The DPYD gene is a fundamental component of human genetics, providing instructions that contribute to how our bodies function at a molecular level. Understanding its role helps in comprehending individual differences in health and treatment responses.
The Role of DPYD in the Body
The DPYD gene provides instructions for creating an enzyme called dihydropyrimidine dehydrogenase (DPD). This DPD enzyme is primarily responsible for breaking down specific substances in the body, particularly a class of chemotherapy drugs known as fluoropyrimidines, including 5-fluorouracil (5-FU) and capecitabine.
The enzyme metabolizes approximately 80% of these drugs into inactive forms, which are then excreted. This metabolic process is also a step in the normal breakdown pathway of molecules like uracil and thymine, which are building blocks of DNA and RNA. By efficiently breaking down these compounds, the DPD enzyme helps prevent their accumulation.
When DPYD Doesn’t Work: Understanding DPYD Deficiency
Variations in the DPYD gene can lead to reduced or absent DPD enzyme activity, a condition known as DPYD deficiency. When the DPD enzyme is not working properly, the body cannot effectively break down fluoropyrimidine drugs, leading to a buildup of these drugs and reaching toxic levels.
The accumulation of fluoropyrimidine drugs can result in potentially life-threatening side effects. These adverse reactions include severe diarrhea, inflammation of the mouth and gut (mucositis), a reduction in white blood cells (neutropenia) that can increase infection risk, and neurological problems. Severe toxicity can also manifest as hand-foot syndrome, characterized by pain, swelling, redness, and blistering on the palms of the hands and soles of the feet.
Approximately 2% to 8% of the general population may have a low level of the DPD enzyme, making them vulnerable to these toxic reactions. A smaller percentage, around 0.3% of the population, can have a complete absence of DPD function, which can lead to extreme, even fatal, toxicity if standard doses of fluoropyrimidines are administered. Individuals with DPD deficiency are asymptomatic until exposed to these specific chemotherapy drugs.
Detecting DPYD Variations
Identifying DPYD variations is an important step, often taken before starting fluoropyrimidine-based chemotherapy, to assess a patient’s risk of toxicity. Two main methods are used: genetic testing (genotyping) and measuring DPD enzyme activity directly (phenotyping). Genetic testing involves analyzing a patient’s DNA, usually from a blood sample, to look for specific changes or variants in the DPYD gene.
Genotyping aims to identify known DPYD variants associated with decreased or absent enzyme activity. For instance, variants like DPYD2A (c.1905+1G>A), DPYD13 (c.1679T>G), c.2846A>T, and c.1236G>A/HapB3 are commonly screened for, as they are well-established predictors of fluoropyrimidine-associated toxicity. While these four variants can predict 20% to 30% of early-onset, life-threatening toxicities, their absence does not entirely eliminate the risk, as other uncommon variants or non-genetic factors can also play a role.
Phenotyping directly measures the DPD enzyme’s activity in the body. This can involve assessing DPD activity in peripheral blood cells or measuring the levels of uracil and dihydrouracil in plasma or urine. Many guidelines recommend performing both genetic and enzyme tests for maximum accuracy in determining a patient’s DPD status.
Guiding Treatment with DPYD Information
Information about a patient’s DPYD status plays an important role in personalizing cancer treatment, particularly when fluoropyrimidine drugs are involved. If a patient is identified as having a DPYD deficiency or a variant that reduces enzyme activity, their healthcare team can adjust the treatment plan to minimize the risk of severe side effects. This approach aligns with the principles of personalized medicine, tailoring therapy to an individual’s unique genetic profile.
Strategies to prevent toxicity include adjusting the initial drug dosage, with recommendations often suggesting a 50% reduction for patients with decreased DPD activity. In cases of complete DPD deficiency, healthcare providers may recommend avoiding these drugs entirely and exploring alternative chemotherapy regimens. Continuous monitoring for any signs of toxicity is also implemented, even with dose adjustments, to ensure patient safety. This proactive approach aims to maintain treatment effectiveness while reducing the likelihood of severe adverse reactions.