Can This Gene Influence Your Risk of Cancer (COMT)?

Green Tea (Epigallocatechin Gallate)

Green tea is rich in catechol-containing flavanols such as epigallocatechin gallate (EGCG), epicatechin, and catechin [R].

High intake of green tea has been associated with a reduced incidence of several cancer types, such as breast, ovarian, prostate, mouth, esophageal, stomach, colorectal, liver, endometrial, lung, bladder, and lymph system cancers. However, most studies were done in Asian people. Additional studies in other populations will be needed to determine if these effects may be ethnicity-dependent [R, R, R, R, R, R, R, R, R, R, R, R].

Its most abundant flavanol, EGCG, is quickly broken down by COMT and doesn’t seem to impair COMT activity even at high doses. For this reason, its beneficial effects may be enhanced in carriers of underactive COMT variants [R, R].

In a study on Asian American women, only those who carried at least one copy of the ‘A’ variant at rs4680 benefited from the anti-breast cancer effects of green tea. However, drinking green tea reduced the risk of breast cancer in 2 studies on Chinese and Japanese women regardless of their COMT genotypes [R, R, R].

In contrast, the high-activity ‘G’ variant of rs4680 reduced the ability of green tea to prevent lung cancer in a Taiwanese study [R].

In mice and cells, inhibiting COMT enhanced the availability and anticancer effects of EGCG [R, R].

High intake of green tea has been associated with reduced incidence of multiple cancer types. Because its natural flavonoid epigallocatechin gallate is broken down by COMT, people with underactive variants may especially benefit from green tea.

Plant Phytoestrogens (Soy, Flax, Red Clover)

Phytoestrogens are plant-derived flavonoids that resemble the sex hormone estrogen. When consumed, phytoestrogens can bind to estrogen receptors and either mimic or block the effects of this hormone. Additionally, they build up in tissues and can be toxic to cancer cells.

Soy is rich in a class of phytoestrogens called isoflavones. Multiple studies have associated eating a diet rich in soy with a reduced incidence of breast, ovarian, prostate, endometrial, stomach (only non-fermented soy), colorectal, and lung cancer. However, most studies were done in Asian people, and studies including participants of other races have reported somewhat less-promising results [R, R, R, R, R, R, R].

The ‘AA’ genotype of rs4680 increased the risk of breast cancer in Chinese postmenopausal women. However, eating high levels of soy isoflavones reduced its incidence to levels comparable to those of ‘G’ carriers [R, R].

In prostate cancer cells, the combination of the soy isoflavone genistein with the glucosinolate diindolylmethane increased COMT expression and activity, suggesting it helps prevent estrogen-induced cancer [R].

Flaxseed contains another type of phytoestrogen called lignans. Multiple studies have reported that dietary flaxseed can help prevent breast cancer — especially in postmenopausal women — as well as increase the survival of breast cancer patients [R, R].

The minor variants of rs4680 (‘A’) and rs4633 (‘T’) have been associated with increased removal of estrogen byproducts in urine after consumption of flaxseed, suggesting higher benefits in terms of cancer prevention [R, R].

Certain plant foods like soy and flaxseed contain phytoestrogens, which resemble human estrogen. Some studies suggest that COMT variants may influence the anticancer effects of these compounds.

Sufficient Folate Intake

Folate (vitamin B9) is an antioxidant vitamin with key roles in cellular metabolism, blood cell production, immune response, brain development and function, and fertility [R, R, R, R, R].

Importantly, folate helps prevent cancer by controlling gene expression through its role in DNA methylation. This vitamin also restores SAM-e levels by producing its precursor methionine from the amino acid homocysteine. A folate-rich diet (but not above a normal dietary range) is associated with a reduced incidence of several cancer types such as colorectal, esophageal, stomach, pancreatic, lung, and breast cancer [R, R, R, R].

In a study on American women, low blood folate levels were associated with increased breast cancer incidence only in those with two copies of the ‘A’ variant at rs4680. The authors speculated that the increased SAH levels resulting from low folate would have larger inhibitory effects on this underactive COMT variant [R].

Food sources of this vitamin include green leafy vegetables, citrus fruits, and legumes [R].

Folate is an antioxidant vitamin with key roles in cellular metabolism, immune response, brain function, and fertility. Underactive COMT variants can further increase cancer risk in people with folate deficiency.

Dietary Flavonoids (Herbs, Spices, Fruits, and Vegetables)

Flavonoids are phenolic compounds naturally found in plants. Owing to their antioxidant activity, these compounds have been widely investigated due to their potential role in preventing chronic conditions, such as heart disease and cancer. Food sources of these compounds include many herbs and spices, onions, apples, grapes, pomegranates, berries, green leafy vegetables, and red wine [R].

