How alcohol damages DNA and increases cancer risk

Scientists have shown how alcohol damages DNA in stem cells, helping to explain why drinking increases your risk of cancer, according to research part-funded by Cancer Research UK and published in Nature today (Wednesday).

Much previous research looking at the precise ways in which alcohol causes cancer has been done in cell cultures. But in this study, researchers have used mice to show how alcohol exposure leads to permanent genetic damage.

Scientists at the MRC Laboratory of Molecular Biology, Cambridge, gave diluted alcohol, chemically known as ethanol, 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.

They found that acetaldehyde can break and damage DNA within blood stem cells leading to rearranged chromosomes and permanently altering the DNA sequences within these cells.

It is important to understand how the DNA blueprint within stem cells is damaged because when healthy stem cells become faulty, they can give rise to cancer.

These new findings therefore help us to understand how drinking alcohol increases the risk of developing 7 types of cancer including common types like breast and bowel.

Professor Ketan Patel, lead author of the study and scientist, part funded by Cancer Research UK, at the MRC Laboratory of Molecular Biology, said: "Some cancers develop due to DNA damage in stem cells. While some damage occurs by chance, our findings suggest that drinking alcohol can increase the risk of this damage."

The study also examined how the body tries to protect itself against damage caused by alcohol. The first line of defence 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 South East 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 defence 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.

Professor Patel added: "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. 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 defence mechanisms are intact."

This research was funded by Cancer Research UK, Wellcome and the Medical Research Council (MRC).

Professor Linda Bauld, Cancer Research UK's expert on cancer prevention, said: "This thought-provoking research highlights the damage alcohol can do to our cells, costing some people more than just a hangover.

"We know that alcohol contributes to over 12,000 cancer cases in the UK each year, so it's a good idea to think about cutting down on the amount you drink."

What makes alcoholics drink? Research shows it's more complex than supposed

What makes alcoholics drink? New research has found that in both men and women with alcohol dependence, the major factor predicting the amount of drinking seems to be a question of immediate mood. They found that suffering from long-term mental health problems did not affect alcohol consumption, with one important exception: men with a history of depression had a different drinking pattern than men without a history of depression; surprisingly those men were drinking less often than men who were not depressed

"This work once again shows that alcoholism is not a one-size-fits-all condition," said lead researcher, Victor Karpyak (Mayo Clinic, MN, USA). "So the answer to the question of why alcoholics drink is probably that there is no single answer; this will probably have implications for how we diagnose and treat alcoholism."

The work, presented at the ECNP congress by researchers from the Mayo Clinic*, determined the alcohol consumption of 287 males and 156 females with alcohol dependence over the previous 90 days, using the accepted Time Line Follow Back method and standardized diagnostic assessment for life time presence of psychiatric disorders (PRISM); they were then able to associate this with whether the drinking coincided with a positive or negative emotional state (feeling "up" or "down"), and whether the individual had a history of anxiety, depression (MDD) or substance abuse.

The results showed that alcohol dependent men tended to drink more alcohol per day than alcohol dependent women. As expected, alcohol consumption in both men and women was associated with feeling either up or down on a particular day, with no significant association with anxiety or substance use disorders. However, men with a history of major depressive disorder had fewer drinking days (p=0.0084), and fewer heavy drinking days (p=0.0214) than men who never a major depressive disorder.

Victor Karpyak continued: "Research indicates that many people drink to enhance pleasant feelings, while other people drink to suppress negative moods, such as depression or anxiety. However, previous studies did not differentiate between state-dependent mood changes and the presence of clinically diagnosed anxiety or depressive disorders. The lack of such differentiation was likely among the reasons for controversial findings about the usefulness of antidepressants in treatment of alcoholics with comorbid depression.

This work will need to be replicated and confirmed, but from what we see here, it means that the reasons why alcoholics drink depend on their background as well as the immediate circumstances. There is no single reason. And this means that there is probably no single treatment, so we will have to refine our diagnostic methods and tailor treatment to the individual. It also means that our treatment approach may differ depending on targeting different aspects of alcoholism (craving or consumption) and the alcoholic patient (i.e. man or a woman) with or without depression or anxiety history to allow really effective treatment."

Commenting, Professor Wim van den Brink (Professor of Psychiatry and Addiction at the Academic Medical Centre, University of Amsterdam) said:

"This is indeed a very important issue. Patients with an alcohol use disorder often show a history of other disorders, including mood and anxiety disorders, they also often present with alcohol induced anxiety and mood disorders and finally the may report mood symptoms that do not meet criteria for a mood or anxiety disorder (due to a failure to meet the minimal number of criteria or a duration of less than two weeks). All these different conditions may influence current levels or patterns of drinking.

The current study seems to show that the current presence of mood/anxiety symptoms is associated with more drinking in both male and female alcoholics, whereas a clinical history of major depression in male alcoholics is associated with lower current dinking levels. Although, the study does not provide a clear reason for this difference, it may have consequences for treatment. For example, antidepressant treatment of males with a history major depression may have no effect on drinking levels. However, these findings may also result from residual confounding, e.g. patients with a history of major depression might also be patients with a late age of onset of their alcohol use disorder and this type of alcohol use disorder is associated with a different pattern of drinking with more daily drinking and less heavy drinking days and less binging. More prospective studies are needed to resolve this important but complex clinical issue."

*This work was presented on Sunday 3rd September, 2017.

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