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  • Writer's pictureDženita Omerkić Dautovic, MSc & Dr Edin Hamzić

The DPYD Gene and Chemotherapy: A Guide to Understanding DPD Deficiency

Updated: Jun 11, 2023

This is the first blog post in a series of posts focused on the DPYD gene. In this first blog post, we would like to describe the DPYD gene and its role but also focus on its mutations and protein deficiency. This blog post is followed by one more post focused on the pharmacogenomics of the DPYD gene.

Where Is Located the DPYD Gene? What Does The DPYD Gene Encodes?

The DPYD gene is located on chromosome 1, roughly 843 kbp long, and it encodes a pyrimidine catabolic enzyme called dihydropyrimidine dehydrogenase (DPD) [citation].

What Does Dihydropyrimidine Dehydrogenase (DPD) Do?

Dihydropyrimidine dehydrogenase is a catabolic enzyme that breaks down the nucleotide type of molecules called uracil and thymine when unnecessary. Therefore, the pyrimidine catabolic enzyme is one of the critical elements in the uracil and thymine catabolism pathway, as illustrated in Figure 1 [citation].



Figure 1: Representation of the metabolic pathways for fluoropyrimidines. Source: https://www.pharmgkb.org/pathway/PA150653776

Dihydropyrimidine dehydrogenase is essential in the breakdown of uracil and thymidine. Therefore, when the DPYD gene is mutated, it causes dihydropyrimidine dehydrogenase deficiency, leading to thymine-uraciluria and increased toxicity risk in cancer patients taking 5-fluorouracil chemotherapy. [citation].

Thymine-uraciluria (TYUR) is characterized by high levels of thymine and uracil in the urine due to a deficiency in the enzyme dihydropyrimidine dehydrogenase (DPD).

Mutations [citation] in the DPYD gene have been associated with the following diseases:

  1. Dihydropyrimidine Dehydrogenase Deficiency

  2. Coloboma [citation] and

  3. Macroglossia [citation; citation], but more about that later in this blog post, where we will explain this in more detail.

What Are DPYD Mutations With Functional Effects? What Are the DPD Mutations That Cause DPYD Deficiency?

DPD deficiency happens when we have low or no levels of the DPD enzyme, and the cause of this are mutational changes in the DPYD gene [citation]. DPD deficiency is mainly the result of deleterious polymorphisms in the DPYD gene [citation].

The most prevalent defective variants associated with DPYD deficiency are:

  1. rs55886062 also known as c.1679T>G (encodes for DPYD*13)

  2. rs3918290, or c.1905 + 1G>A (encodes for DPYD*2A)

  3. rs67376798 or c.2846A>T, and

  4. rs75017182; rs56038477, also known as Haplotype B3 (c.1236G>A or c.1129–5923C>G) [citation; citation].

From all the mutations mentioned above that occur on the DPYD gene, the most common is rs3918290 (c.1905+1G>A; DPYD*2A) and, located at the splice site [citation], causing the in-frame deletion of amino acids corresponding to exon 14 [citation].

Important to underline that the above list of mutations is not a final one. If you are interested in the full list of DPYD mutations that affect functionality of DPD enzyme please check the CPIC pharmacogenomic guidelines here.

What Is DPD Enzyme Deficiency?

Dihydropyrimidine dehydrogenase deficiency is a pharmacogenetic syndrome associated with potentially life-threatening toxicity following the administration of standard doses of 5 - fluorouracil [citation].

Deleterious polymorphisms in DPYD mainly cause DPD enzyme deficiency; therefore, they represent predictors of fluoropyrimidine-related toxicity [citation]. DPD deficiency is found in 39-61% of patients having severe toxicity [citation]. As mentioned, you can find the complete list of the DPYD gene mutations here.

Interestingly, the usual DPYD polymorphisms found in the European population are not so frequent in the Korean population [citation].

What Mutations Increase DPD Levels?

