Alcohol: A direct carcinogen impairing DNA repair

Alcohol causes cancer directly, according to new evidence from a large-scale genetic study led by Oxford Population Health. A new study published in the journal Lancet Oncology by the World Health Organization’s (WHO) International Agency for Research on Cancer (IARC) has discovered a link between alcohol and a significantly greater risk of numerous types of cancer, including breast, colon, and oral cancers. Alcohol impairs DNA repair, leading to cancer.

Alcohol causes cancer

Alcohol, a chemical substance found in alcoholic beverages, is produced by the fermentation of carbohydrates and starches by yeast. Alcohol causes various types of cancer directly, and these risks may be heightened in those with genetically low alcohol tolerance who are unable to adequately metabolize alcohol. Alcohol drinking is a major cause of cancer worldwide. Alcohol can cause cancer in a variety of ways:

Impairing DNA repair
Chronic alcohol consumption leading to liver cirrhosis
Dysregulation of sex hormones resulting in breast cancer
For smokers, alcohol increases the absorption of carcinogens from cigarettes, increasing the risk of head and neck cancer.

Several studies have been conducted to see if different types of alcoholic beverages have varied impacts on the risk of cancer. Some studies revealed no discernible variations in the cancer risks linked with other beverages, while others concluded that spirits pose a larger risk than wine or beer.

Researchers in Normandy, France, found a link between apple-based drinks and an increased incidence of esophageal cancer (e.g., apple brandy and hard cider). After correcting for overall alcohol consumption, two Italian studies indicated that those who consumed simply wine had higher risks of oral, pharyngeal, and esophageal cancer than people who ingested wine along with distilled spirits or beer.

In contrast, a Danish study showed no link between wine drinking and an increased incidence of upper digestive tract cancer.

At numerous sites, excessive alcohol use increases the risk of cancer development. A modestly higher risk of different malignancies is associated with lower levels of intake.

Alcohol consumption & cancer risk

The direct causal relationship between drinking alcohol and developing cancer has been confirmed by a massive genomic study that followed 150,000 people for almost a decade. The findings show a relationship between alcohol use and esophageal and head and neck malignancies. Heavy drinking is frequently linked to a poor diet, smoking, and a lack of exercise, all of which are known to raise the risk of cancer. As a result, some researchers believe that these factors are to blame for any link between alcohol intake and cancer.

It’s been difficult to determine if alcohol causes cancer directly or if it’s linked to confounding factors (such as smoking and diet) that could lead to skewed results.

Alcohol is a direct cause of cancer in the head, neck, esophagus, liver, colon, and breast, according to evidence from Western countries; however, it is not known whether alcohol is linked to other malignancies, such as lung and stomach cancers.

Researchers from Oxford Population Health, Peking University, and Beijing’s Chinese Academy of Medical Sciences investigated gene variations linked to lower alcohol intake in Asian populations using a genomic technique.

Two common genetic variations (alleles) in Chinese and other East Asian populations impair alcohol tolerance and are highly related to lower alcohol intake because they cause an unpleasant ‘flushing’ effect. Both mutations cause the hazardous chemical acetaldehyde, a Group I carcinogen, to build in the bloodstream, disrupting the activity of enzymes involved in alcohol detoxification.

A loss-of-function mutation in the gene for the enzyme aldehyde dehydrogenase 2 is the first mutation (ALDH2). The second mutation boosts alcohol dehydrogenase 1B’s activity (ADH1B). Both are frequent in East Asians but uncommon in people of European heritage.
These genotypes can be used as a proxy for alcohol consumption to analyze how alcohol consumption influences disease risks because they are assigned at birth and are independent of other lifestyle factors (such as smoking).
The researchers examined DNA samples from over 150,000 people in the China Kadoorie Biobank project (around 60,000 men and 90,000 women) to determine the frequency of low-alcohol tolerance alleles for ALDH2 and ADH1B. The information was paired with questionnaires about drinking behaviors filled out by individuals at the time of recruitment and follow-up visits. Because women in China rarely drink alcohol, the focus of the study was on men.
Through the use of health insurance information and death registers, the participants were followed for an average of 11 years.
Low-alcohol tolerance alleles were found in 21% of ALDH2 alleles and 69% of ADH1B alleles in the Chinese study population. Low-alcohol tolerance alleles were highly connected to lower alcohol consumption, both in terms of frequency and total amount consumed. Approximately, 4,500 men (7.4%) acquired cancer during the follow-up period. Men with one or two of the ADH1B low-alcohol tolerance alleles had a 13-25% decreased risk of total cancer and alcohol-related cancers, especially head and neck cancer and esophageal cancer.
Overall, men who had two copies of the ALDH2 low-alcohol tolerance allele consumed very little alcohol and had a 14 percent reduced risk of any cancer and a 31 percent lower risk of malignancies previously associated with alcohol (cancers of the head and neck; esophagus, colon, rectum, and liver).

Men who drank on a regular basis despite having one copy of the ALDH2 low-alcohol tolerance allele had considerably increased risks of head and neck cancer and esophageal cancer. There was no overall link between carrying one copy of the low-alcohol tolerance allele for ALDH2 and elevated cancer risk among non-drinkers or infrequent drinkers.

When the data was corrected for other cancer risk variables like smoking, nutrition, physical activity, body mass, and family history of cancer, the results remained the same.

These low-alcohol toleration alleles were not related to an increased risk of cancer in women (only 2% of whom drank frequently), indicating that the lowered risks for males who carried these gene polymorphisms were due to their lower alcohol use.

The significantly higher risks reported in individuals with the low-alcohol tolerance ALDH2 gene variation who still drank on a regular basis implies that acetaldehyde buildup may directly enhance cancer risk.

These data suggest that alcohol causes various types of cancer directly, and that these risks may be amplified in persons who have inherited low alcohol tolerance and are unable to adequately metabolize alcohol.

In 2020, alcohol consumption could be directly responsible for 740,000 additional cancer cases.

Acetaldehyde is generated when alcohol is metabolized. Interstrand crosslinking (ICL) is a hazardous type of DNA damage caused by acetaldehyde, a highly reactive, DNA-damaging chemical. As a result, cell division and protein production are hampered. An accumulation of ICL damage may eventually lead to cell death and cancer.

DNA crosslink repair protects cells from acetaldehyde-induced damage, according to the authors of the study. When DNA crosslink repair is hindered, it causes Fanconi anemia (FA), a condition characterized by a failure to form blood cells and a proclivity for malignancy. The mechanism of acetaldehyde-induced DNA damage, on the other hand, is unknown.

Thankfully, every cell in our body has a toolset that allows it to repair DNA damage. The ALDH2 enzyme, which largely breaks down acetaldehyde before it causes any harm, is the first line of defense against ICLs induced by acetaldehyde. However, not everyone benefits from this enzyme—a mutation in the gene coding for this enzyme affects nearly half of the Asian population, or more than two billion individuals worldwide. They are more likely to develop alcohol-related cancer because they are unable to break down acetaldehyde.