A lot of them, including flavonols (quercetin, fisetin, and resveratrol) and flavones (luteolin), are catechol-containing substances that can be broken down by COMT. Depending on the flavonoid, methylation by COMT can either reduce its effects or be required to convert it to an active compound [R].

Among flavonoid classes, flavonols are most effective at preventing breast, ovarian, mouth, throat, colorectal, lung, and prostate cancer, while flavones mainly reduce the risk of breast, colorectal, and kidney cancers [R, R].

Aside from this, plant catechols can act as COMT inhibitors that reduce the ability of this enzyme to break down neurotransmitters and estrogens. For instance, quercetin is a strong COMT inhibitor. This means quercetin may have detrimental effects when taken alone. However, it may reduce the breakdown of other flavonoids such as green tea polyphenols and resveratrol by COMT, thus enhancing their effects [R, R, R, R, R, R, R, R].

In a clinical trial in which healthy volunteers drank quercetin-rich blueberry and apple juice for 4 weeks, carriers of the ‘A’ variant at rs4680 were observed to benefit less in terms of DNA damage reduction [R].

In animal studies, quercetin reduced the breakdown of estrogens by COMT and increased the risk of breast and kidney cancer [R, R, R].

Plant flavonoids are potent dietary antioxidants that have been studied extensively for their potential to protect against cancer. Quercetin is a COMT inhibitor that may be recommended or best avoided depending on your COMT genotype and combination with other flavonoids.

Maintaining a Healthy Weight

In addition to many other health issues, excess weight is associated with an increased incidence of some cancer types, especially of the kidneys, colon (only in men), breast, endometrium, and ovaries (in women not using hormone replacement therapy) [R].

In a study on Canadian women, the increased breast cancer risk due to high BMI was only observed in carriers of the ‘G’ variant at rs4680 [R].

In addition to a healthy diet low in saturated fats and refined carbohydrates, engagement in regular physical exercise is important in maintaining a healthy weight. Unfortunately, exercise may be less effective in carriers of the ‘A’ variant at rs4680. In two clinical trials on overweight postmenopausal women, this allele reduced weight loss and muscle gain from exercise [R, R].

Excess weight is associated with some cancer types. Certain COMT variants may influence not only the risk of cancer from excess weight, but also the effectiveness of exercise in regards to losing weight.

Avoiding Cigarette Smoke

In addition to its well-known role in causing lung cancer, both active- and second-hand exposure to cigarette smoke have been associated with several types of cancer, including breast, head and neck, upper digestive, prostate, colorectal, cervical, bladder, and kidney cancer [R, R, R, R, R, R, R, R].

The ‘A’ variant of rs4680 further increased the risk of lung cancer in a study on Japanese smokers [R].

In the case of breast cancer, the ‘G’ allele has been associated with an increased risk of breast cancer linked to smoking. An increased breakdown of the anticancer compound 2-methoxyestradiol was proposed as the most likely mechanism [R].

Possibly because it encodes a COMT form that breaks down nicotine more slowly, the ‘A’ variant at this polymorphism is associated with increased dependence [R, R, R, R].

However, carriers of the ‘G’ variant experience worse cognitive symptoms during abstinence and break down nicotine replacement faster. This may explain why carrying the ‘A’ variant is associated with better success of nicotine replacement therapies [R, R, R, R].

Bupropion is an antidepressant often prescribed as an aid to smoking cessation that increases dopamine levels by inhibiting its removal. In a clinical trial, carrying the ‘A’ variant at rs165599 was associated with increased success of this therapy in African Americans, while ‘G’ combined with the ‘G’ allele of rs737865 predicted failure in European Americans [R].

Exposure to cigarette smoke has been associated with increased rates and worse outcomes of cancer. Different COMT variants can influence the risk of smoking-associated cancers and the success rate of smoking cessation therapies.

Reducing Exposure to Toxic Chemicals

Exposure to different chemicals, such as polycyclic aromatic hydrocarbons (PAH) and fuel combustion byproducts, has been consistently associated with different cancer types. These chemicals cause DNA damage that may trigger tumor development [R, R, R, R, R, R, R].

PAHs are found in fuels such as coal and gasoline. We are exposed to them when we breathe air contaminated with vehicle exhaust, cigarette smoke, wood smoke and fumes from asphalt roads, and when we eat charred or grilled foods.

COMT effectively broke down PAH in test tubes. This suggests that carrying underactive COMT variants may pose disadvantages in terms of their detoxification ability [R].

In line with this, both the ‘T’ variant of rs4633 and the ‘A’ variant of rs4680 further increased the risk of lung cancer from occupational exposure to cooking fumes, soot, and other toxic chemicals in Chinese non-smoking women [R].

