Stem Cells”) that appeared January 3 in the journal Nature. This article describes how acetaldehyde causes DNA double-stranded breaks that, despite stimulating recombination repair, also cause chromosome rearrangements.

“We combined transplantation of single haematopoietic stem cells with whole-genome sequencing to show that this damage occurs in stem cells, leading to deletions and rearrangements that are indicative of microhomology-mediated end-joining repair,” the article's authors wrote. “Moreover, deletion of p53 completely rescues the survival of aldehyde-stressed and mutated haematopoietic stem cells, but does not change the pattern or the intensity of genome instability within individual stem cells.”

Much previous research looking at the precise ways in which alcohol causes cancer has been done in cell cultures. But in this study, researchers gave diluted alcohol to mice. They then used chromosome analysis and DNA sequencing to examine the genetic damage caused by acetaldehyde, a harmful chemical produced when the body processes alcohol.

The study also examined how the body tries to protect itself against damage caused by alcohol. The first line of defense is a family of enzymes called aldehyde dehydrogenases (ALDH). These enzymes break down harmful acetaldehyde into acetate, which our cells can use as a source of energy.

Worldwide, millions of people, particularly those from Southeast Asia, either lack these enzymes or carry faulty versions of them. So, when they drink, acetaldehyde builds up which causes a flushed complexion, and also leads to them feeling unwell.

In the study, when mice lacking the critical ALDH enzyme, ALDH2, were given alcohol, it resulted in four times as much DNA damage in their cells compared to mice with the fully functioning ALDH2 enzyme.

The second line of defense used by cells is a variety of DNA repair systems, which, most of the time, allow them to fix and reverse different types of DNA damage. But they don't always work, and some people carry mutations, which mean their cells aren't able to carry out these repairs effectively.

“Our study highlights that not being able to process alcohol effectively can lead to an even higher risk of alcohol-related DNA damage and therefore certain cancers,” commented Prof. Patel. “But it's important to remember that alcohol clearance and DNA repair systems are not perfect and alcohol can still cause cancer in different ways, even in people whose defense mechanisms are intact.”