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DPYD and fluorouracil

Key takeaways:
~ Variants in the DPYD gene impact 5-fluorouracil metabolism in cancer patients.
~ Knowing your genetics here can give you the “heads up” to talk with your doctor about DPYD variants before cancer treatment.

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Dihydropyrimidine dehydrogenase deficiency:

Dihydropyridine dehydrogenase is an enzyme that breaks down uracil and thymine, which are two of the nucleotide base pairs that make up DNA and RNA. Essentially, the enzyme keeps the proper balance of the nucleotides in the cells.  A deficiency in the enzyme can result in a build-up of uracil and thymine.

Having two copies of mutations in the DPYD gene can cause a more severe dihydropyridine dehydrogenase deficiency, which for some people results in neurological problems such as epilepsy, learning disabilities, motor skill problems, and autistic behaviors.  

Heterozygous (1 copy) mutations in DPYD:

While you are unlikely to have notable effects of dihydropyridine dehydrogenase deficiency from having one copy of a DPYD mutation, the impaired function can interact negatively with certain chemotherapy drugs called fluoropyrimidines. Fluoropyrimidines are widely used as chemo for solid tumors.  The reduced ability to break down uracil causes a buildup of these types of drugs, including 5-fluorouracil (5-FU), capecitabine, or tegafur. This increases the toxicity of the chemo drugs, leading to increased toxicity. [ref]

Here is an explanation of the mutation from the Genetics Home Reference.

People with dihydropyrimidine dehydrogenase deficiency, including those who otherwise exhibit no symptoms, are vulnerable to severe, potentially life-threatening toxic reactions to certain drugs called fluoropyrimidines that are used to treat cancer. Common examples of these drugs are 5-fluorouracil and capecitabine. These drugs are not broken down efficiently by people with dihydropyrimidine dehydrogenase deficiency and build up to toxic levels in the body (fluoropyrimidine toxicity). Severe inflammation and ulceration of the lining of the gastrointestinal tract (mucositis) may occur, which can lead to signs and symptoms including mouth sores, abdominal pain, bleeding, nausea, vomiting, and diarrhea. Fluoropyrimidine toxicity may also lead to low numbers of white blood cells (neutropenia), which increases the risk of infections. It can also be associated with low numbers of platelets in the blood (thrombocytopenia), which impairs blood clotting and may lead to abnormal bleeding (hemorrhage). Redness, swelling, numbness, and peeling of the skin on the palms and soles (hand-foot syndrome); shortness of breath; and hair loss may also occur.”

One specific antifungal medication, flucytosine, is also partially deaminated to 5-FU and may cause toxicity in people with DPYD deficiency.[ref] Flucytosine is used to treat severe candida or cryptococcus infections. [ref]


Genotype report: DPYD gene

Please keep in mind that 23andMe and AncestryDNA data are not guaranteed to be clinically accurate, so there is a chance of a false positive or false negative. There are other rare mutations and copy number variants that aren’t covered in 23andMe/AncestryDNA data.

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If you have a mutation in DPYD, take this information as a ‘heads up’ to talk with your doctor about if you are ever diagnosed with cancer. Additionally, it is something to mention to your children, siblings, or parents, if they are facing chemotherapy choices.

While I can’t find research studies specific to this, it would also make sense that uracil supplements may not be the best idea for someone with a DPYD mutation.


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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering from Colorado School of Mines and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.