A comparative study measuring the DPD enzyme’s capacity to convert 5-FU to dihydrofluorouracil shows the mutations that increase the DPD activity compared to wild-type [citation]. Those mutations that increase the DPD levels are

  1. M166V

  2. E828K

  3. K861R, and

  4. P1023T


How Common Is DPD Deficiency? How Do You Know if You Have DPD Deficiency? What Are the Symptoms of DPD Deficiency?

DPD deficiency occurs in 3-5% of the population [citation]. DPD deficiency is difficult to detect clinically in the early period. It is assumed that out of 2 million patients who receive 5-FU therapy, 30% have forms of cytotoxicity and the reason is mainly DPD deficiency [citation].

Patient education and checking the patient's medical history or any family adverse drug reaction for 5-FU is of great importance, along with observing symptoms if they occur to achieve the best outcome [citation].

Symptoms that are indicative of toxicity caused by DPD deficiency include

  1. mucositis (71%)

  2. diarrhea (43%)

  3. skin rash (43%)

  4. memory loss/altered mental status (43%)

  5. cytopenias (43%)

  6. nausea (29%)

  7. hypotension (14%)

  8. respiratory distress (14%) and

  9. acute renal failure (14%) [citation].

There are several methods for DPD activity determination:

  1. the detection of relevant DPYD gene single-nucleotide polymorphism (SNPs)

  2. measurement of the level of DPYD mRNA expression, the evaluation of DPD activity in PBMC

  3. the measurement of uracil in plasma and urea

  4. evaluation of the UH2/U (dihydrouracil/uracil) and THYH2/THY (dihydrothymine/tymine) ratio in plasma and urea

  5. [2-C13] uracil breath test

  6. the analysis of fluorouracil and dihydrofluorouracil in plasma after administered a test dose of fluorouracil and

  7. measurement of 2-fluoro-beta-alanine [citation].

Can DPD Deficiency Be Treated? How Is DPD Deficiency Treated?

The treatment of DPD deficiency depends on the severity of the symptoms and the affected individual's age. There is no cure for DPD deficiency, but various interventions can help manage the symptoms.

The European Medicines Agency (EMA) has recommended that patients should be tested for the lack of the enzyme DPD before starting cancer treatment with fluorouracil given by injection or infusion. Patients who lack DPD entirely must not be given any fluorouracil medicines.

The doctor may consider starting cancer treatment at lower doses than normal for patients with partial DPD deficiency or stopping flucytosine treatment if severe side effects occur. These recommendations do not apply to fluorouracil medicines used on the skin for conditions such as actinic keratosis and warts, as only very low medicine levels are absorbed through the skin [citation].

How Do You Test for DPD Deficiency?

Patients can be tested for DPD deficiency by measuring the level of uracil (a substance broken down by DPD) in the blood or by checking for the presence of certain mutations (changes) in the gene for DPD by PCR. It is mainly tested for the most common mutation such as DPYD*2A [citation; citation]. Routine tests and screening for DPD deficiency are not always available. However, they are done if assumptions related to deficiency symptoms are found [citation].

Ribonucleic acid (RNA) extract from peripheral blood mononuclear cells is another method for DPD deficiency, done by radioassay. DPD mRNA copy counting is performed using PCR [citation].

What Is a DPYD Test? What Is DPYD Genotyping (Test)?

A test recommended by the European Medicines Agency (EMA) aims to detect the lack of the enzyme DPD in patients before starting cancer treatment with fluorouracil given by injection or infusion (drip) or with the related medicines, capecitabine, and tegafur [citation].

DPD testing (either the enzyme activity of dihydropyrimidine dehydrogenase (DPD) or the DPYD genotype) identifies patients at higher risk for toxicity which may be treated more safely with a lower drug dose [citation].

DPYD genotyping test is a test that detects genetic variants leading to DPD enzyme deficiency. The accurate interpretation of DPYD genotyping enables the proper prescription of fluoropyrimidines (5-fluorouracil, capecitabine, and tegafur) [citation].

DPD eliminates >80% of administered 5-fluorouracil, while the rest is excreted into the urine [citation]. However, differentmutations can cause different levels of DPD enzyme activity which can lead to different response or effects in patients, so testing for mutations is the first step in the treatment [citation].





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