Perfluorinated compounds are extremely stable chemicals mainly used in the production of teflon, water-proof and stain-resistant fabrics, and fire-fighting foam. Due to their widespread presence, persistence, and toxic effects in animals, they are recognized as environmental contaminants. 

Human research is sparse, but  these compounds have been associated with some cancer types such as leukemia, prostate, kidney, bladder, breast, and testicular cancer [R].

In women exposed to high levels of perfluorinated compounds, carrying at least one copy of the ‘A’ variant at rs4680 further increased the risk of breast cancer [R, R].

Many toxic chemicals may cause DNA damage. People exposed to pollutants are at greater risk of DNA damage, especially if they carry certain COMT variants.

Reducing Alcohol Intake

Consumption of alcohol is a well-known risk factor for several cancer types. Even at low or moderate doses, it increases the risk of mouth, throat, esophageal, breast, and colorectal cancer. Higher levels of consumption may further increase the risk of these cancers, and have also been associated with stomach, liver, gallbladder, pancreatic, and lung cancer. This risk may be amplified in people who also smoke [R, R, R, R].

In a Japanese study, carrying the ‘A’ variant of rs4680 further increased the risk of lung cancer in heavy drinkers [R].

Alcohol intake is a well-known risk factor for several cancer types. An underactive COMT variant has been associated with lung cancer in heavy drinkers.

Discussing Hormone Therapies with a Doctor

Postmenopausal women often experience symptoms such as hot flashes and vaginal discomfort because their ovaries stop producing estrogen. Hormone replacement therapy (HRT) with estrogen, usually combined with progesterone to help prevent endometrial cancer, is often prescribed to manage these symptoms.

HRT has been associated with a slightly higher risk of breast and ovarian cancers, especially if combining estrogen and progesterone. However, the results are inconsistent and most doctors agree that the benefits often outweigh the risks [R, R, R, R, R, R].

In a study on Danish women, the incidence of breast cancer among HRT users was lower for those with the ‘AA’ genotype at rs4680 when compared to carriers of the ‘G’ variant. However, the ‘A’ variant increased the risk of breast cancer in women using HRT that also carried certain variants of the gene encoding the detoxifying enzyme glutathione-S-transferase (GST) [R, R].

Hormone-based birth control methods such as oral contraceptives, birth control shots, patches, and implants (IUDs and rings) have also been associated with an increased risk of breast cancer. Conversely, they may help prevent ovarian cancer, possibly because they suppress ovulation [R, R, R].

In a Canadian study, an increased breast cancer risk from oral contraceptives was only observed in carriers of the major ’G’ allele at rs4680. The authors suggested that the high exposure to estrogens from contraceptives increases the production of the anticancer 2-methoxyestradiol over cancer-causing byproducts. By reducing the breakdown of 2-methoxyestradiol, the ‘A’ variant would be protective in this case [R].

Tamoxifen is a drug that binds to estrogen receptors and blocks their effects in the breasts. For this reason, tamoxifen is used for both the treatment and prevention of estrogen receptor-positive breast tumors.

In female rats, treatment with tamoxifen increased COMT expression and activity, especially in the prefrontal cortex and kidneys [R].

Breast and ovarian cancers are often highly sensitive to estrogen and other hormones. Your COMT genotype may determine whether you should use HRT, birth control, or other hormone-based therapies.

Vitamin E

Vitamin E is a fat-soluble, antioxidant vitamin essential to maintaining brain, heart, skin, and immune system health, as well as maintaining fertility. Deficiency in this vitamin has been associated with increased incidence of several cancer types, heart disease, and dementia [R, R, R].

In a large-scale study on American women, vitamin E supplementation reduced cancer incidence in women with two copies of the ‘A’ allele at rs4680 and ‘C’ at rs4818, but increased it in those carrying only the major variants of these polymorphisms [R].

In addition to supplementing, you can obtain vitamin E from food sources such as nuts, cereal grains, and plant oils [R]. 

Vitamin E is an antioxidant vitamin essential to maintain brain, heart, skin, and immune health. Supplementation with vitamin E may be beneficial or detrimental in cancer prevention depending on your COMT variant.

SAM-e

SAM-e, the primary “methyl donor” used to activate the COMT enzyme, is classified as a supplement in the US and a prescription drug in some European countries.

By supporting methylation, SAM-e may prevent the uncontrolled division of cancer cells and inhibit cancer-promoting enzymes [R].

In mice studies, scientists observed inhibitory effects of SAM-e on breast, liver, stomach, and bone cancer [R, R, R, R].

SAM-e is the methyl donor required for COMT activity. Preliminary research suggests its potential in cancer prevention.